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1
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Mews P, Mason AV, Kirchner EG, Estill M, Nestler EJ. Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens. Commun Biol 2025; 8:919. [PMID: 40506501 PMCID: PMC12163090 DOI: 10.1038/s42003-025-08327-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 06/02/2025] [Indexed: 06/16/2025] Open
Abstract
Cocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven in part by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated nucleus sorting coupled with single-nucleus RNA sequencing to analyze D1 and D2 medium spiny neurons in this brain region of male mice subjected to acute cocaine exposure or to prolonged withdrawal from repeated cocaine exposure without or with an acute cocaine rechallenge. This approach allowed us to precisely delineate and contrast transcriptionally distinct neuronal subpopulations─or ensembles─across various treatment conditions. We identified significant heterogeneity within both D1 and D2 MSNs, revealing distinct clusters with unique transcriptional profiles. Notably, we identified a discrete D1 MSN population characterized by the upregulation of immediate early genes, as well as another group of D1 MSNs linked to prolonged withdrawal, uncovering novel regulators of withdrawal-related transcriptome dynamics. Our findings provide a high-resolution transcriptomic map of D1 and D2 MSNs, illustrating the dynamic changes induced by cocaine exposure and withdrawal. These insights into the molecular mechanisms underlying cocaine use disorder highlight potential targets for therapeutic intervention aimed at preventing relapse.
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Affiliation(s)
- Philipp Mews
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
| | - Autumn Va Mason
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Emily G Kirchner
- Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Molly Estill
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eric J Nestler
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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2
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Davis JL, Kennedy C, McMahon CL, Keegan L, Clerkin S, Treacy NJ, Hoban AE, Kelly Y, Brougham DF, Crean J, Murphy KJ. Cocaine perturbs neurodevelopment and increases neuroinflammation in a prenatal cerebral organoid model. Transl Psychiatry 2025; 15:94. [PMID: 40140359 PMCID: PMC11947122 DOI: 10.1038/s41398-025-03315-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 01/17/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Prenatal exposure to cocaine causes abnormalities in foetal brain development, which are linked to later development of anxiety, depression and cognitive dysfunction. Previous studies in rodent models have indicated that prenatal cocaine exposure affects proliferation, differentiation and connectivity of neural cell types. Here, using cerebral organoids derived from the human iPSC cell line HPSI1213i-babk_2, we investigated cocaine-induced changes of the gene expression regulatory landscape at an early developmental time point, leveraging recent advances in single cell RNA-seq and single cell ATAC-seq. iPSC-cerebral organoids replicated well-established cocaine responses observed in vivo and provided additional information about the cell-type specific regulation of gene expression following cocaine exposure. Cocaine altered gene expression patterns, in part through epigenetic landscape remodelling, and revealed disordered neural plasticity mechanisms in the cerebral organoids. Perturbed neurodevelopmental cellular signalling and an inflammatory-like activation of astrocyte populations were also evident following cocaine exposure. The combination of altered neuroplasticity, neurodevelopment and neuroinflammatory signalling suggests cocaine exposure can mediate substantial disruption of normal development and maturation of the brain. These findings offer new insights into the cellular mechanism underlying the adverse effects of cocaine exposure on neurodevelopment and point to the possible pathomechanisms of later neuropsychiatric disturbances.
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Affiliation(s)
- Jessica L Davis
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Ciaran Kennedy
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Ciara L McMahon
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Louise Keegan
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Shane Clerkin
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Niall J Treacy
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Alan E Hoban
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Yazeed Kelly
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Dermot F Brougham
- School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
| | - John Crean
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Keith J Murphy
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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3
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Southey BR, Sunderland GR, Gomez AN, Bhamidi S, Rodriguez-Zas SL. Incidence of alternative splicing associated with sex and opioid effects in the axon guidance pathway. Gene 2025; 942:149215. [PMID: 39756548 PMCID: PMC11863264 DOI: 10.1016/j.gene.2025.149215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/19/2024] [Accepted: 01/02/2025] [Indexed: 01/07/2025]
Abstract
The alternative splicing of a gene results in distinct transcript isoforms that can result in proteins that differ in function. Alternative splicing processes are prevalent in the brain, have varying incidence across brain regions, and can present sexual dimorphism. Exposure to opiates and other substances of abuse can also alter the type and incidence of the splicing process and the relative abundance of the isoforms produced. The disruption of alternative splicing patterns associated with sex differences and morphine exposure in the prefrontal cortex of a pig model was studied. The numbers of genes presenting one or more significant (FDR-adjusted p-value < 0.05) alternative splicing events were 933 and 1,368 genes when comparing females relative to males and morphine- relative to saline-treated animals, respectively. The sex-dependent opioid effect was most extreme in the contrast between morphine- versus saline-treated males with 1,934 significantly differentially spliced genes. The most frequent and significant alternative splicing type was skipped exon (∼56 % event), followed by retained intron (∼15 % events). The pathways encompassing a significant number of differentially spliced genes included axon guidance, glutamatergic synapses, circadian rhythm, and lysine degradation. Genes in these pathways included ROBO1, SEMA6C, GRIN3A, GRM2, ARNTL, CLOCK, HYKK, and DOT1L. Transcription factors ETV7 and DMAP1 presented a significant number of differentially spliced target genes. The distribution of the genes presenting differential alternative splicing in the axon guidance and circadian rhythm pathways indicates that this regulatory mechanism impacts hubs and peripheral genes. The identification of sexual dimorphism in the effect of morphine across multiple pathways confirms the necessity to explore the effects of drugs of abuse within sex. Altogether, our findings advance the understanding of the response to factors that can impact the activity of excitatory synapses by modulating transcriptional mechanisms that support the plasticity of the prefrontal cortex.
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Affiliation(s)
- Bruce R Southey
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Gloria R Sunderland
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Andrea N Gomez
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Sreelaya Bhamidi
- Informatics Program, University of Illinois at Urbana-Champaign, Urbana, IL 61820 USA
| | - Sandra L Rodriguez-Zas
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA; Informatics Program, University of Illinois at Urbana-Champaign, Urbana, IL 61820 USA; Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA; Department of Statistics, University of Illinois at Urbana-Champaign, Urbana, IL 61820 USA.
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4
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Samanta S, Bagchi D, Gold MS, Badgaiyan RD, Barh D, Blum K. A Complex Relationship Among the Circadian Rhythm, Reward Circuit and Substance Use Disorder (SUD). Psychol Res Behav Manag 2024; 17:3485-3501. [PMID: 39411118 PMCID: PMC11479634 DOI: 10.2147/prbm.s473310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 09/30/2024] [Indexed: 10/19/2024] Open
Abstract
The human brain not only controls the various physiological functions but is also the prime regulator of circadian rhythms, rewards, and behaviors. Environmental factors, professional stress, and social disintegration are regarded as the initial causative factors of addiction behavior. Shift work, artificial light exposure at night, and chronic and acute jet lag influence circadian rhythm dysfunction. The result is impaired neurotransmitter release, dysfunction of neural circuits, endocrine disturbance, and metabolic disorder, leading to advancement in substance use disorder. There is a bidirectional relationship between chronodisruption and addiction behavior. Circadian rhythm dysfunction, neuroadaptation in the reward circuits, and alteration in clock gene expression in the mesolimbic areas influence substance use disorder (SUD), and chronotherapy has potential benefits in the treatment strategies. This review explores the relationship among the circadian rhythm dysfunction, reward circuit, and SUD. The impact of chronotherapy on SUD has also been discussed.
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Affiliation(s)
- Saptadip Samanta
- Department of Physiology, Midnapore College, Midnapore, West Bengal, 721101, India
| | - Debasis Bagchi
- Department of Biology, College of Arts and Sciences, Adelphi University, Garden City, NY, USA and Department of Psychology, Gordon F. Derner School of Psychology, Adelphi University, Garden City, NY, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, Southern University, Houston, TX, 77004, USA
| | - Mark S Gold
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Rajendra D Badgaiyan
- Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Debmalya Barh
- Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Federal University of Minas Gerais, BeloHorizonte, 31270-901, Brazil
- Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur, 721172, West Bengal, India
| | - Kenneth Blum
- Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University Health Sciences, Pomona, CA, 91766, USA
- Institute of Psychology, Eotvos Loránd University, Budapest, 1053, Hungary
- Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Center, Dayton, OH, 45435, USA
- Department of Psychiatry, University of Vermont, Burlington, VT, 05405, USA
- Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX, 78701, USA
- Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel
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5
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Castro-Zavala A, Alegre-Zurano L, Cantacorps L, Gallego-Landin I, Welz PS, Benitah SA, Valverde O. Bmal1-knockout mice exhibit reduced cocaine-seeking behaviour and cognitive impairments. Biomed Pharmacother 2022; 153:113333. [PMID: 35779420 DOI: 10.1016/j.biopha.2022.113333] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 11/30/2022] Open
Abstract
Brain and Muscle Arnt-like Protein 1 (BMAL1) is an essential component of the molecular clock underlying circadian rhythmicity. Its function has been recently associated with mood and reward processing alterations. We investigated the behavioural and neurobiological impact of Bmal1 gene deletion in mice, and how this could affect rewarding effects of cocaine. Additionally, key clock genes and components of the dopamine system were assessed in several brain areas. Our results evidence behavioural alterations in Bmal1-KO mice, including changes in locomotor activity with impaired habituation to environments, short-term memory and social recognition impairments. In addition, Bmal1-KO mice experienced reduced cocaine-induced sensitisation and rewarding effects of cocaine as well as reduced cocaine-seeking behaviour. Furthermore, Bmal1 deletion influenced the expression of other clock-related genes in the mPFC and striatum, as well as alterations in the expression of dopaminergic elements. Overall, the present article offers a novel and extensive characterisation of Bmal1-KO animals. We suggest that reduced cocaine's rewarding effects in these mutant mice might be related to Bmal1 role as an expression regulator of MAO and TH, two essential enzymes involved in dopamine metabolism.
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Affiliation(s)
- Adriana Castro-Zavala
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - Laia Alegre-Zurano
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - Lídia Cantacorps
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - Ines Gallego-Landin
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - Patrick-S Welz
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; Program in Cancer Research, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Salvador A Benitah
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Olga Valverde
- Neurobiology of Behaviour Research Group (GReNeC-NeuroBio), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain; Neuroscience Research Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain.
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6
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Cromar GL, Epp JR, Popovic A, Gu Y, Ha V, Walters BJ, St. Pierre J, Xiong X, Howland JG, Josselyn SA, Frankland PW, Parkinson J. Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease. PLoS Negl Trop Dis 2022; 16:e0010600. [PMID: 35857765 PMCID: PMC9342775 DOI: 10.1371/journal.pntd.0010600] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 08/01/2022] [Accepted: 06/21/2022] [Indexed: 11/18/2022] Open
Abstract
During chronic infection, the single celled parasite, Toxoplasma gondii, can migrate to the brain where it has been associated with altered dopamine function and the capacity to modulate host behavior, increasing risk of neurocognitive disorders. Here we explore alterations in dopamine-related behavior in a new mouse model based on stimulant (cocaine)-induced hyperactivity. In combination with cocaine, infection resulted in heightened sensorimotor deficits and impairment in prepulse inhibition response, which are commonly disrupted in neuropsychiatric conditions. To identify molecular pathways in the brain affected by chronic T. gondii infection, we investigated patterns of gene expression. As expected, infection was associated with an enrichment of genes associated with general immune response pathways, that otherwise limits statistical power to identify more informative pathways. To overcome this limitation and focus on pathways of neurological relevance, we developed a novel context enrichment approach that relies on a customized ontology. Applying this approach, we identified genes that exhibited unexpected patterns of expression arising from the combination of cocaine exposure and infection. These include sets of genes which exhibited dampened response to cocaine in infected mice, suggesting a possible mechanism for some observed behaviors and a neuroprotective effect that may be advantageous to parasite persistence. This model offers a powerful new approach to dissect the molecular pathways by which T. gondii infection contributes to neurocognitive disorders.
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Affiliation(s)
- Graham L. Cromar
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
| | - Jonathan R. Epp
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada
| | - Ana Popovic
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
- Dept. of Biochemistry, University of Toronto, Toronto, Canada
| | - Yusing Gu
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada
| | - Violet Ha
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada
| | - Brandon J. Walters
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada
| | - James St. Pierre
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
| | - Xuejian Xiong
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada
| | - John G. Howland
- Dept. of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada
| | - Sheena A. Josselyn
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada
- Dept. of Physiology, University of Toronto, Toronto, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
- Dept. of Psychology, University of Toronto, Toronto, Canada
| | - Paul W. Frankland
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada
- Dept. of Physiology, University of Toronto, Toronto, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
- Dept. of Psychology, University of Toronto, Toronto, Canada
- * E-mail: (PF); (JP)
| | - John Parkinson
- Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada
- Dept. of Biochemistry, University of Toronto, Toronto, Canada
- Dept. of Molecular Genetics, University of Toronto, Toronto, Canada
- * E-mail: (PF); (JP)
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7
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Cervantes M, Lewis RG, Della-Fazia MA, Borrelli E, Sassone-Corsi P. Dopamine D2 receptor signaling in the brain modulates circadian liver metabolomic profiles. Proc Natl Acad Sci U S A 2022; 119:e2117113119. [PMID: 35271395 PMCID: PMC8931347 DOI: 10.1073/pnas.2117113119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 02/08/2022] [Indexed: 02/04/2023] Open
Abstract
SignificanceWe analyzed the liver metabolome of mice deficient in the expression of the dopamine D2 receptor (D2R) in striatal medium spiny neurons (iMSN-D2RKO) and found profound changes in the liver circadian metabolome compared to control mice. Additionally, we show activation of dopaminergic circuits by acute cocaine administration in iMSN-D2RKO mice reprograms the circadian liver metabolome in response to cocaine. D2R signaling in MSNs is key for striatal output and essential for regulating the first response to the cellular and rewarding effects of cocaine. Our results suggest changes in dopamine signaling in specific striatal neurons evoke major changes in liver physiology. Dysregulation of liver metabolism could contribute to an altered allostatic state and therefore be involved in continued use of drugs.
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Affiliation(s)
- Marlene Cervantes
- INSERM U1233, Center for Epigenetics and Metabolism, University of California, Irvine, CA 92697
- Department of Biological Chemistry, University of California, Irvine, CA 92697
| | - Robert G. Lewis
- INSERM U1233, Center for Epigenetics and Metabolism, University of California, Irvine, CA 92697
- Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697
| | | | - Emiliana Borrelli
- INSERM U1233, Center for Epigenetics and Metabolism, University of California, Irvine, CA 92697
- Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697
| | - Paolo Sassone-Corsi
- INSERM U1233, Center for Epigenetics and Metabolism, University of California, Irvine, CA 92697
- Department of Biological Chemistry, University of California, Irvine, CA 92697
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8
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Lewis RG, Florio E, Punzo D, Borrelli E. The Brain's Reward System in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1344:57-69. [PMID: 34773226 DOI: 10.1007/978-3-030-81147-1_4] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Rhythmic gene expression is found throughout the central nervous system. This harmonized regulation can be dependent on- and independent of- the master regulator of biological clocks, the suprachiasmatic nucleus (SCN). Substantial oscillatory activity in the brain's reward system is regulated by dopamine. While light serves as a primary time-giver (zeitgeber) of physiological clocks and synchronizes biological rhythms in 24-h cycles, nonphotic stimuli have a profound influence over circadian biology. Indeed, reward-related activities (e.g., feeding, exercise, sex, substance use, and social interactions), which lead to an elevated level of dopamine, alters rhythms in the SCN and the brain's reward system. In this chapter, we will discuss the influence of the dopaminergic reward pathways on circadian system and the implication of this interplay on human health.
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Affiliation(s)
- Robert G Lewis
- School of Medicine, Department of Microbiology and Molecular Genetics, INSERMU1233, Center for Epigenetics and Metabolism, University of California - Irvine, Irvine, CA, USA
| | - Ermanno Florio
- School of Medicine, Department of Microbiology and Molecular Genetics, INSERMU1233, Center for Epigenetics and Metabolism, University of California - Irvine, Irvine, CA, USA
| | - Daniela Punzo
- School of Medicine, Department of Microbiology and Molecular Genetics, INSERMU1233, Center for Epigenetics and Metabolism, University of California - Irvine, Irvine, CA, USA
| | - Emiliana Borrelli
- School of Medicine, Department of Microbiology and Molecular Genetics, INSERMU1233, Center for Epigenetics and Metabolism, University of California - Irvine, Irvine, CA, USA. .,University of California - Irvine, Irvine, CA, USA.
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9
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Zhang P, Perez OC, Southey BR, Sweedler JV, Pradhan AA, Rodriguez-Zas SL. Alternative Splicing Mechanisms Underlying Opioid-Induced Hyperalgesia. Genes (Basel) 2021; 12:1570. [PMID: 34680965 PMCID: PMC8535871 DOI: 10.3390/genes12101570] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/19/2021] [Accepted: 09/30/2021] [Indexed: 12/13/2022] Open
Abstract
Prolonged use of opioids can cause opioid-induced hyperalgesia (OIH). The impact of alternative splicing on OIH remains partially characterized. A study of the absolute and relative modes of action of alternative splicing further the understanding of the molecular mechanisms underlying OIH. Differential absolute and relative isoform profiles were detected in the trigeminal ganglia and nucleus accumbens of mice presenting OIH behaviors elicited by chronic morphine administration relative to control mice. Genes that participate in glutamatergic synapse (e.g., Grip1, Grin1, Wnk3), myelin protein processes (e.g., Mbp, Mpz), and axon guidance presented absolute and relative splicing associated with OIH. Splicing of genes in the gonadotropin-releasing hormone receptor pathway was detected in the nucleus accumbens while splicing in the vascular endothelial growth factor, endogenous cannabinoid signaling, circadian clock system, and metabotropic glutamate receptor pathways was detected in the trigeminal ganglia. A notable finding was the prevalence of alternatively spliced transcription factors and regulators (e.g., Ciart, Ablim2, Pbx1, Arntl2) in the trigeminal ganglia. Insights into the nociceptive and antinociceptive modulatory action of Hnrnpk were gained. The results from our study highlight the impact of alternative splicing and transcriptional regulators on OIH and expose the need for isoform-level research to advance the understanding of morphine-associated hyperalgesia.
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Affiliation(s)
- Pan Zhang
- Illinois Informatics Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA;
| | - Olivia C. Perez
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (O.C.P.); (B.R.S.)
| | - Bruce R. Southey
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (O.C.P.); (B.R.S.)
| | - Jonathan V. Sweedler
- Department of Chemistry and the Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA;
| | - Amynah A. Pradhan
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA;
| | - Sandra L. Rodriguez-Zas
- Illinois Informatics Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA;
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (O.C.P.); (B.R.S.)
- Department of Statistics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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10
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Saad L, Zwiller J, Kalsbeek A, Anglard P. Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction. Genes (Basel) 2021; 12:1263. [PMID: 34440437 PMCID: PMC8394526 DOI: 10.3390/genes12081263] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/04/2021] [Accepted: 08/11/2021] [Indexed: 12/19/2022] Open
Abstract
Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction.
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Affiliation(s)
- Lamis Saad
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands;
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Jean Zwiller
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France
| | - Andries Kalsbeek
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands;
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Patrick Anglard
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- Institut National de la Santé et de la Recherche Médicale (INSERM), 75013 Paris, France
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11
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Saad L, Kalsbeek A, Zwiller J, Anglard P. Rhythmic Regulation of DNA Methylation Factors and Core-Clock Genes in Brain Structures Activated by Cocaine or Sucrose: Potential Role of Chromatin Remodeling. Genes (Basel) 2021; 12:genes12081195. [PMID: 34440369 PMCID: PMC8392220 DOI: 10.3390/genes12081195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/25/2022] Open
Abstract
The circadian system interacts with the mesocorticolimbic reward system to modulate reward and memory in a time-of-day dependent manner. The circadian discrimination of reward, however, remains difficult to address between natural reinforcers and drugs of abuse. Circadian rhythms control cocaine sensitization and conversely cocaine causes long-term alteration in circadian periodicity in part through the serotonergic neurotransmission. Since neural circuits activated by cocaine and natural reinforcers do not completely overlap, we compared the effect of cocaine with that of sucrose, a strong reinforcer in rodents, by using passive chronic administration. The expression of fifteen genes playing a major role in DNA methylation (Dnmts, Tets), circadian rhythms (Clock, Bmal1, Per1/2, Cry1/2, Rev-Erbβ, Dbp1), appetite, and satiety (Orexin, Npy) was analyzed in dopamine projection areas like the prefrontal cortex, the caudate putamen, and the hypothalamus interconnected with the reward system. The corresponding proteins of two genes (Orexin, Per2) were examined by IHC. For many factors controlling biological and cognitive functions, striking opposite responses were found between the two reinforcers, notably for genes controlling DNA methylation/demethylation processes and in global DNA methylation involved in chromatin remodeling. The data are consistent with a repression of critical core-clock genes by cocaine, suggesting that, consequently, both agents differentially modulate day/night cycles. Whether observed cocaine and sucrose-induced changes in DNA methylation in a time dependent manner are long lasting or contribute to the establishment of addiction requires further neuroepigenetic investigation. Understanding the mechanisms dissociating drugs of abuse from natural reinforcers remains a prerequisite for the design of selective therapeutic tools for compulsive behaviors.
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Affiliation(s)
- Lamis Saad
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, 1066 EA Amsterdam, The Netherlands
| | - Andries Kalsbeek
- The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, 1066 EA Amsterdam, The Netherlands
- Correspondence: (A.K.); or (P.A.)
| | - Jean Zwiller
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- CNRS, Centre National de la Recherche Scientifique, 75016 Paris, France
| | - Patrick Anglard
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Université de Strasbourg, Neuropôle de Strasbourg, 67000 Strasbourg, France; (L.S.); (J.Z.)
- INSERM, Institut National de la Santé et de la Recherche Médicale, 75013 Paris, France
- Correspondence: (A.K.); or (P.A.)
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12
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Tamura EK, Oliveira-Silva KS, Ferreira-Moraes FA, Marinho EAV, Guerrero-Vargas NN. Circadian rhythms and substance use disorders: A bidirectional relationship. Pharmacol Biochem Behav 2021; 201:173105. [PMID: 33444601 DOI: 10.1016/j.pbb.2021.173105] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 01/03/2021] [Accepted: 01/04/2021] [Indexed: 01/23/2023]
Abstract
The circadian system organizes circadian rhythms (biological cycles that occur around 24 h) that couple environmental cues (zeitgebers) with internal functions of the organism. The misalignment between circadian rhythms and external cues is known as chronodisruption and contributes to the development of mental, metabolic and other disorders, including cancer, cardiovascular diseases and addictive disorders. Drug addiction represents a global public health concern and affects the health and well-being of individuals, families and communities. In this manuscript, we reviewed evidence indicating a bidirectional relationship between the circadian system and the development of addictive disorders. We provide information on the interaction between the circadian system and drug addiction for each drug or drug class (alcohol, cannabis, hallucinogens, psychostimulants and opioids). We also describe evidence showing that drug use follows a circadian pattern, which changes with the progression of addiction. Furthermore, clock gene expression is also altered during the development of drug addiction in many brain areas related to drug reward, drug seeking and relapse. The regulation of the glutamatergic and dopaminergic neurocircuitry by clock genes is postulated to be the main circadian mechanism underlying the escalation of drug addiction. The bidirectional interaction between the circadian system and drug addiction seems to be mediated by the effects caused by each drug or class of drugs of abuse. These studies provide new insights on the development of successful strategies aimed at restoring/stabilizing circadian rhythms to reduce the risk for addiction development and relapse.
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Affiliation(s)
- Eduardo K Tamura
- Department of Health Sciences, Universidade Estadual de Santa Cruz, BR-415, Rodovia Ilhéus- Itabuna, Km-16, Salobrinho, Ilhéus, Bahia 45662-000, Brazil.
| | - Kallyane S Oliveira-Silva
- Department of Health Sciences, Universidade Estadual de Santa Cruz, BR-415, Rodovia Ilhéus- Itabuna, Km-16, Salobrinho, Ilhéus, Bahia 45662-000, Brazil
| | - Felipe A Ferreira-Moraes
- Department of Health Sciences, Universidade Estadual de Santa Cruz, BR-415, Rodovia Ilhéus- Itabuna, Km-16, Salobrinho, Ilhéus, Bahia 45662-000, Brazil
| | - Eduardo A V Marinho
- Department of Health Sciences, Universidade Estadual de Santa Cruz, BR-415, Rodovia Ilhéus- Itabuna, Km-16, Salobrinho, Ilhéus, Bahia 45662-000, Brazil
| | - Natalí N Guerrero-Vargas
- Department of Anatomy, Faculty of Medicine, Universidad Nacional Autonóma de México, Av Universidad 3000, Ciudad Universitaria, México City 04510, Mexico
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13
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Effects of Kappa opioid receptor blockade by LY2444296 HCl, a selective short-acting antagonist, during chronic extended access cocaine self-administration and re-exposure in rat. Psychopharmacology (Berl) 2020; 237:1147-1160. [PMID: 31915862 DOI: 10.1007/s00213-019-05444-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/27/2019] [Indexed: 12/14/2022]
Abstract
RATIONALE Cocaine addiction is a chronic brain disease characterized by compulsive drug intake and dysregulation of brain reward systems. Few preclinical studies have modeled the natural longitudinal course of cocaine addiction. Extended access self-administration protocols are powerful tools for modeling the advanced stages of addiction; however, few studies have duration of drug access longer than 12 h/session, potentially limiting their construct validity. Identification of changes in cocaine intake patterns during the development of addictive-like states may allow better treatments for vulnerable subjects. The kappa opioid receptor (KOPr) system has been implicated in the neurobiological regulation of addictive states as well as mood and stress disorders, with selective KOPr antagonists proposed as possible pharmacotherapeutic agents. Chronic cocaine exposure increases the expression of KOPr and its endogenous agonists, the dynorphins, in several brain areas in rodents. OBJECTIVES To examine the behavioral pattern of intake during chronic (14 days) 18 h intravenous cocaine self-administration (0.5 mg/kg/infusion) and the effect of a novel short-acting KOPr antagonist LY2444296 HCl (3 mg/kg) administered during sessions 8 to 14 of chronic 18 h/day cocaine self-administration and prior to a single re-exposure session after 2 cocaine-free withdrawal days. RESULTS Both daily and hourly cocaine intake patterns changed over 14 days of 18 h self-administration. LY pretreatment affected the pattern of self-administration across the second week of extended access cocaine self-administration and prevented the increase in cocaine intake during re-exposure. CONCLUSIONS Overall, the KOPr antagonist attenuated escalated cocaine consumption in a rat model of extended access cocaine self-administration.
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Liu L, Luo T, Dong H, Zhang C, Liu T, Zhang X, Hao W. Genome-Wide DNA Methylation Analysis in Male Methamphetamine Users With Different Addiction Qualities. Front Psychiatry 2020; 11:588229. [PMID: 33192735 PMCID: PMC7645035 DOI: 10.3389/fpsyt.2020.588229] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/24/2020] [Indexed: 12/20/2022] Open
Abstract
This paper aimed to explore the genome-wide DNA methylation status of methamphetamine (MA) abusers with different qualities to addiction and to identify differentially methylated candidate genes. A total of 207 male MA abusers with an MA abuse frequency of ≥10 times and an MA abuse duration of ≥1 year were assigned to the high MA addiction quality group (HMAQ group; 168 subjects who met the diagnostic criteria for MA dependence according to the DSM-IV) or to the low MA addictive quality group (LMAQ group; 39 subjects who did not meet the criteria for MA dependence). In addition 105 healthy controls were recruited. Eight HMAQ subjects, eight LMAQ subjects, and eight healthy controls underwent genome-wide DNA methylation scans with an Infinium Human Methylation 450 array (Illumina). The differentially methylated region (DMR) data were entered into pathway analysis, and the differentially methylated position (DMP) data were screened for candidate genes and verified by MethyLight qPCR with all samples. Seven specific pathways with an abnormal methylation status were identified, including the circadian entrainment, cholinergic synapse, glutamatergic synapse, retrograde endocannabinoid signaling, GABAergic synapse, morphine addiction and PI3K-Akt signaling pathways. SLC1A6, BHLHB9, LYNX1, CAV2, and PCSK9 showed differences in their methylation levels in the three groups. Only the number of methylated copies of CAV2 was significantly higher in the LMAQ group than in the HMAQ group. Our findings suggest that the circadian entrainment pathway and the caveolin-2 gene may play key roles in MA addiction quality. Further studies on their functions and mechanisms will help us to better understand the pathogenesis of MA addiction and to explore new targets for drug intervention.
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Affiliation(s)
- Liang Liu
- Department of Geriatric Psychiatry, Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China.,Hunan Key Laboratory of Psychiatry and Mental Health, Department of Psychiatry and Mental Health Institute of the Second Xiangya Hospital, National Clinical Research Center on Mental Disorders, National Technology Institute on Mental Disorders, Central South University, Changsha, China
| | - Tao Luo
- Hunan Key Laboratory of Psychiatry and Mental Health, Department of Psychiatry and Mental Health Institute of the Second Xiangya Hospital, National Clinical Research Center on Mental Disorders, National Technology Institute on Mental Disorders, Central South University, Changsha, China.,Department of Clinic Psychiatry, Jiangxi Mental Hospital, Nanchang University, Nanchang, China
| | - Huixi Dong
- Hunan Key Laboratory of Psychiatry and Mental Health, Department of Psychiatry and Mental Health Institute of the Second Xiangya Hospital, National Clinical Research Center on Mental Disorders, National Technology Institute on Mental Disorders, Central South University, Changsha, China
| | - Chenxi Zhang
- Hunan Key Laboratory of Psychiatry and Mental Health, Department of Psychiatry and Mental Health Institute of the Second Xiangya Hospital, National Clinical Research Center on Mental Disorders, National Technology Institute on Mental Disorders, Central South University, Changsha, China
| | - Tieqiao Liu
- Hunan Key Laboratory of Psychiatry and Mental Health, Department of Psychiatry and Mental Health Institute of the Second Xiangya Hospital, National Clinical Research Center on Mental Disorders, National Technology Institute on Mental Disorders, Central South University, Changsha, China
| | - Xiangyang Zhang
- Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Wei Hao
- Hunan Key Laboratory of Psychiatry and Mental Health, Department of Psychiatry and Mental Health Institute of the Second Xiangya Hospital, National Clinical Research Center on Mental Disorders, National Technology Institute on Mental Disorders, Central South University, Changsha, China
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15
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Lafaye G, Desterke C, Marulaz L, Benyamina A. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addict Biol 2019; 24:921-934. [PMID: 30307084 DOI: 10.1111/adb.12660] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 06/19/2018] [Accepted: 06/22/2018] [Indexed: 12/27/2022]
Abstract
Cannabis is often used by consumers for sleep disorders. Studies show that circadian rhythm could be affected by a misuse of cannabis. Recent research has connected the role of microglial cells with psychiatric disorders such as substance abuse. The aim was to show the effect of two major components of cannabis on circadian genes regulation in microglial cells. In BV-2 microglial cells, cannabidiol (CBD) induces a deregulation of circadian genes with (P-value = 0.039) or without (P-value = 0.0015) lipopolisaccharides stimulation. CBD up regulated Arntl (P = 9.72E-5) and down regulated Clock (P = 0.0034) in BV-2 cells. Temporal expression of Arntl (light and dark P = 0.0054) and Clock (light and dark P = 0.047) was confirmed to have 24 hours light and dark rhythmic regulation in dissected suprachiasmatic nucleus as well as of Cb1 cannabinoid receptor (light and dark P = 0.019). In BV-2 microglia cells, CBD also up regulated CRY2 (P = 0.0473) and PER1 (P = 0.0131). Other nuclear molecules show a deregulation of circadian rhythm in microglial cells by CBD, such as RORA, RevErbα, RORB, CREBBP, AFT4, AFT5 and NFIL3. Our study suggests that circadian rhythm in microglial cells is deregulated by CBD but not by THC. It is consistent with clinical observations of the use of therapeutic cannabis to treat insomnia.
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Affiliation(s)
- Geneviève Lafaye
- Dpt Addictologie, AP-HP, GH Paris-Sud, Hôpital Paul Brousse, Villejuif, France
- INSERM U1178, Villejuif, France
| | | | - Laurent Marulaz
- Dpt Addictologie, AP-HP, GH Paris-Sud, Hôpital Paul Brousse, Villejuif, France
- INSERM U1178, Villejuif, France
| | - Amine Benyamina
- Dpt Addictologie, AP-HP, GH Paris-Sud, Hôpital Paul Brousse, Villejuif, France
- INSERM U1178, Villejuif, France
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16
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Roy K, Bhattacharyya P, Deb I. Naloxone precipitated morphine withdrawal and clock genes expression in striatum: A comparative study in three different protocols for the development of morphine dependence. Neurosci Lett 2018; 685:24-29. [DOI: 10.1016/j.neulet.2018.07.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 07/03/2018] [Accepted: 07/16/2018] [Indexed: 12/21/2022]
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17
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Onaolapo OJ, Onaolapo AY. Melatonin in drug addiction and addiction management: Exploring an evolving multidimensional relationship. World J Psychiatry 2018; 8:64-74. [PMID: 29988891 PMCID: PMC6033744 DOI: 10.5498/wjp.v8.i2.64] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 05/06/2018] [Accepted: 05/10/2018] [Indexed: 02/05/2023] Open
Abstract
Melatonin is a pleiotropic signalling molecule that regulates several physiological functions, and synchronises biological rhythms. Recent evidences are beginning to reveal that a dysregulation of endogenous melatonin rhythm or action may play a larger role in the aetiology and behavioural expression of drug addiction, than was previously considered. Also, the findings from a number of animal studies suggest that exogenous melatonin supplementation and therapeutic manipulation of melatonin/melatonin receptor interactions may be beneficial in the management of behavioural manifestations of drug addiction. However, repeated exogenous melatonin administration may cause a disruption of its endogenous rhythm and be associated with potential drawbacks that might limit its usefulness. In this review, we examine the roles of melatonin and its receptors in addictive behaviours; discussing how our understanding of melatonin’s modulatory effects on the brain rewards system and crucial neurotransmitters such as dopamine has evolved over the years. Possible indications(s) for melatonergic agents in addiction management, and how manipulations of the endogenous melatonin system may be of benefit are also discussed. Finally, the potential impediments to application of melatonin in the management of addictive behaviours are considered.
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Affiliation(s)
- Olakunle J Onaolapo
- Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Ladoke Akintola University of Technology, Osogbo 230263, Osun State, Nigeria
| | - Adejoke Y Onaolapo
- Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomosho 210211, Oyo State, Nigeria
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18
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Wang Y, Teng H, Sapozhnikov DM, Du Q, Zhao M. Transcriptome Sequencing Reveals Candidate NF-κB Target Genes Involved in Repeated Cocaine Administration. Int J Neuropsychopharmacol 2018; 21:697-704. [PMID: 29982443 PMCID: PMC6030870 DOI: 10.1093/ijnp/pyy031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 03/19/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Drug-induced alterations in gene expression play an important role in the development of addictive behavior. Numerous transcription factors have been implicated in mediating the gene expression changes that occur in drug addiction. Nuclear factor kappa B is an inducible transcription factor complex that is rapidly activated by diverse stimuli. METHODS We performed next-generation high-throughput sequencing of the prefrontal cortex in a mouse model of repeated cocaine administration combined with pharmacological nuclear factor kappa B inhibition to identify nuclear factor kappa B target genes that participate in the cocaine addiction process. RESULTS We found that the nuclear factor kappa B antagonist sodium diethyldithiocarbamate trihydrate significantly reversed the cocaine-induced expression changes of the amphetamine addiction pathway. Genes that demonstrated differential expression in response to cocaine treatment that was also reversed by sodium diethyldithiocarbamate trihydrate were enriched for the axon guidance pathway. Furthermore, the nuclear factor kappa B homo-dimer motif could be mapped to 86 of these sodium diethyldithiocarbamate trihydrate-reversed genes, which were also enriched for axon guidance. CONCLUSIONS We suggest that nuclear factor kappa B directly modifies the expression of axon guidance pathway members, leading to cocaine sensitization. Our findings reveal the role of prefrontal cortex nuclear factor kappa B activity in addiction and uncover the molecular mechanisms by which nuclear factor kappa B drives changes in the addicted brain.
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Affiliation(s)
- Yan Wang
- Key Lab of Mental Health, Institute of Psychology, Chinese Academy of Sciences, China,University of Chinese Academy of Sciences, Beijing, China
| | - Huajing Teng
- University of Chinese Academy of Sciences, Beijing, China,Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing China
| | - Daniel M Sapozhnikov
- Department of Pharmacology and Therapeutics, McGill University Montreal, Quebec, Canada
| | - Quansheng Du
- Department of Life Sciences, National Natural Science Foundation of China, Beijing, China
| | - Mei Zhao
- Key Lab of Mental Health, Institute of Psychology, Chinese Academy of Sciences, China,University of Chinese Academy of Sciences, Beijing, China,Correspondence: Dr. Mei Zhao, 16 Lincui Road, Chao Yang District, Beijing 100101, China ()
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19
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Schuch JB, Genro JP, Bastos CR, Ghisleni G, Tovo-Rodrigues L. The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research. Am J Med Genet B Neuropsychiatr Genet 2018; 177:181-198. [PMID: 28902457 DOI: 10.1002/ajmg.b.32599] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 08/24/2017] [Indexed: 12/29/2022]
Abstract
The circadian clock system drives daily rhythms in physiology, metabolism, and behavior in mammals. Molecular mechanisms of this system consist of multiple clock genes, with Circadian Locomotor Output Cycles Kaput (CLOCK) as a core member that plays an important role in a wide range of behaviors. Alterations in the CLOCK gene are associated with common psychiatric disorders as well as with circadian disturbances comorbidities. This review addresses animal, molecular, and genetic studies evaluating the role of the CLOCK gene on many psychiatric conditions, namely autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, anxiety disorder, and substance use disorder. Many animal experiments focusing on the effects of the Clock gene in behavior related to psychiatric conditions have shown consistent biological plausibility and promising findings. In humans, genetic and gene expression studies regarding disorder susceptibility, sleep disturbances related comorbidities, and response to pharmacological treatment, in general, are in agreement with animal studies. However, the number of controversial results is high. Literature suggests that the CLOCK gene exerts important influence on these conditions, and influences the susceptibility to phenotypes of psychiatric disorders.
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Affiliation(s)
- Jaqueline B Schuch
- Laboratory of Immunosenescence, Graduate Program in Biomedical Gerontology, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Julia P Genro
- Graduate Program in Bioscience, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Clarissa R Bastos
- Laboratory of Clinical Neuroscience, Graduate Program in Health and Behavior, Universidade Católica de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Gabriele Ghisleni
- Laboratory of Clinical Neuroscience, Graduate Program in Health and Behavior, Universidade Católica de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Luciana Tovo-Rodrigues
- Graduate Program in Epidemiology, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
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20
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Neural Mechanisms of Circadian Regulation of Natural and Drug Reward. Neural Plast 2017; 2017:5720842. [PMID: 29359051 PMCID: PMC5735684 DOI: 10.1155/2017/5720842] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 09/07/2017] [Accepted: 10/11/2017] [Indexed: 01/26/2023] Open
Abstract
Circadian rhythms are endogenously generated near 24-hour variations of physiological and behavioral functions. In humans, disruptions to the circadian system are associated with negative health outcomes, including metabolic, immune, and psychiatric diseases, such as addiction. Animal models suggest bidirectional relationships between the circadian system and drugs of abuse, whereby desynchrony, misalignment, or disruption may promote vulnerability to drug use and the transition to addiction, while exposure to drugs of abuse may entrain, disrupt, or perturb the circadian timing system. Recent evidence suggests natural (i.e., food) and drug rewards may influence overlapping neural circuitry, and the circadian system may modulate the physiological and behavioral responses to these stimuli. Environmental disruptions, such as shifting schedules or shorter/longer days, influence food and drug intake, and certain mutations of circadian genes that control cellular rhythms are associated with altered behavioral reward. We highlight the more recent findings associating circadian rhythms to reward function, linking environmental and genetic evidence to natural and drug reward and related neural circuitry.
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21
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Li M, Xu P, Xu Y, Teng H, Tian W, Du Q, Zhao M. Dynamic Expression Changes in the Transcriptome of the Prefrontal Cortex after Repeated Exposure to Cocaine in Mice. Front Pharmacol 2017; 8:142. [PMID: 28386228 PMCID: PMC5362609 DOI: 10.3389/fphar.2017.00142] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Accepted: 03/07/2017] [Indexed: 01/07/2023] Open
Abstract
Prefrontal cortex (PFC)-dependent functions, such as executive function, explicit learning, and memory, are negatively affected in cocaine abusers and experimental animal models of cocaine treatment. However, its molecular mechanisms are less understood. In the present study, we performed transcriptome profiling of the dynamic changes in the PFC after repeated cocaine administration in mice. We found 463, 14, and 535 differentially expressed genes (DEGs) at 2 h, 24 h, and 7 days, respectively, after the withdrawal of chronic cocaine treatment. Time-series correlation analysis identified 5 clusters of statistically significant expression patterns. The expression levels of DEGs in Clusters 1 and 5 exhibited a gradual or fluctuant decrease, Cluster 2 exhibited an initial increase followed by a decrease or return to the baseline level, and Clusters 3 and 4 exhibited a fluctuant increase in the expression of DEGs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that genes related to oxidative phosphorylation, ribosomes, and neurodegenerative disorder were enriched in Cluster 1; genes related to the mitogen activated protein kinase (MAPK), transforming growth factor (TGF)-β, insulin signaling, and circadian pathways were enriched in Cluster 2; genes related to plasticity-related pathways were enriched in Clusters 3 and 4; and genes related to the proteasome were enriched in Cluster 5. Our results suggest that maladaptive neural plasticity associated with psychostimulant dependence may be an ongoing degenerative process with dynamic changes in the gene network at different stages of withdrawal. Furthermore, it could be helpful to develop new therapeutic approaches according to different periods of abstinence.
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Affiliation(s)
- Mingzhen Li
- Key Lab of Mental Health, Institute of Psychology Chinese Academy of SciencesBeijing, China; Beijing Center for Physical and Chemical AnalysisBeijing, China
| | - Peng Xu
- Drug Intelligence and Forensic Center, Ministry of Public Security Beijing, China
| | - Yanhua Xu
- Key Lab of Mental Health, Institute of Psychology Chinese Academy of Sciences Beijing, China
| | - Huajing Teng
- Beijing Institutes of Life Science, Chinese Academy of SciencesBeijing, China; University of Chinese Academy of SciencesBeijing, China
| | - Weiping Tian
- Key Lab of Mental Health, Institute of Psychology Chinese Academy of Sciences Beijing, China
| | - Quansheng Du
- Key Lab of Mental Health, Institute of Psychology Chinese Academy of SciencesBeijing, China; Department of Life Sciences, National Natural Science Foundation of ChinaBeijing, China
| | - Mei Zhao
- Key Lab of Mental Health, Institute of Psychology Chinese Academy of SciencesBeijing, China; University of Chinese Academy of SciencesBeijing, China
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22
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Circadian Plasticity of Mammalian Inhibitory Interneurons. Neural Plast 2017; 2017:6373412. [PMID: 28367335 PMCID: PMC5358450 DOI: 10.1155/2017/6373412] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 01/15/2017] [Accepted: 02/19/2017] [Indexed: 12/11/2022] Open
Abstract
Inhibitory interneurons participate in all neuronal circuits in the mammalian brain, including the circadian clock system, and are indispensable for their effective function. Although the clock neurons have different molecular and electrical properties, their main function is the generation of circadian oscillations. Here we review the circadian plasticity of GABAergic interneurons in several areas of the mammalian brain, suprachiasmatic nucleus, neocortex, hippocampus, olfactory bulb, cerebellum, striatum, and in the retina.
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Abstract
Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ∼24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.
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Branstetter SA, Horton WJ, Mercincavage M, Buxton OM. Severity of Nicotine Addiction and Disruptions in Sleep Mediated by Early Awakenings. Nicotine Tob Res 2016; 18:2252-2259. [DOI: 10.1093/ntr/ntw179] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 07/02/2016] [Indexed: 01/11/2023]
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Parekh PK, McClung CA. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity. Front Psychiatry 2016; 6:187. [PMID: 26793129 PMCID: PMC4709415 DOI: 10.3389/fpsyt.2015.00187] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 12/21/2015] [Indexed: 12/18/2022] Open
Abstract
Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward-related behavior.
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Affiliation(s)
- Puja K. Parekh
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Colleen A. McClung
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Hasler BP, Soehner AM, Clark DB. Sleep and circadian contributions to adolescent alcohol use disorder. Alcohol 2015; 49:377-87. [PMID: 25442171 DOI: 10.1016/j.alcohol.2014.06.010] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Revised: 06/27/2014] [Accepted: 06/30/2014] [Indexed: 11/16/2022]
Abstract
Adolescence is a time of marked changes across sleep, circadian rhythms, brain function, and alcohol use. Starting at puberty, adolescents' endogenous circadian rhythms and preferred sleep times shift later, often leading to a mismatch with the schedules imposed by secondary education. This mismatch induces circadian misalignment and sleep loss, which have been associated with affect dysregulation, increased drug and alcohol use, and other risk-taking behaviors in adolescents and adults. In parallel to developmental changes in sleep, adolescent brains are undergoing structural and functional changes in the circuits subserving the pursuit and processing of rewards. These developmental changes in reward processing likely contribute to the initiation of alcohol use during adolescence. Abundant evidence indicates that sleep and circadian rhythms modulate reward function, suggesting that adolescent sleep and circadian disturbance may contribute to altered reward function, and in turn, alcohol involvement. In this review, we summarize the relevant evidence and propose that these parallel developmental changes in sleep, circadian rhythms, and neural processing of reward interact to increase risk for alcohol use disorder (AUD).
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Affiliation(s)
- Brant P Hasler
- Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 15213, USA.
| | - Adriane M Soehner
- Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 15213, USA
| | - Duncan B Clark
- Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 15213, USA
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27
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Woelfle R, D'Aquila AL, Pavlović T, Husić M, Lovejoy DA. Ancient interaction between the teneurin C-terminal associated peptides (TCAP) and latrophilin ligand-receptor coupling: a role in behavior. Front Neurosci 2015; 9:146. [PMID: 25964737 PMCID: PMC4408839 DOI: 10.3389/fnins.2015.00146] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Accepted: 04/08/2015] [Indexed: 12/28/2022] Open
Abstract
Teneurins are multifunctional transmembrane proteins that are found in all multicellular animals and exist as four paralogous forms in vertebrates. They are highly expressed in the central nervous system, where they exert their effects, in part, by high-affinity binding to latrophilin (LPHN), a G-protein coupled receptor (GPCR) related to the adhesion and secretin GPCR families. The teneurin C-terminal associated peptides (TCAPs) are encoded by the terminal exon of all four teneurins, where TCAPs 1 and 3 are independently transcribed as soluble peptides, and TCAPs 2 and 4 remain tethered to their teneurin proprotein. Synthetic TCAP-1 interacts with LPHN, with an association with β-dystroglycan, to induce a tissue-dependent signal cascade to modulate cytoskeletal dynamics. TCAP-1 reduces stress-induced behaviors associated with anxiety, addiction and depression in a variety of models, in part, by regulating synaptic plasticity. Therefore, the TCAP-1-teneurin-LPHN interaction represents a novel receptor-ligand model and may represent a key mechanism underlying the association of behavior and neurological conditions.
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Affiliation(s)
- Rebecca Woelfle
- Department of Cell and Systems Biology, University of Toronto Toronto, ON, Canada
| | - Andrea L D'Aquila
- Department of Cell and Systems Biology, University of Toronto Toronto, ON, Canada
| | - Téa Pavlović
- Department of Cell and Systems Biology, University of Toronto Toronto, ON, Canada
| | - Mia Husić
- Department of Cell and Systems Biology, University of Toronto Toronto, ON, Canada
| | - David A Lovejoy
- Department of Cell and Systems Biology, University of Toronto Toronto, ON, Canada ; Protagenic Therapeutics Inc. New York, NY, USA
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28
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Ozburn AR, Falcon E, Twaddle A, Nugent AL, Gillman AG, Spencer SM, Arey RN, Mukherjee S, Lyons-Weiler J, Self DW, McClung CA. Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biol Psychiatry 2015; 77:425-433. [PMID: 25444159 PMCID: PMC4315729 DOI: 10.1016/j.biopsych.2014.07.030] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 07/31/2014] [Accepted: 07/31/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. METHODS We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. RESULTS Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. CONCLUSIONS Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.
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Affiliation(s)
- Angela R. Ozburn
- Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Edgardo Falcon
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390-9070
| | - Alan Twaddle
- Bioinformatics Analysis Core, Clinical and Translational Science Institute at the University of Pittsburgh School of Medicine, Pittsburgh, PA
| | | | - Andrea G. Gillman
- Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Sade M. Spencer
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390-9070
| | - Rachel N. Arey
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390-9070
| | - Shibani Mukherjee
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390-9070
| | - James Lyons-Weiler
- Bioinformatics Analysis Core, Clinical and Translational Science Institute at the University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - David W. Self
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390-9070
| | - Colleen A. McClung
- Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
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29
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Webb IC, Lehman MN, Coolen LM. Diurnal and circadian regulation of reward-related neurophysiology and behavior. Physiol Behav 2015; 143:58-69. [PMID: 25708277 DOI: 10.1016/j.physbeh.2015.02.034] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 02/09/2015] [Accepted: 02/17/2015] [Indexed: 12/16/2022]
Abstract
Here, we review work over the past two decades that has indicated drug reward is modulated by the circadian system that generates daily (i.e., 24h) rhythms in physiology and behavior. Specifically, drug-self administration, psychomotor stimulant-induced conditioned place preference, and locomotor sensitization vary widely across the day in various species. These drug-related behavioral rhythms are associated with rhythmic neural activity and dopaminergic signaling in the mesocorticolimbic pathways, with a tendency toward increased activity during the species typical wake period. While the mechanisms responsible for such cellular rhythmicity remain to be fully identified, circadian clock genes are expressed in these brain areas and can function locally to modulate both dopaminergic neurotransmission and drug-associated behavior. In addition, neural and endocrine inputs to these brain areas contribute to cellular and reward-related behavioral rhythms, with the medial prefrontal cortex playing a pivotal role. Acute or chronic administration of drugs of abuse can also alter clock gene expression in reward-related brain regions. Emerging evidence suggests that drug craving in humans is under a diurnal regulation and that drug reward may be influenced by clock gene polymorphisms. These latter findings, in particular, indicate that the development of therapeutic strategies to modulate the circadian influence on drug reward may prove beneficial in the treatment of substance abuse disorders.
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Affiliation(s)
- Ian C Webb
- Dept. of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA.
| | - Michael N Lehman
- Dept. of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA
| | - Lique M Coolen
- Dept. of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA; Dept. of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
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Stowie AC, Amicarelli MJ, Prosser RA, Glass JD. Chronic cocaine causes long-term alterations in circadian period and photic entrainment in the mouse. Neuroscience 2014; 284:171-179. [PMID: 25301751 DOI: 10.1016/j.neuroscience.2014.08.057] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Revised: 08/27/2014] [Accepted: 08/27/2014] [Indexed: 11/17/2022]
Abstract
The disruptive effects of cocaine on physiological, behavioral and genetic processes are well established. However, few studies have focused on the actions of cocaine on the adult circadian timekeeping system, and none have explored the circadian implications of long-term (weeks to months) cocaine exposure. The present study was undertaken to explore the actions of such long-term cocaine administration on core circadian parameters in mice, including rhythm period, length of the nocturnal activity period and photic entrainment. For cocaine dosing over extended periods, cocaine was provided in drinking water using continuous and scheduled regimens. The impact of chronic cocaine on circadian regulation was evidenced by disruptions of the period of circadian entrainment and intrinsic free-running circadian period. Specifically, mice under a skeleton photoperiod (1-min pulse of dim light delivered daily) receiving continuous ad libitum cocaine entrained rapidly to the light pulse at activity onset. Conversely, water controls entrained more slowly at activity offset through a process of phase-delays, which resulted in their activity rhythms being entrained 147° out of phase with the cocaine group. This pattern persisted after cocaine withdrawal. Next, mice exposed to scheduled daily cocaine presentations exhibited free-running periods under constant darkness that were significantly longer than water controls and which also persisted after cocaine withdrawal. These cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence.
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Affiliation(s)
- A C Stowie
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - M J Amicarelli
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - R A Prosser
- Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA
| | - J D Glass
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
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31
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Mendoza J, Challet E. Circadian insights into dopamine mechanisms. Neuroscience 2014; 282:230-42. [PMID: 25281877 DOI: 10.1016/j.neuroscience.2014.07.081] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 07/22/2014] [Accepted: 07/24/2014] [Indexed: 01/11/2023]
Abstract
Almost every physiological or behavioral process in mammals follows rhythmic patterns, which depend mainly on a master circadian clock located in the hypothalamic suprachiasmatic nucleus (SCN). The dopaminergic (DAergic) system in the brain is principally implicated in motor functions, motivation and drug intake. Interestingly, DA-related parameters and behaviors linked to the motivational and arousal states, show daily rhythms that could be regulated by the SCN or by extra-SCN circadian oscillator(s) modulating DAergic systems. Here we examine what is currently understood about the anatomical and functional central multi-oscillatory circadian system, highlighting how the main SCN clock communicates timing information with other brain clocks to regulate the DAergic system and conversely, how DAergic cues may have feedback effects on the SCN. These studies give new insights into the role of the brain circadian system in DA-related neurologic pathologies, such as Parkinson's disease, attention deficit/hyperactive disorder and drug addiction.
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Affiliation(s)
- J Mendoza
- Institute of Cellular and Integrative Neurosciences, CNRS UPR-3212, University of Strasbourg, 5 rue Blaise Pascal, 67084 Strasbourg cedex, France.
| | - E Challet
- Institute of Cellular and Integrative Neurosciences, CNRS UPR-3212, University of Strasbourg, 5 rue Blaise Pascal, 67084 Strasbourg cedex, France
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32
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Logan RW, Williams WP, McClung CA. Circadian rhythms and addiction: mechanistic insights and future directions. Behav Neurosci 2014; 128:387-412. [PMID: 24731209 DOI: 10.1037/a0036268] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug-induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction.
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Affiliation(s)
- Ryan W Logan
- Department of Psychiatry, University of Pittsburgh School of Medicine
| | - Wilbur P Williams
- Department of Psychiatry, University of Pittsburgh School of Medicine
| | - Colleen A McClung
- Department of Psychiatry, University of Pittsburgh School of Medicine
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33
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Southey BR, Lee JE, Zamdborg L, Atkins N, Mitchell JW, Li M, Gillette MU, Kelleher NL, Sweedler JV. Comparing label-free quantitative peptidomics approaches to characterize diurnal variation of peptides in the rat suprachiasmatic nucleus. Anal Chem 2013; 86:443-52. [PMID: 24313826 PMCID: PMC3886391 DOI: 10.1021/ac4023378] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
![]()
Mammalian
circadian rhythm is maintained by the suprachiasmatic nucleus (SCN)
via an intricate set of neuropeptides and other signaling molecules.
In this work, peptidomic analyses from two times of day were examined
to characterize variation in SCN peptides using three different label-free
quantitation approaches: spectral count, spectra index and SIEVE.
Of the 448 identified peptides, 207 peptides were analyzed by two
label-free methods, spectral count and spectral index. There were
24 peptides with significant (adjusted p-value <
0.01) differential peptide abundances between daytime and nighttime,
including multiple peptides derived from secretogranin II, cocaine
and amphetamine regulated transcript, and proprotein convertase subtilisin/kexin
type 1 inhibitor. Interestingly, more peptides were analyzable and
had significantly different abundances between the two time points
using the spectral count and spectral index methods than with a prior
analysis using the SIEVE method with the same data. The results of
this study reveal the importance of using the appropriate data analysis
approaches for label-free relative quantitation of peptides. The detection
of significant changes in so rich a set of neuropeptides reflects
the dynamic nature of the SCN and the number of influences such as
feeding behavior on circadian rhythm. Using spectral count and spectral
index, peptide level changes are correlated to time of day, suggesting
their key role in circadian function.
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Affiliation(s)
- Bruce R Southey
- Department of Animal Sciences, ‡Department of Chemistry, §Institute for Genomic Biology, ∥Neuroscience Program, ⊥Department of Cell and Developmental Biology, and ¶Beckman Institute, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States
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Campos-Melo D, Galleguillos D, Sánchez N, Gysling K, Andrés ME. Nur transcription factors in stress and addiction. Front Mol Neurosci 2013; 6:44. [PMID: 24348325 PMCID: PMC3844937 DOI: 10.3389/fnmol.2013.00044] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 11/09/2013] [Indexed: 12/16/2022] Open
Abstract
The Nur transcription factors Nur77 (NGFI-B, NR4A1), Nurr1 (NR4A2), and Nor-1 (NR4A3) are a sub-family of orphan members of the nuclear receptor superfamily. These transcription factors are products of immediate early genes, whose expression is rapidly and transiently induced in the central nervous system by several types of stimuli. Nur factors are present throughout the hypothalamus-pituitary-adrenal (HPA) axis where are prominently induced in response to stress. Drugs of abuse and stress also induce the expression of Nur factors in nuclei of the motivation/reward circuit of the brain, indicating their participation in the process of drug addiction and in non-hypothalamic responses to stress. Repeated use of addictive drugs and chronic stress induce long-lasting dysregulation of the brain motivation/reward circuit due to reprogramming of gene expression and enduring alterations in neuronal function. Here, we review the data supporting that Nur transcription factors are key players in the molecular basis of the dysregulation of neuronal circuits involved in chronic stress and addiction.
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Affiliation(s)
- Danae Campos-Melo
- Nucleus Millennium in Stress and Addiction, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile Santiago, Chile
| | - Danny Galleguillos
- Nucleus Millennium in Stress and Addiction, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile Santiago, Chile
| | - Natalia Sánchez
- Nucleus Millennium in Stress and Addiction, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile Santiago, Chile
| | - Katia Gysling
- Nucleus Millennium in Stress and Addiction, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile Santiago, Chile
| | - María E Andrés
- Nucleus Millennium in Stress and Addiction, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile Santiago, Chile
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The ClockΔ19 mutation in mice fails to alter the primary and secondary reinforcing properties of nicotine. Drug Alcohol Depend 2013; 133:733-9. [PMID: 24054990 DOI: 10.1016/j.drugalcdep.2013.08.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 08/27/2013] [Accepted: 08/27/2013] [Indexed: 01/26/2023]
Abstract
BACKGROUND Clock genes have been demonstrated to play a role in behavioral responses to a variety of drugs of abuse, including cocaine, amphetamine, morphine, and ethanol. However, no studies to date have examined the role of Clock genes on nicotine-mediated behaviors. We examined the involvement of Clock, one of several Clock genes, on the effects of nicotine by examining mice with the ClockΔ19 mutation in behaviors commonly used to assess drug effects in rodents. METHODS We first measured the locomotor effects of nicotine in mutants and wild type mice in response to repeated nicotine injections (0.175 mg/kg, IP). To assess the secondary properties of nicotine, we measured the ability of nicotine (0.175 mg/kg, IP) to induce a conditioned place preference. Finally, we measured the primary reinforcing properties of nicotine at two doses (0.01 and 0.03 mg/kg/infusion, IV) using the self-administration paradigm. RESULTS Mutant mice demonstrated no difference in magnitude of the sensitized response to nicotine as compared to wild-type controls. In the conditioned place preference paradigm, mutant and wild-type mice demonstrated a similar preference for a nicotine-paired environment. And finally, mutant and wild-type mice demonstrated a similar acquisition of nicotine self-administration, as indicated by the number of responses on a nicotine-paired lever and the number of nicotine reinforcers achieved during sessions. CONCLUSIONS The ClockΔ19 mutation appears to have no effect on the reinforcing properties of nicotine, in contrast to its demonstrated role in cocaine reinforcement. Further studies are needed to determine the effect of other Clock genes on nicotine reinforcement.
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36
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Differential regulation of the period genes in striatal regions following cocaine exposure. PLoS One 2013; 8:e66438. [PMID: 23776671 PMCID: PMC3679086 DOI: 10.1371/journal.pone.0066438] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 05/09/2013] [Indexed: 11/19/2022] Open
Abstract
Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (Npas2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2.
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Wongchitrat P, Mukda S, Phansuwan-Pujito P, Govitrapong P. Effect of amphetamine on the clock gene expression in rat striatum. Neurosci Lett 2013; 542:126-30. [PMID: 23518151 DOI: 10.1016/j.neulet.2013.03.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 03/06/2013] [Accepted: 03/11/2013] [Indexed: 11/17/2022]
Abstract
Drug addicts have severe disruptions in many physiological and behavioral rhythms, such as the sleep/wake cycle. Interestingly, amphetamine, a psychostimulant, is able to alter many circadian patterns, which are independent of the master biological clock located in the suprachiasmatic nucleus. To increase our understanding of the circadian regulation of amphetamine on clock gene expression, rats received subcutaneous injections of d-amphetamine and the clock gene mRNA levels were analyzed using real-time PCR to obtain a daily profile. In the striatum, acute injection of d-amphetamine did not alter Period (Per)1, Per2 and Reverse erythroblastosis virus α (Rev-erbα) expressions. Chronic administration shifted the phase of Per1 and Per2 expressions from a nocturnal to diurnal pattern and advance shifted the peak of Rev-erbα in d-amphetamine-treated animals. In contrast, the rhythm of Brain and muscle Arnt-like protein-1 (Bmal1) was shifted from a diurnal to a nocturnal pattern by both acute and chronic treatments. These results demonstrated that chronic d-amphetamine treatment altered the expression of clock genes in the striatum. This might further influence the expression of related gene within the striatum and lead to behavioral and physiological changes which are associated to drug addiction.
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Affiliation(s)
- Prapimpun Wongchitrat
- Center for Innovation Development and Technology Transfer, Faculty of Medical Technology, Mahidol University, Salaya, Nakornpathom, Thailand
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38
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The mPer2 clock gene modulates cocaine actions in the mouse circadian system. Behav Brain Res 2013; 243:255-60. [PMID: 23333842 DOI: 10.1016/j.bbr.2013.01.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 01/08/2013] [Accepted: 01/12/2013] [Indexed: 12/28/2022]
Abstract
Cocaine is a potent disruptor of photic and non-photic pathways for circadian entrainment of the master circadian clock of the suprachiasmatic nucleus (SCN). These actions of cocaine likely involve its modulation of molecular (clock gene) components for SCN clock timekeeping. At present, however, the physiological basis of such an interaction is unclear. To address this question, we compared photic and non-photic phase-resetting responses between wild-type (WT) and Per2 mutant mice expressing nonfunctional PER2 protein to systemic and intra-SCN cocaine administrations. In the systemic trials, cocaine was administered i.p. (20 mg/kg) either at midday or prior to a light pulse in the early night to assess its non-photic and photic behavioral phase-resetting actions, respectively. In the intra-SCN trial, cocaine was administered by reverse microdialysis at midday to determine if the SCN is a direct target for its non-photic phase-resetting action. Non-photic phase-advancing responses to i.p. cocaine at midday were significantly (∼3.5-fold) greater in Per2 mutants than WTs. However, the phase-advancing action of intra-SCN cocaine perfusion at midday did not differ between genotypes. In the light pulse trial, Per2 mutants exhibited larger photic phase-delays than did WTs, and the attenuating action of cocaine on this response was proportionately larger than in WTs. These data indicate that the Per2 clock gene is a potent modulator of cocaine's actions in the circadian system. With regard to non-photic phase-resetting, the SCN is confirmed as a direct target of cocaine action; however, Per2 modulation of this effect likely occurs outside of the SCN.
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Lee MJ, Burau KD, Dafny N. Behavioral daily rhythmic activity pattern of adolescent female rat is modulated by acute and chronic cocaine. J Neural Transm (Vienna) 2013; 120:733-44. [PMID: 23297093 DOI: 10.1007/s00702-012-0929-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Accepted: 11/16/2012] [Indexed: 01/10/2023]
Abstract
Cocaine is one of well-known drugs of abuse, and many children experience early exposure to cocaine. Because of an immature neuronal system in adolescents, they may react differently to repeated cocaine administration compared to adults. Most of the published papers report the effect of cocaine on adult male rats and this paper focused on the effects of cocaine on the 24 h locomotor activity rhythm patterns activity of adolescent Sprague Dawley (SD) female rats. Changes in the locomotor activity rhythm patterns could indicate that cocaine elicits long-term changes in the clock genes of the body that regulate different physiological processes. The objective of this study was to investigate whether cocaine in adolescent female rats modulated their daily activity pattern. Animals were divided into control (saline), 3.0, 7.5, 15.0 mg/kg cocaine groups. On experimental day 1 (ED 1), all groups were given saline injection. From ED 2 to ED 7, either saline or cocaine (3.0, 7.5, or 15.0 mg/kg) was given daily. ED 8 to ED 10 were the washout days, where no injection was given. On ED 11, the animals were injected with saline or with the same dose of cocaine as they were treated on ED 2 to ED 7. Each animal's locomotor activities was recorded nonstop following saline or cocaine injection for 11 consecutive days using the open field assay. In conclusion, it was observed that all three groups receiving repeated cocaine administration (3.0, 7.5, and 15.0 mg/kg) displayed significantly altered locomotor activity rhythm patterns.
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Affiliation(s)
- Min J Lee
- Department of Neurobiology and Anatomy, The University of Texas-Medical School at Houston, PO Box 20708, Houston, TX 77225, USA
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Ozburn AR, Larson EB, Self DW, McClung CA. Cocaine self-administration behaviors in ClockΔ19 mice. Psychopharmacology (Berl) 2012; 223:169-77. [PMID: 22535308 PMCID: PMC3670183 DOI: 10.1007/s00213-012-2704-2] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 03/25/2012] [Indexed: 12/13/2022]
Abstract
RATIONALE A key role has been identified for the circadian locomotor output cycles kaput (Clock) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the Clock gene (ClockΔ19 mice) exhibit increased cocaine-induced conditioned place preference, reduced anxiety- and depression-like behavior, increased sensitivity to intracranial self-stimulation, and increased dopaminergic cell activity in the ventral tegmental area. OBJECTIVES We sought to determine if this hyperhedonic phenotype extends to cocaine self-administration and measures of motivation. METHODS Two separate serial testing procedures were carried out (n = 7-10/genotype/schedule). Testing began with acquisition of sucrose pellet self-administration, implantation of intravenous catheter, acquisition of cocaine self-administration, and dose-response testing (fixed ratio or progressive ratio). To evaluate diurnal variations in acquisition behavior, these sessions occurred at Zeitgeber 2 (ZT2) or ZT14. RESULTS WT and ClockΔ19 mice exhibited similar learning and readily acquired food self-administration at both ZT2 and ZT14. However, only ClockΔ19 mice acquired cocaine self-administration at ZT2. A greater percentage of ClockΔ19 mice reached acquisition criteria at ZT2 and ZT14. ClockΔ19 mice self-administered more cocaine than WT mice. Using fixed ratio and progressive ratio schedules of reinforcement dose-response paradigms, we found that cocaine is a more efficacious reinforcer in ClockΔ19 mice than in WT mice. CONCLUSION Our results demonstrate that the Clock gene plays an important role in cocaine reinforcement and that decreased CLOCK function increases vulnerability for cocaine use.
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Affiliation(s)
- Angela Renee Ozburn
- Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, 450 Technology Dr. (BSPII Ste 233), Pittsburgh, PA 15219, USA.
| | - Erin Beth Larson
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
| | - David W. Self
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
| | - Colleen A. McClung
- Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, 450 Technology Dr. (BSPII Ste 233), Pittsburgh, PA 15219, USA. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
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Piechota M, Korostynski M, Sikora M, Golda S, Dzbek J, Przewlocki R. Common transcriptional effects in the mouse striatum following chronic treatment with heroin and methamphetamine. GENES BRAIN AND BEHAVIOR 2012; 11:404-14. [PMID: 22390687 DOI: 10.1111/j.1601-183x.2012.00777.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The molecular alterations that underlie the long-lasting behavioural effects of drugs of abuse, such as psychomotor sensitization and physical dependence, are still not known. Moreover, it is not known which molecular effects are similar for addictive drugs from various pharmacological classes. In this study, we utilized whole-genome microarray profiling to evaluate the detailed time-course of transcriptional alterations in the mouse striatum during chronic treatment with heroin (HER) and methamphetamine (METH) and after period of spontaneous withdrawal. We identified 27 genes regulated by chronic drug administration. The overlap between lists of HER- and METH-induced genes was highly significant. The most substantial impact on the gene expression profile was observed for circadian genes (Per1, Per2 and Nr1d1). However, changing the treatment scheme from diurnal to nocturnal was sufficient to attenuate the drug-induced changes in circadian gene mRNA levels. Both of the drugs caused a dose-dependent induction in glucocorticoid-dependent genes with relatively long mRNA half-lives (Fkbp5, Sult1a1 and Plin4). The analysis also showed a drug-regulated group of transcripts enriched in the nucleus accumbens and includes well known (Pdyn, Cartpt and Rgs2) as well as new (Fam40b and Inmt) candidate genes. All identified alterations in the striatal transcriptome were transient and persisted up to 6 days after withdrawal. Behavioural sensitization, however, was maintained throughout the 12-day withdrawal period for both HER and METH. We suggest that transient gene expression alterations during drug treatment and in the early period of withdrawal are involved in the establishment of persistent neuroplastic alterations responsible for the development of drug addiction.
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Affiliation(s)
- M Piechota
- Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Smetna 12, Krakow, Poland
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Glass JD, Brager AJ, Stowie AC, Prosser RA. Cocaine modulates pathways for photic and nonphotic entrainment of the mammalian SCN circadian clock. Am J Physiol Regul Integr Comp Physiol 2012; 302:R740-50. [PMID: 22218419 DOI: 10.1152/ajpregu.00602.2011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cocaine abuse is highly disruptive to circadian physiological and behavioral rhythms. The present study was undertaken to determine whether such effects are manifest through actions on critical photic and nonphotic regulatory pathways in the master circadian clock of the mouse suprachiasmatic nucleus (SCN). Impairment of SCN photic signaling by systemic (intraperitoneal) cocaine injection was evidenced by strong (60%) attenuation of light-induced phase-delay shifts of circadian locomotor activity during the early night. A nonphotic action of cocaine was apparent from its induction of 1-h circadian phase-advance shifts at midday. The serotonin receptor antagonist, metergoline, blocked shifting by 80%, implicating a serotonergic mechanism. Reverse microdialysis perfusion of the SCN with cocaine at midday induced 3.7 h phase-advance shifts. Control perfusions with lidocaine and artificial cerebrospinal fluid had little shifting effect. In complementary in vitro experiments, photic-like phase-delay shifts of the SCN circadian neuronal activity rhythm induced by glutamate application to the SCN were completely blocked by cocaine. Cocaine treatment of SCN slices alone at subjective midday, but not the subjective night, induced 3-h phase-advance shifts. Lidocaine had no shifting effect. Cocaine-induced phase shifts were completely blocked by metergoline, but not by the dopamine receptor antagonist, fluphenazine. Finally, pretreatment of SCN slices for 2 h with a low concentration of serotonin agonist (to block subsequent serotonergic phase resetting) abolished cocaine-induced phase shifts at subjective midday. These results reveal multiple effects of cocaine on adult circadian clock regulation that are registered within the SCN and involve enhanced serotonergic transmission.
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Affiliation(s)
- J David Glass
- Department of Biological Sciences, Kent State Univ., Kent, OH 44242, USA.
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Sharma A, Hu XT, Napier TC, Al-Harthi L. Methamphetamine and HIV-1 Tat down regulate β-catenin signaling: implications for methampetamine abuse and HIV-1 co-morbidity. J Neuroimmune Pharmacol 2011; 6:597-607. [PMID: 21744004 PMCID: PMC3714216 DOI: 10.1007/s11481-011-9295-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Accepted: 06/30/2011] [Indexed: 12/13/2022]
Abstract
Methamphetamine (Meth) abuse exacerbates HIV-1-associated neurocognitive disorders (HAND). The underlying mechanism for this effect is not entirely clear but likely involves cooperation between Meth and HIV-1 virotoxins, such as the transactivator of transcription, Tat. HIV-1 Tat mediates damage in the CNS by inducing inflammatory processes including astrogliosis. Wnt/β-catenin signaling regulates survival processes for both neurons and astrocytes. Here, we evaluated the impact of Meth on the Wnt/β-catenin pathway in astrocytes transfected with Tat. Meth and Tat downregulated Wnt/β-catenin signaling by >50%, as measured by TOPflash reporter activity in both an astrocytoma cell line and primary human fetal astrocytes. Meth and Tat also downregulated LEF-1 transcript by >30%. LEF-1 is a key partner of β-catenin to regulate cognate gene expression. Interestingly, estrogen, which induces β-catenin signaling in a cell-type specific manner, at physiological concentrations of 1.5 and 3 nM normalized individual Meth and Tat effects on β-catenin signaling but not their combined effects. These findings suggest that Meth and Tat likely exert different mechanisms to mediate down regulation of β-catenin signaling. The consequences of which may contribute to the pathophysiologic effects of HIV-1 and Meth co-morbidity in the CNS.
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Affiliation(s)
- Amit Sharma
- Department of Immunology/Microbiology, Rush University Medical Center, 1735 W. Harrison Street, 614 Cohn, Chicago, IL 60612, USA
- Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA
| | - Xiu-Ti Hu
- Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA
- Chicago Center for AIDS Research, Rush University Medical Center, Chicago, IL, USA
- Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA
| | - T. Celeste Napier
- Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA
- Chicago Center for AIDS Research, Rush University Medical Center, Chicago, IL, USA
- Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA
| | - Lena Al-Harthi
- Department of Immunology/Microbiology, Rush University Medical Center, 1735 W. Harrison Street, 614 Cohn, Chicago, IL 60612, USA
- Chicago Center for AIDS Research, Rush University Medical Center, Chicago, IL, USA
- Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA
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Higuera-Matas A, Montoya GL, Coria SM, Miguéns M, García-Lecumberri C, Ambrosio E. Differential gene expression in the nucleus accumbens and frontal cortex of lewis and Fischer 344 rats relevant to drug addiction. Curr Neuropharmacol 2011; 9:143-50. [PMID: 21886580 PMCID: PMC3137170 DOI: 10.2174/157015911795017290] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 04/17/2010] [Accepted: 05/26/2010] [Indexed: 11/22/2022] Open
Abstract
Drug addiction results from the interplay between social and biological factors. Among these, genetic variables play a major role. The use of genetically related inbred rat strains that differ in their preference for drugs of abuse is one approach of great importance to explore genetic determinants. Lewis and Fischer 344 rats have been extensively studied and it has been shown that the Lewis strain is especially vulnerable to the addictive properties of several drugs when compared with the Fischer 344 strain. Here, we have used microarrays to analyze gene expression profiles in the frontal cortex and nucleus accumbens of Lewis and Fischer 344 rats. Our results show that only a very limited group of genes were differentially expressed in Lewis rats when compared with the Fischer 344 strain. The genes that were induced in the Lewis strain were related to oxygen transport, neurotransmitter processing and fatty acid metabolism. On the contrary genes that were repressed in Lewis rats were involved in physiological functions such as drug and proton transport, oligodendrocyte survival and lipid catabolism. These data might be useful for the identification of genes which could be potential markers of the vulnerability to the addictive properties of drugs of abuse.
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Affiliation(s)
- A Higuera-Matas
- Departamento de Psicobiología, Facultad de Psicología, UNED, Madrid, Spain
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Dzirasa K, McGarity DL, Bhattacharya A, Kumar S, Takahashi JS, Dunson D, McClung CA, Nicolelis MAL. Impaired limbic gamma oscillatory synchrony during anxiety-related behavior in a genetic mouse model of bipolar mania. J Neurosci 2011; 31:6449-56. [PMID: 21525286 PMCID: PMC3112006 DOI: 10.1523/jneurosci.6144-10.2011] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Revised: 02/07/2011] [Accepted: 02/27/2011] [Indexed: 02/04/2023] Open
Abstract
Alterations in anxiety-related processing are observed across many neuropsychiatric disorders, including bipolar disorder. Though polymorphisms in a number of circadian genes confer risk for this disorder, little is known about how changes in circadian gene function disrupt brain circuits critical for anxiety-related processing. Here we characterize neurophysiological activity simultaneously across five limbic brain areas (nucleus accumbens, amygdala, prelimbic cortex, ventral hippocampus, and ventral tegmental area) as wild-type (WT) mice and mice with a mutation in the circadian gene, CLOCK (Clock-Δ19 mice) perform an elevated zero maze task. In WT mice, basal limbic gamma oscillatory synchrony observed before task performance predicted future anxiety-related behaviors. Additionally, dynamic changes in limbic gamma oscillatory synchrony were observed based on the position of WT mice in the zero maze. Clock-Δ19 mice, which displayed an increased propensity to enter the open section of the elevated maze, showed profound deficits in these anxiety-related circuit processes. Thus, our findings link the anxiety-related behavioral deficits observed in Clock-Δ19 mice with dysfunctional gamma oscillatory tuning across limbic circuits and suggest that alterations in limbic oscillatory circuit function induced by circadian gene polymorphisms may contribute to the behavioral manifestations seen in bipolar mania.
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Affiliation(s)
- Kafui Dzirasa
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA.
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Mains RE, Kiraly DD, Eipper-Mains JE, Ma XM, Eipper BA. Kalrn promoter usage and isoform expression respond to chronic cocaine exposure. BMC Neurosci 2011; 12:20. [PMID: 21329509 PMCID: PMC3048553 DOI: 10.1186/1471-2202-12-20] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 02/17/2011] [Indexed: 12/31/2022] Open
Abstract
Background The long-term effects of cocaine on behavior are accompanied by structural changes in excitatory glutamatergic synapses onto the medium spiny neurons of the striatum. The Kalrn gene encodes several functionally distinct isoforms; these multidomain guanine nucleotide exchange factors (GEFs) contain additional domains known to interact with phosphatidylinositides as well as with a number of different proteins. Through their activation of Rho proteins and their interactions with other proteins, the different Kalirin isoforms affect cytoskeletal organization. Chronic exposure of adult male rodents to cocaine increases levels of Kalirin 7 in the striatum. When exposed chronically to cocaine, mice lacking Kalirin 7, the major adult isoform, fail to show an increase in dendritic spine density in the nucleus accumbens, show diminished place preference for cocaine, and exhibit increased locomotor activity in response to cocaine. Results The use of alternate promoters and 3'-terminal exons of the mouse Kalrn gene were investigated using real-time quantitative polymerase chain reaction. While the two most distal full-length Kalrn promoters are used equally in the prefrontal cortex, the more proximal of these promoters accounts for most of the transcripts expressed in the nucleus accumbens. The 3'-terminal exon unique to the Kalirin 7 isoform accounts for a greater percentage of the Kalrn transcripts in prefrontal cortex than in nucleus accumbens. Western blot analyses confirmed these differences. Chronic cocaine treatment increases usage of the promoter encoding the Δ-Kalirin isoforms but does not alter full-length Kalirin promoter usage. Usage of the 3'-terminal exon unique to Kalirin 7 increases following chronic cocaine exposure. Conclusions Kalrn promoter and 3'-terminal exon utilization are region-specific. In the nucleus accumbens, cocaine-mediated alterations in promoter usage and 3'-terminal exon usage favor expression of Kalirin 7 and Δ-Kalirin 7. The Δ-isoform, which lacks a Sec14p domain and four of the nine spectrin-like repeats found in full-length Kalirin isoforms, increases spine headsize without increasing dendritic spine numbers. Thus cocaine-mediated changes in alternative splicing of the Kalrn gene may contribute importantly to the behavioral, morphological and biochemical responses observed.
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Affiliation(s)
- Richard E Mains
- Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-3401, USA.
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Nr4a1-eGFP is a marker of striosome-matrix architecture, development and activity in the extended striatum. PLoS One 2011; 6:e16619. [PMID: 21305052 PMCID: PMC3030604 DOI: 10.1371/journal.pone.0016619] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Accepted: 01/07/2011] [Indexed: 11/19/2022] Open
Abstract
Transgenic mice expressing eGFP under population specific promoters are widely used in neuroscience to identify specific subsets of neurons in situ and as sensors of neuronal activity in vivo. Mice expressing eGFP from a bacterial artificial chromosome under the Nr4a1 promoter have high expression within the basal ganglia, particularly within the striosome compartments and striatal-like regions of the extended amygdala (bed nucleus of the stria terminalis, striatal fundus, central amygdaloid nucleus and intercalated cells). Grossly, eGFP expression is inverse to the matrix marker calbindin 28K and overlaps with mu-opioid receptor immunoreactivity in the striatum. This pattern of expression is similar to Drd1, but not Drd2, dopamine receptor driven eGFP expression in structures targeted by medium spiny neuron afferents. Striosomal expression is strong developmentally where Nr4a1-eGFP expression overlaps with Drd1, TrkB, tyrosine hydroxylase and phospho-ERK, but not phospho-CREB, immunoreactivity in “dopamine islands”. Exposure of adolescent mice to methylphenidate resulted in an increase in eGFP in both compartments in the dorsolateral striatum but eGFP expression remained brighter in the striosomes. To address the role of activity in Nr4a1-eGFP expression, primary striatal cultures were prepared from neonatal mice and treated with forskolin, BDNF, SKF-83822 or high extracellular potassium and eGFP was measured fluorometrically in lysates. eGFP was induced in both neurons and contaminating glia in response to forskolin but SKF-83822, brain derived neurotrophic factor and depolarization increased eGFP in neuronal-like cells selectively. High levels of eGFP were primarily associated with Drd1+ neurons in vitro detected by immunofluorescence; however ∼15% of the brightly expressing cells contained punctate met-enkephalin immunoreactivity. The Nr4a1-GFP mouse strain will be a useful model for examining the connectivity, physiology, activity and development of the striosome system.
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Nakamura M, Gao S, Okamura H, Nakahara D. Intrathecal cocaine delivery enables long-access self-administration with binge-like behavior in mice. Psychopharmacology (Berl) 2011; 213:119-29. [PMID: 20862455 DOI: 10.1007/s00213-010-2021-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2010] [Accepted: 09/05/2010] [Indexed: 11/28/2022]
Abstract
RATIONALE Long-access intravenous drug self-administration shows diurnal alterations in drug intake, with escalation and binge patterns, in rats. A similar long-access model in mice would allow the use of genetically modified animals to better understand the molecular mechanisms underlying drug addiction and relapse. However, attempts to transfer this model to mice have been less successful, mainly because of technical difficulties with long-term maintenance of the indwelling catheter implanted into small veins. OBJECTIVES We devised an intrathecal probe implanted in the supracerebellar cistern as an alternative for intravenous drug administration to address this challenge and allow continuous, chronic drug self-administration in mice. RESULTS We found that mice readily self-administered intrathecal infusions of cocaine as a drug reward, and, under daily 24-h access conditions, animals exhibited a binge-like behavior comparable to rats. CONCLUSIONS This innovation enables a full analysis of long-access drug self-administration behavior in mice not possible with intravenous administration.
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Affiliation(s)
- Masato Nakamura
- Department of Psychology and Behavioral Neuroscience, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Japan
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Dzirasa K, Coque L, Sidor MM, Kumar S, Dancy EA, Takahashi JS, McClung CA, Nicolelis MAL. Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania. J Neurosci 2010; 30:16314-23. [PMID: 21123577 PMCID: PMC3165036 DOI: 10.1523/jneurosci.4289-10.2010] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 09/27/2010] [Accepted: 10/04/2010] [Indexed: 12/17/2022] Open
Abstract
Polymorphisms in circadian genes such as CLOCK convey risk for bipolar disorder. While studies have begun to elucidate the molecular mechanism whereby disruption of Clock alters cellular function within mesolimbic brain regions, little remains known about how these changes alter gross neural circuit function and generate mania-like behaviors in Clock-Δ19 mice. Here we show that the phasic entrainment of nucleus accumbens (NAC) low-gamma (30-55 Hz) oscillations to delta (1-4 Hz) oscillations is negatively correlated with the extent to which wild-type (WT) mice explore a novel environment. Clock-Δ19 mice, which display hyperactivity in the novel environment, exhibit profound deficits in low-gamma and NAC single-neuron phase coupling. We also demonstrate that NAC neurons in Clock-Δ19 mice display complex changes in dendritic morphology and reduced GluR1 expression compared to those observed in WT littermates. Chronic lithium treatment ameliorated several of these neurophysiological deficits and suppressed exploratory drive in the mutants. These results demonstrate that disruptions of Clock gene function are sufficient to promote alterations in NAC microcircuits, and raise the hypothesis that dysfunctional NAC phase signaling may contribute to the mania-like behavioral manifestations that result from diminished circadian gene function.
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Affiliation(s)
- Kafui Dzirasa
- Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA.
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Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. J Neurosci 2010; 30:14046-58. [PMID: 20962226 DOI: 10.1523/jneurosci.2128-10.2010] [Citation(s) in RCA: 179] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
A role for dopamine (DA) in the regulation of clock genes in the mammalian brain is suggested by evidence that manipulations of DA receptors can alter the expression of some clock genes outside the suprachiasmatic nucleus (SCN), the master circadian clock. The role of endogenous DA in the regulation of clock gene expression is unknown. Here, we demonstrate a direct relationship between extracellular DA levels and the rhythm of expression of the clock protein PERIOD2 (PER2) in the dorsal striatum of the male Wistar rat. Specifically, we show that the peak of the daily rhythm of extracellular DA in the dorsal striatum precedes the peak of PER2 by ∼6 h and that depletion of striatal DA by 6-hydroxydopamine or α-methyl-para-tyrosine or blockade of D(2) DA receptors by raclopride blunts the rhythm of striatal PER2. Furthermore, timed daily activation of D(2) DA receptors, but not D(1) DA receptors, restores and entrains the PER2 rhythm in the DA-depleted striatum. None of these manipulations had any effect on the PER2 rhythm in the SCN. Our findings are consistent with the idea that the rhythm of expression of PER2 in the dorsal striatum depends on daily dopaminergic activation of D(2) DA receptors. These observations may have implications for circadian abnormalities seen in Parkinson's disease.
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