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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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2
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Etchepare L, Gréa H, Durand P, Bouchet D, Groc L. NMDA receptor membrane dynamics tunes the firing pattern of midbrain dopaminergic neurons. J Physiol 2021; 599:2933-2951. [PMID: 33651437 DOI: 10.1113/jp281104] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/22/2021] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS NMDA receptors (NMDARs) expressed by dopamine neurons of the ventral tegmental area (VTA) play a central role in glutamate synapse plasticity, neuronal firing and adaptative behaviours. The NMDAR surface dynamics shapes synaptic adaptation in hippocampal networks, as well as associative memory. We investigated the basic properties and role of the NMDAR surface dynamics on cultured mesencephalic and VTA dopamine neurons in rodents. Using a combination of single molecule imaging and electrophysiological recordings, we demonstrate that NMDARs are highly diffusive at the surface of mesencephalic dopamine neurons. Unexpectedly, the NMDAR membrane dynamics per se regulates the firing pattern of VTA dopaminergic neurons, probably through a functional interplay between NMDARs receptors and small-conductance calcium-dependent potassium (SK) channels. ABSTRACT Midbrain dopaminergic (DA) neurons play a central role in major physiological brain functions, and their dysfunctions have been associated with neuropsychiatric diseases. The activity of midbrain DA neurons is controlled by ion channels and neurotransmitter receptors, such as the glutamate NMDA receptor (NMDAR) and small-conductance calcium-dependent potassium (SK) channels. However, the cellular mechanisms through which these channels tune the firing pattern of midbrain DA neurons remain unclear. Here, we investigated whether the surface dynamics and distribution of NMDARs tunes the firing pattern of midbrain DA neurons. Using a combination of single molecule imaging and electrophysiological recordings, we report that NMDARs are highly diffusive at the surface of cultured midbrain DA neurons from rodents and humans. Reducing acutely the NMDAR membrane dynamics, which leaves the ionotropic function of the receptor intact, robustly altered the firing pattern of midbrain DA neurons without altering synaptic glutamatergic transmission. The reduction of NMDAR surface dynamics reduced apamin (SK channel blocker)-induced firing change and the distribution of SK3 channels in DA neurons. Together, these data show that the surface dynamics of NMDAR, and not solely its ionotropic function, tune the firing pattern of midbrain DA neurons partly through a functional interplay with SK channel function.
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Affiliation(s)
- Laetitia Etchepare
- Interdisciplinary Institute for Neuroscience, Université de Bordeaux, UMR 5297, Bordeaux, F-33000, France.,CNRS, IINS UMR 5297, Bordeaux, France
| | - Hélène Gréa
- Interdisciplinary Institute for Neuroscience, Université de Bordeaux, UMR 5297, Bordeaux, F-33000, France.,CNRS, IINS UMR 5297, Bordeaux, France
| | - Pauline Durand
- Interdisciplinary Institute for Neuroscience, Université de Bordeaux, UMR 5297, Bordeaux, F-33000, France.,CNRS, IINS UMR 5297, Bordeaux, France
| | - Delphine Bouchet
- Interdisciplinary Institute for Neuroscience, Université de Bordeaux, UMR 5297, Bordeaux, F-33000, France.,CNRS, IINS UMR 5297, Bordeaux, France
| | - Laurent Groc
- Interdisciplinary Institute for Neuroscience, Université de Bordeaux, UMR 5297, Bordeaux, F-33000, France.,CNRS, IINS UMR 5297, Bordeaux, France
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3
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Orzeł-Gryglewska J, Matulewicz P, Jurkowlaniec E. Brainstem system of hippocampal theta induction: The role of the ventral tegmental area. Synapse 2015; 69:553-75. [PMID: 26234671 DOI: 10.1002/syn.21843] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 07/03/2015] [Accepted: 07/22/2015] [Indexed: 12/13/2022]
Abstract
This article summarizes the results of studies concerning the influence of the ventral tegmental area (VTA) on the hippocampal theta rhythm. Temporary VTA inactivation resulted in transient loss of the hippocampal theta. Permanent destruction of the VTA caused a long-lasting depression of the power of the theta and it also had some influence on the frequency of the rhythm. Activation of glutamate (GLU) receptors or decrease of GABAergic tonus in the VTA led to enhancement of dopamine release and increased hippocampal theta power. High time and frequency cross-correlation was detected for the theta band between the VTA and hippocampus during paradoxical sleep and active waking. Thus, the VTA may belong to the broad network involved in theta rhythm regulation. This article also presents a model of brainstem-VTA-hippocampal interactions in the induction of the hippocampal theta rhythm. The projections from the VTA which enhance theta rhythm are incorporated into the main theta generation pathway, in which the septum acts as the central node. The neuronal activity that may be responsible for the ability of the VTA to regulate theta probably derives from the structures associated with rapid eye movement (sleep) (REM) sleep or with sensorimotor activity (i.e., mainly from the pedunculopontine and laterodorsal tegmental nuclei and also from the raphe).
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Affiliation(s)
| | - Paweł Matulewicz
- Department of Animal and Human Physiology, University of Gdańsk, Gdańsk, 80-308, Poland
| | - Edyta Jurkowlaniec
- Department of Animal and Human Physiology, University of Gdańsk, Gdańsk, 80-308, Poland
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4
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Schweimer JV, Coullon GSL, Betts JF, Burnet PWJ, Engle SJ, Brandon NJ, Harrison PJ, Sharp T. Increased burst-firing of ventral tegmental area dopaminergic neurons in D-amino acid oxidase knockout mice in vivo. Eur J Neurosci 2014; 40:2999-3009. [PMID: 25040393 DOI: 10.1111/ejn.12667] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 05/19/2014] [Accepted: 06/10/2014] [Indexed: 01/19/2023]
Abstract
d-Amino acid oxidase (DAO) degrades the N-methyl-d-aspartate (NMDA) receptor co-agonist d-serine, and is implicated in schizophrenia as a risk gene and therapeutic target. In schizophrenia, the critical neurochemical abnormality affects dopamine, but to date there is little evidence that DAO impacts on the dopamine system. To address this issue, we measured the electrophysiological properties of dopaminergic (DA) and non-DA neurons in the ventral tegmental area (VTA) of anaesthetised DAO knockout (DAO(-/-) ) and DAO heterozygote (DAO(+/-) ) mice as compared with their wild-type (DAO(+/+) ) littermates. Genotype was confirmed at the protein level by western blotting and immunohistochemistry. One hundred and thirty-nine VTA neurons were recorded in total, and juxtacellular labelling of a subset revealed that neurons immunopositive for tyrosine hydroxylase had DA-like electrophysiological properties that were distinct from those of neurons that were tyrosine hydroxylase-immunonegative. In DAO(-/-) mice, approximately twice as many DA-like neurons fired in a bursting pattern than in DAO(+/-) or DAO(+/+) mice, but other electrophysiological properties did not differ between genotypes. In contrast, non-DA-like neurons had a lower firing rate in DAO(-/-) mice than in DAO(+/-) or DAO(+/+) mice. These data provide the first direct evidence that DAO modulates VTA DA neuron activity, which is of interest for understanding both the glutamatergic regulation of dopamine function and the therapeutic potential of DAO inhibitors. The increased DA neuron burst-firing probably reflects increased availability of d-serine at VTA NMDA receptors, but the site, mechanism and mediation of the effect requires further investigation, and may include both direct and indirect processes.
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Affiliation(s)
- Judith V Schweimer
- University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, UK; University Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK
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5
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NMDA-glutamatergic activation of the ventral tegmental area induces hippocampal theta rhythm in anesthetized rats. Brain Res Bull 2014; 107:43-53. [PMID: 24915630 DOI: 10.1016/j.brainresbull.2014.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 05/20/2014] [Accepted: 06/02/2014] [Indexed: 01/07/2023]
Abstract
Glutamate afferents reaching the ventral tegmental area (VTA) affect dopamine (DA) cells in this structure probably mainly via NMDA receptors. VTA appears to be one of the structures involved in regulation of hippocampal theta rhythm, and this work aimed at assessing the role of glutamatergic activation of the VTA in the theta regulation. Male Wistar rats (n=17) were divided into groups, each receiving intra-VTA microinjection (0.5 μl) of either solvent (water), glutamatergic NMDA agonist (0.2 μg) or antagonist (MK-801, 3.0 μg). Changes in local field potential were assessed on the basis of peak power (Pmax) and corresponding peak frequency (Fmax) for the delta (0.5-3 Hz) and theta (3-6 Hz) bands. NMDA microinjection evoked long-lasting hippocampal theta. The rhythm appeared with a latency of ca. 12 min post-injection and lasted for over 30 min; Pmax in this band was significantly increased for 50 min, while simultaneously Pmax in the delta band remained lower than in control conditions. Theta Fmax and delta Fmax were increased in almost entire post-injection period (by 0.3-0.5 Hz and 0.3-0.7 Hz, respectively). MK-801 depressed the sensory-evoked theta: tail pinch could not induce theta for 30 min after the injection; Pmax significantly decreased in the theta band and at the same time it increased in the delta band. Theta Fmax decreased 10 and 20 min post injection (by 0.4-0.5 Hz) and delta Fmax decreased in almost entire post injection period (by 0.3-0.7 Hz). NMDA injection generates theta rhythm probably through stimulation of dopaminergic activity within the VTA.
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6
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Betts JF, Schweimer JV, Burnham KE, Burnet PWJ, Sharp T, Harrison PJ. D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine. Front Synaptic Neurosci 2014; 6:11. [PMID: 24822045 PMCID: PMC4014674 DOI: 10.3389/fnsyn.2014.00011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 04/09/2014] [Indexed: 12/11/2022] Open
Abstract
D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study.
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Affiliation(s)
- Jill F Betts
- Department of Psychiatry, University of Oxford Oxford, UK ; Department of Pharmacology, University of Oxford Oxford, UK
| | - Judith V Schweimer
- Department of Psychiatry, University of Oxford Oxford, UK ; Department of Pharmacology, University of Oxford Oxford, UK
| | - Katherine E Burnham
- Department of Psychiatry, University of Oxford Oxford, UK ; Department of Pharmacology, University of Oxford Oxford, UK
| | | | - Trevor Sharp
- Department of Pharmacology, University of Oxford Oxford, UK
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7
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Ducrot C, Fortier E, Bouchard C, Rompré PP. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area. Front Syst Neurosci 2013; 7:57. [PMID: 24106463 PMCID: PMC3789217 DOI: 10.3389/fnsys.2013.00057] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 09/11/2013] [Indexed: 01/02/2023] Open
Abstract
Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to modulate reward.
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Affiliation(s)
- Charles Ducrot
- Département de Physiologie, Université de Montréal Montréal, QC, Canada
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8
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Abstract
Anterograde tract-tracing and immunohistochemical methods were used to study projections from the pedunculopontine tegmental nucleus (PPN) to midbrain dopaminergic neurons in the squirrel monkey (Saimiri sciureus). The PPN harbored numerous cholinergic and glutamatergic neurons, as well as neurons that displayed both cholinergic and glutamatergic markers. Injections of anterograde tracer into the PPN led to intense fiber labeling in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). This pedunculonigral projection was partly bilateral. At the electron microscopic level, about 40-60% of the anterogradely labeled terminal boutons were glutamate-positive and formed asymmetric synapses with the dopaminergic neurons of the SNc-VTA complex. These data provide direct evidence for a pedunculonigral glutamatergic projection. This projection may play a crucial role in the control of the firing pattern of SNc-VTA dopaminergic neurons and could be involved in glutamate-mediated excitotoxicity that is believed to lead to SNc cell death in Parkinson's disease.
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9
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Lodge DJ, Grace AA. Developmental pathology, dopamine, stress and schizophrenia. Int J Dev Neurosci 2011; 29:207-13. [PMID: 20727962 PMCID: PMC3022957 DOI: 10.1016/j.ijdevneu.2010.08.002] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Revised: 08/11/2010] [Accepted: 08/12/2010] [Indexed: 01/12/2023] Open
Abstract
Psychological stress is a contributing factor for a wide variety of neuropsychiatric diseases including substance use disorders, anxiety, depression and schizophrenia. However, it has not been conclusively determined how stress augments the symptoms of these diseases. Here we review evidence that the ventral hippocampus may be a site of convergence whereby a number of seemingly discrete risk factors, including stress, may interact to precipitate psychosis in schizophrenia. Specifically, aberrant hippocampal activity has been demonstrated to underlie both the elevated dopamine neuron activity and associated behavioral hyperactivity to dopamine agonists in a verified animal model of schizophrenia. In addition, stress, psychostimulant drug use, prenatal infection and select genetic polymorphisms all appear to augment ventral hippocampal function that may therefore exaggerate or precipitate psychotic symptoms. Such information is critical for our understanding into the pathology of psychiatric disease with the ultimate aim being the development of more effective therapeutics.
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Affiliation(s)
- Daniel J Lodge
- Department of Pharmacology & Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7764, San Antonio, TX 78229, USA.
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10
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Nakamoto T, Matsukawa K, Liang N, Wakasugi R, Wilson LB, Horiuchi J. Coactivation of renal sympathetic neurons and somatic motor neurons by chemical stimulation of the midbrain ventral tegmental area. J Appl Physiol (1985) 2011; 110:1342-53. [PMID: 21393462 DOI: 10.1152/japplphysiol.01233.2010] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We examined whether neurons in the midbrain ventral tegmental area (VTA) play a role in generating central command responsible for autonomic control of the cardiovascular system in anesthetized rats and unanesthetized, decerebrated rats with muscle paralysis. Small volumes (60 nl) of an N-methyl-D-aspartate receptor agonist (L-homocysteic acid) and a GABAergic receptor antagonist (bicuculline) were injected into the VTA and substantia nigra (SN). In anesthetized rats, L-homocysteic acid into the VTA induced short-lasting increases in renal sympathetic nerve activity (RSNA; 66 ± 21%), mean arterial pressure (MAP; 5 ± 2 mmHg), and heart rate (HR; 7 ± 2 beats/min), whereas bicuculline into the VTA produced long-lasting increases in RSNA (130 ± 45%), MAP (26 ± 2 mmHg), and HR (66 ± 6 beats/min). Bicuculline into the VTA increased blood flow and vascular conductance of the hindlimb triceps surae muscle, suggesting skeletal muscle vasodilatation. However, neither drug injected into the SN affected all variables. Renal sympathetic nerve and cardiovascular responses to chemical stimulation of the VTA were not essentially affected by decerebration at the premammillary-precollicular level, indicating that the ascending projection to the forebrain from the VTA was not responsible for evoking the sympathetic and cardiovascular responses. Furthermore, bicuculline into the VTA in decerebrate rats produced long-lasting rhythmic bursts of RSNA and tibial motor nerve discharge, which occurred in good synchrony. It is likely that the activation of neurons in the VTA is capable of eliciting synchronized stimulation of the renal sympathetic and tibial motor nerves without any muscular feedback signal.
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Affiliation(s)
- Tomoko Nakamoto
- Department of Physiology, Graduate School of Health Sciences, Hiroshima University, Hiroshima, Japan
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11
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Majkutewicz I, Cecot T, Jerzemowska G, Myślińska D, Plucińska K, Trojniar W, Wrona D. Lesion of the ventral tegmental area amplifies stimulation-induced Fos expression in the rat brain. Brain Res 2010; 1320:95-105. [PMID: 20079346 DOI: 10.1016/j.brainres.2010.01.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 12/31/2009] [Accepted: 01/05/2010] [Indexed: 11/17/2022]
Abstract
Unilateral lesions of the ventral tegmental area (VTA), the key structure of the mesolimbic system, facilitate behavioral responses induced by electrical stimulation of the VTA in the contralateral hemisphere. In search of the neuronal mechanism behind this phenomenon, Fos expression was used to measure neuronal activation of the target mesolimbic structures in rats subjected to unilateral electrocoagulation and simultaneously to contralateral electrical stimulation of the VTA (L/S group). These were compared to the level of mesolimbic activation after unilateral electrocoagulation of the VTA (L group), unilateral electrical stimulation of the VTA (S group) and bilateral electrode implantation into the VTA in the sham (Sh) group. We found that unilateral stimulation of the VTA alone increased the density of Fos containing neurons in the ipsilateral mesolimbic target structures: nucleus accumbens, lateral septum and amygdala in comparison with the sham group. However, unilateral lesion of the VTA was devoid of effect in non-stimulated (L) rats and it significantly amplified the stimulation-induced Fos-immunoreactivity (L/S vs S group). Stimulation of the VTA performed after contralateral lesion (L/S) evoked strong bilateral induction of Fos expression in the mesolimbic structures involved in motivation and reward (nucleus accumbens and lateral septum) and the processing of the reinforcing properties of olfactory stimuli (anterior cortical amygdaloid nucleus) in parallel with facilitation of behavioral function measured as shortened latency of eating or exploration. Our data suggest that VTA lesion sensitizes mesolimbic system to stimuli by suppressing an inhibitory influence of brain areas afferenting the VTA.
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Affiliation(s)
- Irena Majkutewicz
- Department of Animal Physiology, University of Gdańsk, 24 Kładki St., 80-822 Gdańsk, Poland
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12
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Zellner MR, Ranaldi R. How conditioned stimuli acquire the ability to activate VTA dopamine cells: a proposed neurobiological component of reward-related learning. Neurosci Biobehav Rev 2009; 34:769-80. [PMID: 19914285 DOI: 10.1016/j.neubiorev.2009.11.011] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2009] [Revised: 11/09/2009] [Accepted: 11/10/2009] [Indexed: 02/04/2023]
Abstract
The ability to learn about conditioned stimuli (CS) associated with rewards is a crucial adaptive mechanism. Activity in the mesocorticolimbic dopamine (DA) system, as well as in the ventral tegmental area (VTA), is correlated with responding to and learning about CSs. The mechanism by which VTA neurons become activated by signals associated with conditioned stimuli is not fully understood. Our model suggests that NMDA receptor stimulation in the VTA allows originally weak glutamate signals carrying information about environmental stimuli, coincident with strong excitation correlated with primary rewards, to be strengthened and thereby acquire the ability to activate VTA neurons in themselves, producing approach. Furthermore, once synaptic strengthening occurs, the model suggests that NMDA receptor stimulation in VTA is not necessary for the expression of reward-related learning. In this review we survey evidence that VTA cells respond to cues associated with primary rewards, that this responding is acquired, and that the VTA possesses the attributes to function as a site of integration of signals of primary and conditioned stimuli.
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Affiliation(s)
- Margaret R Zellner
- Laboratory of Neurobiology & Behavior, The Rockefeller University, New York, NY, United States
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13
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Grace AA. Physiology of the normal and dopamine-depleted basal ganglia: insights into levodopa pharmacotherapy. Mov Disord 2009; 23 Suppl 3:S560-9. [PMID: 18781673 DOI: 10.1002/mds.22020] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Dopamine (DA) neurons exist in two activity states; either spontaneously firing or quiescent and nonfiring. When faced with a behavioral demand, the quiescent DA neurons can be activated to facilitate normal motor output. Levodopa appears to increase DA output by activating these nonfiring neurons; as a consequence, DA release is increased, but behavioral demand can now overwhelm the system, potentially leading to the inactivation and on/off phenomena. Levodopa administered in a pulsatile manner may also lead to the induction of synaptic plasticity within the DA systems. In the ventral mesolimbic system, this could lead to the loss of behavioral flexibility, impulsive behavior, and cognitive impairment, whereas in the dorsal nigrostriatal system, this may underlie Levodopa-induced dyskinesia. Continuous administration of Levodopa may circumvent this sensitization process, enabling a therapeutic response without limbic and motor side effects.
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Affiliation(s)
- Anthony A Grace
- Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Grace AA, Floresco SB, Goto Y, Lodge DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 2007; 30:220-7. [PMID: 17400299 DOI: 10.1016/j.tins.2007.03.003] [Citation(s) in RCA: 756] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2006] [Revised: 02/20/2007] [Accepted: 03/16/2007] [Indexed: 12/15/2022]
Abstract
There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders. These systems include the ventral hippocampus, which is involved in context and focus on tasks, the amygdala, which mediates emotional behavior, and the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility. Each of these systems has overlapping projections to the nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine. Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic-cortical interactions and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.
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Affiliation(s)
- Anthony A Grace
- Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
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15
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Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 2007; 113:296-320. [PMID: 17049611 PMCID: PMC2562467 DOI: 10.1016/j.pharmthera.2006.08.004] [Citation(s) in RCA: 451] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2006] [Accepted: 08/24/2006] [Indexed: 01/19/2023]
Abstract
The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.
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Affiliation(s)
- K D Alex
- Department of Neurosciences, Case Western Reserve School of Medicine, Cleveland, OH 44106, USA
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16
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Lodge DJ, Grace AA. The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons. Proc Natl Acad Sci U S A 2006; 103:5167-72. [PMID: 16549786 PMCID: PMC1458812 DOI: 10.1073/pnas.0510715103] [Citation(s) in RCA: 257] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2005] [Indexed: 02/07/2023] Open
Abstract
In response to behaviorally salient stimuli, dopamine (DA) neurons fire in bursts. Burst firing induces a large transient increase in synaptic DA and is regarded as the functionally relevant mode of transmission that signals reward and modulates goal-directed behavior. DA neuron burst firing is dynamically regulated by afferent inputs, and it is not present in vitro because of severing of afferent processes. However, what afferents are requisite for burst firing in vivo is not known. Here, we show that tonic input from the laterodorsal tegmental nucleus (LDTg) is required for glutamate-elicited burst firing in ventral tegmental area DA neurons of anesthetized rats. Also, after LDTg inactivation, DA neurons fire as they do in vitro (i.e., as pacemakers); even direct glutamate application fails to cause them to burst fire under these conditions. These data show that the LDTg is critical to normal DA function, and thus, pathology within this region may lead to aberrant DA signaling.
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Affiliation(s)
- D J Lodge
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
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17
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Steiniger-Brach B, Kretschmer BD. Different function of pedunculopontine GABA and glutamate receptors in nucleus accumbens dopamine, pedunculopontine glutamate and operant discriminative behavior. Eur J Neurosci 2005; 22:1720-30. [PMID: 16197512 DOI: 10.1111/j.1460-9568.2005.04361.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The nucleus accumbens, as the main input structure of the ventral basal ganglia loop, is described as a limbic-motor interface. Dopamine input to nucleus accumbens modulates processing of concurrent glutamate input from limbic structures carrying motor and motivational information. There is evidence that these dopamine/glutamate interactions are fundamentally involved in response selection processes. However, the pedunculopontine tegmental nucleus (PPTg) in the brainstem is connected with limbic structures as well as dopaminergic midbrain areas, which also project to the nucleus accumbens. Furthermore, behavioral studies implicate the PPTg in complex, motivated behavior. Thus, the PPTg might be involved in motivated behavior by influencing response selection processes in the nucleus accumbens. In this study we used in vivo microdialysis in freely moving rats in order to inhibit (100, 200, 300 and 400 microm baclofen) or stimulate [5, 12.5, 25 or 50 micromalpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)] the PPTg in animals that are performing an operant discrimination task for food reward. The behavioral consequences were correlated with dopamine and glutamate levels in nucleus accumbens and PPTg, respectively. PPTg inhibition by local GABAB receptors impaired the response rate and accuracy of performance in the operant discrimination task. PPTg stimulation by local AMPA receptors exclusively impaired the response rate. Both treatments blocked the performance-driven dopamine signal in nucleus accumbens, whereas glutamate in PPTg was enhanced after AMPA administration only. The data indicate that the PPTg functionally participates in a network of subcortical and cortical structures, which is responsible for the execution of motivated behavior and response selection processes.
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Melis M, Spiga S, Diana M. The dopamine hypothesis of drug addiction: hypodopaminergic state. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2005; 63:101-54. [PMID: 15797467 DOI: 10.1016/s0074-7742(05)63005-x] [Citation(s) in RCA: 190] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Miriam Melis
- B.B. Brodie Department of Neuroscience, University of Cagliari, 09042 Monserrato, Italy
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19
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Cornil CA, Seutin V, Motte P, Balthazart J. Electrophysiological and neurochemical characterization of neurons of the medial preoptic area in Japanese quail (Coturnix japonica). Brain Res 2004; 1029:224-40. [PMID: 15542078 DOI: 10.1016/j.brainres.2004.09.047] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2004] [Indexed: 11/18/2022]
Abstract
Intracellular recordings of medial preoptic neurons demonstrated that most neurons show a spontaneous firing, a linear I-V relationship and low-threshold-like events suppressed by the application of Ni2+. Some neurons had a depolarizing sag of the membrane potential in response to hyperpolarizing current pulses. The majority of the cells exhibited a robust spontaneous synaptic activity suppressed by SR95531 (100 microM), a GABAA receptor antagonist, and/or by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), an (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) glutamate receptor antagonist. Most neurons were affected by the application of AMPA (10 microM), kainate (30 microM), N-methyl-D-aspartic acid (NMDA, 10 microM), isoguvacine (a GABAA receptor agonist, 100 microM), dopamine (100 microM), and norepinephrine (100 microM). Biocytin injections coupled to aromatase immunocytochemistry identified 19 recorded neurons including 3 displaying a dense aromatase immunoreactivity. All of them responded to kainate, dopamine, and norepinephrine, while only one responded to isoguvacine and NMDA. Taken together, these results demonstrate a relative electrical and neurochemical homogeneity of the medial preoptic neurons, including a few aromatase-immunoreactive neurons that could be identified by immunocytochemistry after biocytin labeling of the recorded neurons.
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Affiliation(s)
- Charlotte A Cornil
- Center for Cellular and Molecular Neurobiology, Research Group in Behavioral Neuroendocrinology, University of Liège, 17 Place Delcour (Bat L1), B-4020 Liège, Belgium.
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20
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Kauer JA. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu Rev Physiol 2004; 66:447-75. [PMID: 14977410 DOI: 10.1146/annurev.physiol.66.032102.112534] [Citation(s) in RCA: 155] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
One of the central questions in neurobiology is how experience modifies neural function, and how changes in the nervous system permit an animal to adapt its behavior to a changing environment. Learning and adaptation to a host of different environmental stimuli exemplify processes we know must alter the nervous system because the behavioral output changes after experience. Alterations in behavior after exposure to addictive drugs are a striking example of chemical alterations of nervous system function producing long-lasting changes in behavior. The alterations produced in the central nervous system (CNS) by addictive drugs are of interest because of their relationship to human substance abuse but also because these CNS alterations produce dramatic, easily observed alterations in behavior in response to discrete stimuli. Considerable study has been given to behavioral and biochemical correlates of addiction over the past 50 or more years; however, our understanding of the cellular physiological responses of affected CNS neurons is in its infancy. This review focuses on alterations in cellular and synaptic physiology in the ventral tegmental area (VTA) in response to addictive drugs.
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Affiliation(s)
- Julie A Kauer
- Department of Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
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21
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Ikegami A, Duvauchelle CL. Dopamine Mechanisms and Cocaine Reward. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2004; 62:45-94. [PMID: 15530568 DOI: 10.1016/s0074-7742(04)62002-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Aiko Ikegami
- Division of Pharmacology/Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA
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22
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Mathon DS, Kamal A, Smidt MP, Ramakers GMJ. Modulation of cellular activity and synaptic transmission in the ventral tegmental area. Eur J Pharmacol 2003; 480:97-115. [PMID: 14623354 DOI: 10.1016/j.ejphar.2003.08.097] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The mesolimbic dopamine system, of which the cell bodies are located in the ventral tegmental area, has been implicated in the physiology of reward and the related pathophysiology of drug abuse. This area has been a site of significant interest to study the effects of drugs of abuse and neurotransmitter systems implicated in the rewarding effects of these compounds. One important aspect of synaptic transmission is the ability of synapses to strengthen or weaken their connection as a consequence of synaptic activity. Recently, it has become apparent that this phenomenon is also present in the ventral tegmental area and that this may bear important functional consequences for the ways in which drugs of abuse assert their effect. Here, we will review the effects of neurotransmitter systems and drugs of abuse on cellular activity and synaptic transmission in the ventral tegmental area.
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Affiliation(s)
- Daniel S Mathon
- Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
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23
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Abstract
Dopamine (DA) facilitates male sexual behavior and modulates aromatase activity in the quail preoptic area (POA). Aromatase neurons in the POA receive dopaminergic inputs, but the anatomical substrate that mediates the behavioral and endocrine effects of DA is poorly understood. Intracellular recordings showed that 100 microm DA hyperpolarizes most neurons in the medial preoptic nucleus (80%) by a direct effect, but depolarizes a few others (10%). DA-induced hyperpolarizations were not blocked by D1 or D2 antagonists (SCH-23390 and sulpiride). Extracellular recordings confirmed that DA inhibits the firing of most cells (52%) but excites a few others (24%). These effects also were not affected by DA antagonists (SCH-23390 and sulpiride) but were blocked by alpha2-(yohimbine) and alpha1-(prazosin) noradrenergic receptor antagonists, respectively. Two dopamine-beta-hydroxylase (DBH) inhibitors (cysteine and fusaric acid) did not block the DA-induced effects, indicating that DA is not converted into norepinephrine (NE) to produce its effects. The pK(B) of yohimbine for the receptor involved in the DA- and NE-induced inhibitions was similar, indicating that the two monoamines interact with the same receptor. Together, these results demonstrate that the effects of DA in the POA are mediated mostly by the activation of alpha2 (inhibition) and alpha1 (excitation) adrenoreceptors. This may explain why DA affects the expression of male sexual behavior through its action in the POA, which contains high densities of alpha2-noradrenergic but limited amounts of DA receptors. This study thus clearly demonstrates the existence of a cross talk within CNS catecholaminergic systems between a neurotransmitter and heterologous receptors.
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24
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Activation of ventral tegmental area cells by the bed nucleus of the stria terminalis: a novel excitatory amino acid input to midbrain dopamine neurons. J Neurosci 2002. [PMID: 12077212 DOI: 10.1523/jneurosci.22-12-05173.2002] [Citation(s) in RCA: 186] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
We examined the role of excitatory amino acids (EAAs) in the activation of midbrain dopaminergic (DA) neurons evoked by stimulation of the ventromedial and ventrolateral (subcommissural) bed nucleus of the stria terminalis (vBNST). Using anesthetized rats and extracellular recording techniques, we found that 84.8% of ventral tegmental area (VTA) DA neurons were activated synaptically by single-pulse electrical stimulation of the vBNST. In contrast, similar stimulation did not affect the activity of presumed GABA neurons in the VTA. Three characteristic responses were observed in VTA DA neurons: short latency activation (<25 msec; 55.1% of cells), long latency activation (>65 msec; 56% of cells), and inhibition (61.8% of cells, usually followed by long latency excitation). Microinfusion of antagonists of EAA receptors (3 mm kynurenic acid, 100 microm AP-5, or 50 microm CNQX) from a micropipette adjacent to the recording electrode significantly reduced both short and long latency activations evoked in DA neurons by vBNST stimulation. Specific responses were attenuated similarly by AP-5 alone, CNQX alone, or a cocktail of AP-5+CNQX, indicating that joint activation of NMDA plus non-NMDA receptors was required. Stimulation of the vBNST by local microinfusion of glutamate increased the firing and bursting activity of VTA DA neurons. Similar microinfusion of GABA decreased bursting of VTA DA neurons without altering their firing rate. Retrograde and anterograde labeling and antidromic activation of vBNST neurons by VTA stimulation confirmed a direct projection from the vBNST to the VTA. These results reveal that inputs from the vBNST exert a strong excitatory influence on VTA DA neurons mediated by both NMDA and non-NMDA receptors.
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25
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Erhardt S, Engberg G. Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid. ACTA PHYSIOLOGICA SCANDINAVICA 2002; 175:45-53. [PMID: 11982504 DOI: 10.1046/j.1365-201x.2002.00962.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Kynurenic acid (KYNA) is an antagonist of ionotropic glutamate receptors, preferentially blocking the glycine-site of the N-methyl-D-aspartate (NMDA) receptor. In the present electrophysiological study, the firing pattern of dopamine (DA) neurones of rat ventral tegmental area (VTA) was investigated following pharmacologically elevated endogenous levels of KYNA by means of an inhibitor of kynurenine 3-hydroxylase (PNU 156561A). Pre-treatment with PNU 156561A (40 mg kg-1, i.v., 5-9 h) caused a threefold increase in endogenous KYNA in whole brain levels and also evoked a significant increase in firing rate and bursting activity of VTA DA neurones. Administration of D-cycloserine (2-128 mg kg-1, i.v.), a partial agonist at the glycine-site of the NMDA-receptor, was found to reverse the increase in firing rate and bursting activity as induced by elevated concentrations of KYNA. The electrophysiological effects of elevated KYNA levels were in all essential mimicked by administration of the NMDA-receptor antagonist MK 801 (0.05-1.6 mg kg-1, i.v.). Thus, the effects of elevated endogenous brain KYNA observed in the present study are likely to be carried out by NMDA receptor antagonism. In conclusion, this study shows that an increase in endogenous KYNA levels produces significant actions on the tonic afferent control of the firing pattern of VTA DA neurones. Given the psychotomimetic effects of NMDA-receptor antagonists, e.g. phencyclidine and ketamine, the state of hyperactivity of mesocorticolimbic DA system induced by elevated levels of KYNA may represent a pathophysiological condition analogous to that seen in schizophrenic patients.
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Affiliation(s)
- S Erhardt
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
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26
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Chen BT, Rice ME. Synaptic regulation of somatodendritic dopamine release by glutamate and GABA differs between substantia nigra and ventral tegmental area. J Neurochem 2002; 81:158-69. [PMID: 12067228 DOI: 10.1046/j.1471-4159.2002.00811.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Midbrain dopamine (DA) cells of the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) exhibit somatodendritic release of DA. To address how somatodendritic release is regulated by synaptic glutamatergic and GABAergic input, we examined the effect of ionotropic-receptor antagonists on locally evoked extracellular DA concentration ([DA]o) in guinea pig midbrain slices. Evoked [DA]o was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. In SNc, evoked [DA]o was 160% of control in the presence of the AMPA-receptor antagonist, GYKI-52466, or the NMDA-receptor antagonist, AP5. Similar increases were seen with the GABAA-receptor antagonist, picrotoxin, or the GABA(B)-receptor antagonist, saclofen. The increase seen with GYKI-52466 was prevented when both picrotoxin and saclofen were present, consistent with normal, AMPA-receptor mediated activation of GABAergic inhibition. The increase with AP5 persisted, however, implicating NMDA-receptor mediated activation of another inhibitory circuit in SNc. In the VTA, by contrast, evoked [DA]o was unaffected by GYKI-52466 and fell slightly with AP5. Neither picrotoxin nor saclofen alone or in combination had a significant effect on evoked [DA]o. When GABA receptors were blocked in the VTA, evoked [DA]o was decreased by 20% with either GYKI-52466 or AP5. These data suggest that in SNc, glutamatergic input acts predominantly on GABAergic or other inhibitory circuits to inhibit somatodendritic DA release, whereas in VTA, the timing or strength of synaptic input will govern whether the net effect on DA release is excitatory or inhibitory.
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Affiliation(s)
- Billy T Chen
- Department of Physiology and Neuroscience, New York University School of Medicine, New York 10016, USA
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27
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Erhardt S, Schwieler L, Engberg G. Excitatory and inhibitory responses of dopamine neurons in the ventral tegmental area to nicotine. Synapse 2002; 43:227-37. [PMID: 11835517 DOI: 10.1002/syn.10044] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In the present electrophysiological study the mechanisms by which nicotine activates dopamine neurons in the ventral tegmental area in anesthetized Sprague-Dawley rats were analyzed. Intravenous administration of nicotine caused a dose-dependent increase in firing rate and percentage of spikes fired in bursts of ventral tegmental area dopamine neurons. However, this activation was preceded by an instantaneous but short-lasting inhibition of the firing rate. The excitation of dopamine neurons by nicotine (1.5-400 microg/kg i.v.) was antagonized and even reversed into an inhibitory response by elevated levels (four-fold) of the endogenous glutamate receptor antagonist kynurenic acid, as induced by a potent inhibitor of kynurenine 3-hydroxylase (PNU 156561A, 40 mg/kg, i.v., 5-9 h). The antagonistic action induced by PNU 156561A pretreatment was prevented by administration of D-cycloserine (128 mg/kg, i.v., 5 min). Administration of the GABA(B)-receptor antagonist CGP 35348 (200 mg/kg, i.v., 3 min) facilitated the nicotine-induced increase in burst firing activity of dopamine neurons and antagonized the short-lasting decrease in firing rate by nicotine. The results of the present study show that nicotine produces both inhibition and excitation of ventral tegmental area dopamine neurons, actions that appear to be related to the release of GABA and glutamate, respectively. Whereas the excitatory action of nicotine may be associated with motivational processes underlying learning and cognitive behavior, the inhibitory action of the drug may play a more prominent role in the situation of a profound dysregulation of the mesocorticolimbic dopamine system and may help to explain the high prevalence of tobacco-smoking in schizophrenics.
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Affiliation(s)
- Sophie Erhardt
- Department of Physiology and Pharmacology, Karolinska Institute, SE 171 77 Stockholm, Sweden.
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28
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Abstract
The prefrontal cortex (PFC) has long been known to be involved in the mediation of complex behavioral responses. Considerable research efforts are directed towards refining the knowledge about the function of this brain area and the role it plays in cognitive performance and behavioral output. In the first part, this review provides, from a pharmacological perspective, an overview of anatomical, electrophysiological and neurochemical aspects of the function of the PFC, with an emphasis on the mesocortical dopamine system. Anatomy of the mesocortical system, basic physiological and pharmacological properties of neurotransmission within the PFC, and interactions between dopamine and glutamate as well as other transmitters within the mesocorticolimbic circuit are included. The coverage of these data is largely restricted to what is relevant for the second part of the review which focuses on behavioral studies that have examined the role of the PFC in a variety of phenomena, behaviors and paradigms. These include reward and addiction, locomotor activity and sensitization, learning, cognition, and schizophrenia. Although the focus of this review is on the mesocortical dopamine system, given the intricate interactions of dopamine with other transmitter systems within the PFC and the importance of the PFC as a source of glutamate in subcortical areas, these aspects are also covered in some detail where appropriate. Naturally, a topic as complex as this cannot be covered comprehensively in its entirety. Therefore this review is largely limited to data derived from studies using rats, and it is also specifically restricted to data concerning the medial PFC (mPFC). Since in several fields of research the findings concerning the function or role of the mPFC are relatively inconsistent, the question is addressed whether these inconsistencies might, at least in part, be related to the anatomical and functional heterogeneity of this brain area.
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Affiliation(s)
- T M Tzschentke
- Grünenthal GmbH, Research and Development, Department of Pharmacology, Postfach 500444, 52088, Aachen, Germany.
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29
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Greba Q, Munro LJ, Kokkinidis L. The involvement of ventral tegmental area cholinergic muscarinic receptors in classically conditioned fear expression as measured with fear-potentiated startle. Brain Res 2000; 870:135-41. [PMID: 10869510 DOI: 10.1016/s0006-8993(00)02414-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Accumulating evidence suggests that dopamine (DA) neurons in the ventral tegmental area (VTA) contribute to the complex amygdala-based neurocircuitry that mediates fear-motivated behaviors. Because of acetylcholine's (ACh) role in DA neuronal activation, the involvement of VTA cholinergic muscarinic receptors in Pavlovian conditioned fear responding was evaluated in the present study. Fear-potentiated startle was used to assess the effects of intraVTA infused methylscopolamine on conditioned fear performance in laboratory rats. Application of this nonspecific muscarinic receptor antagonist to VTA neurons was observed to inhibit the ability of a conditioned stimulus (CS) previously paired with footshock to enhance the amplitude of the acoustic startle reflex. Doses of methylscopolamine that blocked conditioned fear expression did not alter baseline sensorimotor responding. These results identify ACh neurotransmission in the VTA as a potential excitatory mechanism underlying the fear-arousing properties of threatening environmental stimuli.
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Affiliation(s)
- Q Greba
- Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
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30
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Rodríguez JJ, Doherty MD, Pickel VM. N-methyl-D-aspartate (NMDA) receptors in the ventral tegmental area: subcellular distribution and colocalization with 5-hydroxytryptamine(2A) receptors. J Neurosci Res 2000; 60:202-11. [PMID: 10740225 DOI: 10.1002/(sici)1097-4547(20000415)60:2<202::aid-jnr9>3.0.co;2-j] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype have been implicated in behavioral sensitization to psychostimulants and in psychotic behaviors involving excitation of ventral tegmental area (VTA) dopaminergic neurons. Antagonists of serotonin (5-hydroxytryptamine, 5-HT) receptors of the 5-HT(2A) subtype are potent antipsychotics that attenuate these NMDA-evoked responses. We examined the electron microscopic immunocytochemical localization of antisera against the NMDA R1 subunit (NMDAR1) and 5-HT(2A) receptors to determine potential sites for their dual activation in the rat paranigral and parabrachial VTA subdivisions that are distinguished, in part, by their respective striatolimbic and cortical projections. In both regions, NMDAR1 immunoreactivity was localized mainly to the cytoplasm of somata and dendrites, and was only occasionally seen near or within excitatory-type asymmetric synapses. Many of the NMDAR1-labeled somata and dendrites also expressed 5-HT(2A) receptors, having a similar, but largely non-overlapping, neuronal distribution. The mean area density of NMDAR1 and dually labeled dendritic profiles was significantly greater in the paranigral than in the parabrachial VTA. NMDAR1 was also present in small axons showing a similar regional difference in area density. No regional difference in area density was seen in dendrites or small axons containing only 5-HT(2A) receptors. Our results indicate that NMDA and 5-HT(2A) receptors in the VTA are transiently expressed on synaptic plasma membranes of single neurons showing widespread cytoplasmic distributions of each of the receptors. They also suggest a major role for NMDA receptors in modulating the output of paranigral neurons and the release of transmitters from axons passing through this region.
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Affiliation(s)
- J J Rodríguez
- Division of Neurobiology, Department of Neurology, Weill Medical College of Cornell University, New York, New York, USA
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31
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Nedergaard S. Regulation of action potential size and excitability in substantia nigra compacta neurons: sensitivity to 4-aminopyridine. J Neurophysiol 1999; 82:2903-13. [PMID: 10601428 DOI: 10.1152/jn.1999.82.6.2903] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Slow, pacemaker-like firing is due to intrinsic membrane properties in substantia nigra compacta (SNc) neurons in vitro. How these properties interact with afferent synaptic inputs is not fully understood. In this study, intracellular recordings from SNc neurons in brain slices showed that spontaneous action potentials (APs) were attenuated when generated from lower than normal threshold. Such APs were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and could be related to non-N-methyl-D-aspartate (NMDA) receptor-mediated spontaneous excitatory postsynaptic potentials (EPSPs). The AP attenuation was reproduced by stimulus-evoked EPSPs and by current injections to the soma. APs evoked from holding potentials between -40 and -60 mV were reduced in width by Cd(2+) (0. 2 mM). Tetraethylammonium chloride (TEA, 10 mM) or 4-aminopyridine (4-AP, 5 mM) increased the AP width. However, at more negative holding potentials, Cd(2+) and TEA were inefficacious, whereas 4-AP enlarged the AP, partly via induction of a Cd(2+)-sensitive component. A monophasic afterhyperpolarization (AHP), following attenuated APs, was little affected by either Cd(2+) or TEA, but inhibited by 4-AP, which induced an additional, slow component, sensitive to Cd(2+) or apamin (100 nM). The AP delay showed a discontinuous relation to the amplitude or slope of the injected current (delay shift), which was sensitive to low doses of 4-AP (0. 05 mM). The initial time window before the delay shift was longer than the rise time of EPSPs. It is suggested that a 4-AP-sensitive current prevents or postpones discharge during slow depolarization's, but allows direct excitation by fast EPSPs. Fast excitation leads to AP attenuation, primarily due to strong activation of 4-AP-sensitive current. This seems to cause inhibition of the Ca(2+) current during the AP and reduction of Ca(2+)-dependent K(+) currents. Together, these properties are likely to influence the excitability and the local, somatodendritic effects of the AP, in a manner that discriminates between firing induced by the intrinsic pacemaker mechanism and fast synaptic potentials.
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Affiliation(s)
- S Nedergaard
- Department of Physiology, University of Aarhus, DK-8000 Aarhus C, Denmark
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Kitai ST, Shepard PD, Callaway JC, Scroggs R. Afferent modulation of dopamine neuron firing patterns. Curr Opin Neurobiol 1999; 9:690-7. [PMID: 10607649 DOI: 10.1016/s0959-4388(99)00040-9] [Citation(s) in RCA: 179] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In recent studies examining the modulation of dopamine (DA) cell firing patterns, particular emphasis has been placed on excitatory afferents from the prefrontal cortex and the subthalamic nucleus. A number of inconsistencies in recently published reports, however, do not support the contention that tonic activation of NMDA receptors is the sole determinate of DA neuronal firing patterns. The results of work on the basic mechanism of DA firing and the action of apamin suggest that excitatory projections to DA neurons from cholinergic and glutamatergic neurons in the tegmental pedunculopontine nucleus, and/or inhibitory GABAergic projections, are also involved in modulating DA neuron firing behavior.
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Affiliation(s)
- S T Kitai
- Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee, Memphis, TN 38163, USA
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Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J Neurosci 1999. [PMID: 10234004 DOI: 10.1523/jneurosci.19-10-03723.1999] [Citation(s) in RCA: 212] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Excitatory inputs to the ventral tegmental area (VTA) influence the activity of both dopaminergic (DA) and GABAergic (GABA) cells, yet little is known about the basic properties of excitatory synapses on these two cell types. Using a midbrain slice preparation and whole-cell recording techniques, we found that excitatory synapses on DA and GABA cells display several differences. Synapses on DA cells exhibit a depression in response to repetitive activation, are minimally affected by the GABAB receptor agonist baclofen, and express NMDA receptor-dependent long-term potentiation (LTP). In contrast, synapses on GABA cells exhibit a facilitation in response to repetitive activation, are depressed significantly by baclofen, and do not express LTP. The relative contribution of NMDA and non-NMDA receptors to the synaptic currents recorded from the two cell types is the same as is the depression of synaptic transmission elicited by the application of adenosine, serotonin, or methionine enkephalin (met-enkephalin). The significant differences in the manner in which excitatory synaptic inputs to DA and GABA cells in the VTA can be modulated have potentially important implications for understanding the behavior of VTA neurons during normal behavior and during pathological states such as addiction.
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Abstract
GABAergic neurons in the ventral tegmental area (VTA) play a primary role in local inhibition of mesocorticolimbic dopamine (DA) neurons but are not physiologically or anatomically well characterized. We used in vivo extracellular and intracellular recordings in the rat VTA to identify a homogeneous population of neurons that were distinguished from DA neurons by their rapid-firing, nonbursting activity (19.1 +/- 1.4 Hz), short-duration action potentials (310 +/- 10 microseconds), EPSP-dependent spontaneous spikes, and lack of spike accommodation to depolarizing current pulses. These non-DA neurons were activated both antidromically and orthodromically by stimulation of the internal capsule (IC; conduction velocity, 2.4 +/- 0.2 m/sec; refractory period, 0.6 +/- 0.1 msec) and were inhibited by stimulation of the nucleus accumbens septi (NAcc). Their firing rate was moderately reduced, and their IC-driven activity was suppressed by microelectrophoretic application or systemic administration of NMDA receptor antagonists. VTA non-DA neurons were recorded intracellularly and showed relatively depolarized resting membrane potentials (-61.9 +/- 1.8 mV) and small action potentials (68.3 +/- 2.1 mV). They were injected with neurobiotin and shown by light microscopic immunocytochemistry to be multipolar cells and by electron microscopy to contain GABA but not the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH). Neurobiotin-filled dendrites containing GABA received asymmetric excitatory-type synapses from unlabeled terminals and symmetric synapses from terminals that also contained GABA. These findings indicate that VTA non-DA neurons are GABAergic, project to the cortex, and are controlled, in part, by a physiologically relevant NMDA receptor-mediated input from cortical structures and by GABAergic inhibition.
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35
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Kiyatkin EA, Rebec GV. Heterogeneity of ventral tegmental area neurons: single-unit recording and iontophoresis in awake, unrestrained rats. Neuroscience 1998; 85:1285-309. [PMID: 9681963 DOI: 10.1016/s0306-4522(98)00054-2] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Single-unit recording combined with iontophoresis of dopamine, GABA, and glutamate was used in awake, unrestrained rats to characterize the electrophysiological and receptor properties of neurons in the ventral tegmental area under naturally occurring behavioural conditions. All isolated ventral tegmental area units (n=90) were analysed and compared with cells (n=58) recorded from dorsally adjacent areas of the pre-rubral area and red nucleus. Two distinct neuronal groups were identified in the ventral tegmental area: units with triphasic, long-duration spikes (78/90) and units with biphasic, short-duration spikes (12/90). Although all long-spike units discharged in an irregular, bursting pattern with varying degrees of within-burst decrements in spike amplitude, they could be further subdivided into at least three distinct subgroups. Type I long-spike units (36/78) discharged at a relatively slow and stable rate (mean: 6.03 imp/s; range: 0.42-15.78) with no evident fluctuations during movement. These cells were inhibited by dopamine and GABA and responded to glutamate with a low-magnitude excitation accompanied by a pronounced decrement in spike amplitude and a powerful rebound inhibition. Type II long-spike units (23/78) had relatively high and unstable discharge rates (mean: 22.82 imp/s; range: 4.42-59.67) and showed movement-related phasic activations frequently followed by partial or complete cessation of firing. Some Type II cells (4/9) were inhibited by dopamine, but all were excited by glutamate at very low currents (0-10 nA). With an increase in current, the glutamate-induced excitation often (18/22) progressed into a cessation of firing. All these cells were inhibited by GABA followed by a strong rebound excitation (8/9), which also frequently (6/8) resulted in cessation of firing. Type III long-spike units (19/78) had properties that differed from either Type I or Type II cells, including a lack of spontaneous firing (5/19). Short-spike ventral tegmental area units were either silent (4/12) and unresponsive to dopamine and GABA or spontaneously active (range: 0.89-34.13 imp/s) and inhibited by GABA and, in some cases (2/8). by dopamine; all were phasically activated during movement and glutamate iontophoresis. It appears that ventral tegmental area neurons, including those with long-duration spikes, do not comprise a uniform population in awake, unrestrained rats. Type I, long-spike units match the characteristics of histochemically-identified dopamine neurons, and they appear to express dopamine autoreceptors, which may explain the relatively slow, stable rate of activity and the limited responsiveness to excitatory inputs. Although the nature of the other long-spike units in our sample is unclear, they may include dopamine neurons without autoreceptors as well as non-dopamine cells. The heterogeneity of ventral tegmental area neurons is an important consideration for further attempts to assess the role of the mesocorticolimbic dopamine system in motivated behaviour.
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Affiliation(s)
- E A Kiyatkin
- Department of Psychology, Indiana University, Bloomington 47405, USA
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36
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David V, Durkin TP, Cazala P. Rewarding effects elicited by the microinjection of either AMPA or NMDA glutamatergic antagonists into the ventral tegmental area revealed by an intracranial self-administration paradigm in mice. Eur J Neurosci 1998; 10:1394-402. [PMID: 9749793 DOI: 10.1046/j.1460-9568.1998.00150.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
In order to study the functional role of the trans-synaptic neuronal interaction between glutamatergic afferents and mesolimbic dopaminergic neurons in internal reward processes, BALB/c male mice were unilaterally implanted with a guide-cannula, the tip of which was positioned 1.5 mm above the ventral tegmental area (VTA). On each day of the following experimental period, a stainless steel injection cannula was inserted into the VTA in order to study the eventual self-administration behaviour of either the competitive N-methyl-D-aspartate antagonist, D(-)-2-amino-7-phosphonoheptanoic acid (AP-7) or the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) (3 ng/50 nL) using a spatial discrimination task in a Y maze. Mice rapidly discriminated between the arm enabling a microinjection of either of these glutamatergic antagonists and the neutral arm of the maze, and a robust self-administration of either of these compounds was observed from the first session of acquisition. These data provide strong evidence that the intra-VTA microinjection of either of these subclasses of glutamatergic antagonist produces an effect which is interpreted centrally by the experimental subjects as being highly rewarding. Once the self-administration response had been fully acquired by the experimental subjects, preinjection of the dopaminergic D2 antagonist, sulpiride (50 mg/kg i.p.), 30 min before the test, produced a rapid extinction of the self-administration response. This latter result demonstrates the dopaminergic D2 receptor dependence of this intra-VTA self-administration of both of these subclasses of glutamatergic antagonist. We conclude that the different glutamatergic afferent neuronal inputs to the VTA globally exert, in vivo, via the mediation of interposed endogenous GABAergic interneurons, a tonic trans-synaptic inhibitory regulation of neuronal activity in the mesolimbic dopaminergic pathway and that this complex neuronal interaction in the VTA plays a significant functional part in the modulation of internal reward processes.
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Affiliation(s)
- V David
- Laboratoire de Neurosciences Comportementales et Cognitives, CNRS URA 339, Université de Bordeaux I, Talence, France
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37
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Enrico P, Bouma M, de Vries JB, Westerink BH. The role of afferents to the ventral tegmental area in the handling stress-induced increase in the release of dopamine in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain. Brain Res 1998; 779:205-13. [PMID: 9473673 DOI: 10.1016/s0006-8993(97)01132-3] [Citation(s) in RCA: 72] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This study was aimed to identify the neuronal pathways that mediate the handling stress induced increase in the release of dopamine in the medial prefrontal cortex (mPFC) of the rat brain. For that purpose a microdialysis probe was implanted in the ventral tegmental area (VTA) and a second probe was placed in the ipsilateral mPFC. Receptor specific compounds acting on GABA(A) (20 microM muscimol), GABA(B) (50 microM baclofen), acetylcholine (100 microM atropine, 100 microM mecamylamine), NMDA (30, 100 and 300 microM CPP; 300 microM AP-5, 1 mM (+)-HA-966) and non-NMDA receptors (500 microM CNQX) were infused into the VTA by retrograde dialysis, whereas extracellular dopamine was recorded in the ipsilateral mPFC. Intrategmental infusion of muscimol, baclofen, CPP, AP-5, (+)-HA-966 and CNQX decreased extracellular dopamine in the ipsilateral mPFC; atropine and mecamylamine were without effect on the basal values. During infusion of the various compounds rats were gently handled for 15 min. The infusions of muscimol, atropine, mecamylamine and (+)-HA-966 did not modify the handling stress induced increase in extracellular dopamine in the mPFC. However, during intrategmental infusion of baclofen, CPP, AP-5 and CNQX the handling stress induced increase in extracellular dopamine (expressed as % of controls) in the mPFC was suppressed. These results indicate that a glutamatergic projection to the VTA, acting via both NMDA and non-NMDA-glutamate receptors, play a major role in the handling stress-induced increase in dopamine release in the mPFC. In addition the results suggest a certain role for GABAergic neurones, acting via GABA(B) receptors, in the handling response.
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Affiliation(s)
- P Enrico
- Institute of Pharmacology, University of Sassari, Italy
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38
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Overton PG, Clark D. Burst firing in midbrain dopaminergic neurons. BRAIN RESEARCH. BRAIN RESEARCH REVIEWS 1997; 25:312-34. [PMID: 9495561 DOI: 10.1016/s0165-0173(97)00039-8] [Citation(s) in RCA: 367] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Midbrain dopaminergic (DA) neurons fire bursts of activity in response to sensory stimuli, including those associated with primary reward. They are therefore conditional bursters - the bursts conveying, amongst other things, motivationally relevant information to the forebrain. In the forebrain, bursts give rise to a supra-additive release of dopamine, and possibly favour the release of co-localised neuropeptides. Evidence is presented that in rat DA neurons, bursts are engendered by the activity of cortically-regulated afferents. Certain factors are identified which, in combination, lead to burst production: (1) A burst of activity in EAAergic afferents to DA neurons arising from non-cortical sources, but controlled by the medial prefrontal cortex; (2) N-methyl-D-aspartate receptor activation, producing a slow depolarising wave in the recipient neuron; (3) activation of a high threshold, dendritically located calcium conductance which produces a 'plateau potential'; (4) activation of a calcium-activated potassium conductance, which terminates the burst. These factors are argued to operate in the context of an 'optimal' level of intracellular calcium buffering for bursting. Other factors which appear to be involved in bursting in other systems, in particular a low threshold calcium conductance, are rejected as being necessary for bursting in DA neurons. The factors which do play a crucial role in burst production in DA neurons are integrated into a theory from which arises a series of hypotheses amenable to empirical investigation. Additional factors are discussed which may modulate bursting. These may either act indirectly through changes in membrane potential (or intracellular calcium concentration), or they may act directly through an interaction with certain conductances, which appear to promote or inhibit burst firing in DA neurons.
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Affiliation(s)
- P G Overton
- Department of Psychology, University of Wales, Swansea, UK.
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39
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Scuvée-Moreau J, Seutin V, Vrijens B, Pirotte B, De Tullio P, Massotte L, Albert A, Delarge J, Dresse A. Effect of potassium channel openers on the firing rate of hippocampal pyramidal cells and A10 dopaminergic neurons in vitro. Arch Physiol Biochem 1997; 105:421-8. [PMID: 9439778 DOI: 10.1076/apab.105.5.421.3285] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The effect of four KATP channel openers (KCOs) on the firing rate of CA1 pyramidal cells and A10 dopaminergic neurons was investigated using extracellular recording techniques in rat brain slices. Pinacidil, lemakalim, diazoxide and a new compound, BPDZ44, had an inhibitory effect on the electrical activity of CA1 pyramidal cells. They all had a similar potency. Only BPDZ44 and diazoxide inhibited the firing rate of A10 dopamine neurons. The sulfonylurea glipizide (1 microM) antagonized the effect of BPDZ44 and diazoxide on A10 neurons but failed to antagonize the effect of KCOs on CA1 pyramidal cells. These results show that differences exist among KCOs in their ability to decrease the electrical activity of various populations of central neurons.
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Affiliation(s)
- J Scuvée-Moreau
- Laboratory of Pharmacology, University of Liège, Sart-Tilman, Belgium
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40
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Meltzer LT, Christoffersen CL, Serpa KA. Modulation of dopamine neuronal activity by glutamate receptor subtypes. Neurosci Biobehav Rev 1997; 21:511-8. [PMID: 9195610 DOI: 10.1016/s0149-7634(96)00030-9] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In vitro and in vivo electrophysiological studies have been used to assess the effects of glutamate, as well as specific agonists and antagonists for ionotropic, N-methyl-D-aspartate (NMDA), (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate, and metabotropic subtypes of the glutamate receptor, on the neuronal firing activity of midbrain, substantia nigra zona compacta (A9) and ventral tegmental area (A10), dopamine neurons. In in vitro experiments, agonists for all glutamate receptor subtypes depolarize the membrane and increase firing rate. In in vivo experiments, iontophoretic application of these agonists increases the firing rate and induces burst-firing. Studies with subtype selective antagonists suggest that a tonic glutamate tone, acting via NMDA receptors, may modulate the firing activity of some dopamine neurons. Glutamatergic afferents from the subthalamus, pedunculopontine nucleus and frontal cortex can modulate the firing activity of dopamine neurons. The role(s) of the different glutamate receptor subtypes and pathways in mediating the physiological and pathological effects on dopamine systems is an area for further investigation.
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Affiliation(s)
- L T Meltzer
- Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI 48105, USA
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41
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Meltzer LT, Serpa KA, Christoffersen CL. Metabotropic glutamate receptor-mediated inhibition and excitation of substantia nigra dopamine neurons. Synapse 1997; 26:184-93. [PMID: 9131777 DOI: 10.1002/(sici)1098-2396(199706)26:2<184::aid-syn9>3.0.co;2-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Microiontophoretic drug application and extracellular recording techniques were used to evaluate the effects of the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate(1S,3R-ACPD) on dopamine (DA) neurons in the substantia nigra zona compacta (SNZC) of chloral hydrate-anesthetized rats. 1S,3R-ACPD had a biphasic effect on the firing rate of DA cells, initially decreasing, then increasing the firing rate. 1S,3R-ACPD also increased the burst-firing activity of DA neurons. Application of the ionotropic receptor (iGluR) agonists (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) increased the firing rates of neurons which had responded to 1S,3R-ACPD, indicating that mGluRs and iGluRs reside on the same neurons. The initial inhibitory period was not antagonized by systemic haloperidol or iontophoretic bicuculline, indicating a lack of DA or gamma-amino-n-butyric acid (GABA) involvement in this effect. Combined application of the AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), and the NMDA antagonist, (I)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP), at currents which antagonized AMPA and NMDA, did not antagonize either the inhibitory or excitatory effects of 1S,3R-ACPD. Application of the metabotropic antagonist (S)-4-carboxy-phenylglycine antagonized both the inhibitory and excitatory effects of 1S,3R-ACPD. These results indicate that mGluRs may play a role in the modulation of dopaminergic activity in the SNZC.
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Affiliation(s)
- L T Meltzer
- Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, Michigan 48105, USA
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42
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Mereu G, Lilliu V, Casula A, Vargiu PF, Diana M, Musa A, Gessa GL. Spontaneous bursting activity of dopaminergic neurons in midbrain slices from immature rats: role of N-methyl-D-aspartate receptors. Neuroscience 1997; 77:1029-36. [PMID: 9130784 DOI: 10.1016/s0306-4522(96)00474-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Dopamine neurons in midbrain coronal slices from adult rats (40-70 days old) discharged only in pacemaker-like mode. Irregular or bursting mode was never observed. In contrast, dopamine neurons in slices from immature rats (15-21 days old) exhibited not only pacemaker-like firing (53.4% of neurons), but also irregular and bursting patterns (28.3 and 18.3%, respectively). Glutamate and kainate increased the firing rate but failed to induce bursts in dopamine neurons from either adult or immature rats. N-Methyl-D-aspartate augmented the firing rate in all neurons from adult rats and produced a modest increase of bursts in only three out of 18 cells. In slices from immature rats, N-methyl-D-aspartate activated the discharge rate in all neurons and also induced bursts in 37 and 53% of pacemaker and irregular neurons, respectively, and increased the occurrence of spikes in bursts in 76% of spontaneously bursting neurons. The selective N-methyl-D-aspartate receptor antagonist (+/-)2-amino,5-phosphonopentanoic acid prevented N-methyl-D-aspartate-induced changes and also reduced spontaneous bursts, suggesting that bursting discharge is mediated by N-methyl-D-aspartate receptor activation. While pacemaker neurons from immature and from adult rats exhibited the same sensitivity to N-methyl-D-aspartate-induced stimulation of firing rate, spontaneously bursting neurons were more sensitive than pacemaker neurons from either immature or adult rats. The present study indicates that spontaneous bursting, dependent on N-methyl-D-aspartate receptor activation, is present, and may be induced, in dopamine neurons in slices from immature rats. Its absence from cells in slices from adult rats may reflect a reduced sensitivity of N-methyl-D-aspartate receptors on dopamine or the loss of the N-methyl-D-aspartate-activated burst generator.
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Affiliation(s)
- G Mereu
- Department of Experimental Biology, B. Loddo, University of Cagliari, Italy
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43
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AMPA and NMDA glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey: an immunohistochemical and in situ hybridization study. J Neurosci 1997. [PMID: 9006980 DOI: 10.1523/jneurosci.17-04-01377.1997] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The objective of the present study was to analyze the cellular and subcellular localization of ionotropic glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey. This was achieved by means of immunohistochemistry at light and electron microscopic levels and in situ hybridization histochemistry. Colocalization studies show that nearly all dopaminergic neurons in both the ventral and dorsal tiers of the substantia nigra compacta (SNc-v, SNc-d) and the ventral tegmental area (VTA) are immunoreactive for AMPA (GluR1, GluR2/3, and GluR4) and NMDAR1 receptor subunits, but not for NMDAR2A/B subunits. The immunoreactivity of the receptor subunits is associated mainly with perikarya and dendritic shafts. Apart from the intensity of immunolabeling for the GluR4 subunit, which is quite similar for the different groups of midbrain dopaminergic neurons, the overall intensity of immunostaining for the other subunits is higher in the SNc-v and SNc-d than in the VTA. In line with these observations, in situ hybridization shows that the average level of labeling for the GluR2 and NMDAR1 subunit mRNAs is significantly higher in the SNc-v than in the VTA, and for the NMDAR1 subunit, higher in the SNc-v than in the SNc-d. In contrast, no significant difference was found for the level of GluR1 mRNA labeling among the three groups of midbrain dopaminergic neurons. At the subcellular level in the SNc-v, AMPA (GluR1 and GluR2/3) and NMDAR1 receptor subunit immunoreactivity is preferentially associated with the postsynaptic densities of asymmetric synapses, but occasionally some immunoreactivity is found along nonsynaptic portions of plasma membranes of dendrites. A small number of preterminal axons, axon terminals, and glial cell processes are also immunoreactive. Our observations indicate that the different groups of midbrain dopaminergic neurons in primates exhibit a certain degree of heterogeneity with regard to the level of expression of some ionotropic glutamate receptor subunits. The widespread neuronal and glial localization of glutamate receptor subunits suggests that excitatory amino acids may act at different levels to control the basal activity and, possibly, to participate in the degeneration of midbrain dopaminergic neurons in Parkinson's disease.
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44
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Andrés ME, Gysling K, Araneda S, Venegas A, Bustos G. NMDA-NR1 receptor subunit mRNA expression in rat brain after 6-OH-dopamine induced lesions: a non-isotopic in situ hybridization study. J Neurosci Res 1996; 46:375-84. [PMID: 8933377 DOI: 10.1002/(sici)1097-4547(19961101)46:3<375::aid-jnr11>3.0.co;2-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Antisense digoxigenin-labeled deoxyoligonucleotides probes and non-isotopic in situ hybridization (HIS) techniques have been used to explore the NMDA-NR1 receptor subunit mRNA distribution in different brain areas of rats which had their dopaminergic nigrostriatal pathway previously lesioned with intracerebral administration of 6-OH-dopamine (6-OH-DA). Intense and significant hybridization signals for NR1 mRNA were found in dentate gyrus and regions CA1-CA2-CA3 of the hippocampus, in layers II-III and V-VI of the cerebral cortex, and in the cerebellum of sham-treated rats. Basal ganglia structures such as the striatum exhibited few NR1 mRNA hybridization signals as compared to the hippocampus and cerebral cortex. In contrast, both zona compacta and reticulata of substantia nigra (SN) showed a reduced number of cells with nevertheless intense NR1 mRNA HIS signals. The NR1 mRNA distribution in the brain was affected in a brain regional selective manner by 6-OH-DA induced lesions of DA neuronal systems. A striking increase in NR1 mRNA HIS signals was observed in both striata after unilateral lesioning with 6-OH-DA. Instead, in SN compacta but not in reticulata, a moderate but significant bilateral reduction of NR1 mRNA was observed after unilateral 6-OH-DA injection. No significant changes in NR1 mRNA were detected in cerebral cortex and other brain regions after 6-OH-DA treatment. These studies, and others reported in the literature, support the view that extensive lesions of nigrostriatal DA-containing neurons in the brain may trigger compensatory or adaptative responses in basal ganglia structures such as striatum and substantia nigra which involve glutamateric neurons and the genic expression of NMDA receptors.
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Affiliation(s)
- M E Andrés
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile
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45
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Overton PG, Tong ZY, Clark D. A pharmacological analysis of the burst events induced in midbrain dopaminergic neurons by electrical stimulation of the prefrontal cortex in the rat. J Neural Transm (Vienna) 1996; 103:523-40. [PMID: 8811499 DOI: 10.1007/bf01273151] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Electrical stimulation of the prefrontal cortex produces an inhibition-excitation (IE) activity pattern in the majority of responsive midbrain dopaminergic neurons. The excitatory phase often contains events, time-locked to the stimulation, which resemble natural bursts. The present study investigated the relationship between the inhibition and time-locked bursts by reducing the impact of the inhibition through membrane hyperpolarisation with the dopamine agonist apomorphine (i.v.) or antagonism with the GABAA antagonist picrotoxin (i.v. and iontophoretic). Apomorphine abolished or reduced time-locked bursting in all IE cells. Picrotoxin reduced the initial inhibition in the majority of IE cells, and abolished or reduced time-locked bursting at the highest intravenous dose. However, reductions in the initial inhibition were not systematically related to reductions in time-locked bursting. Hence, the phenomena do not appear to be causally related. Instead, time-locked bursts appear to be based on a straightforward excitation, which makes them closely analogous to natural bursts.
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Affiliation(s)
- P G Overton
- Department of Psychology, University of Wales, Swansea, United Kingdom
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46
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Tong ZY, Overton PG, Clark D. Stimulation of the prefrontal cortex in the rat induces patterns of activity in midbrain dopaminergic neurons which resemble natural burst events. Synapse 1996; 22:195-208. [PMID: 9132987 DOI: 10.1002/(sici)1098-2396(199603)22:3<195::aid-syn1>3.0.co;2-7] [Citation(s) in RCA: 139] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Evidence suggests that excitatory amino acid-containing afferents from the prefrontal cortex (PFC) play an important role in the induction of burst firing in midbrain dopaminergic (DA) neurons. In the present study, the extracellular activity of individual DA neurons (A10 and A9 cell groups) was recorded during single pulse electrical stimulation (0.25 and 1 mA) of the PFC. The majority of cells were responsive, and two main patterns of activity were elicited: responses characterised by an initial excitation (E responses; 41.8% of responses at 0.25 mA and 26.6% at 1 mA; cell groups combined) and responses characterised by excitation following an initial inhibition (IE responses; 43.3% of responses at 0.25 mA and 56.6% at 1 mA; cell groups combined). Burst analysis performed on the excitatory phase of E and IE responses revealed that the excitation contained events which fulfilled the criteria for natural bursts in DA neurons. A procedure was developed for assessing whether these bursts were time-locked to the stimulus. This showed that 27.9% of E responses and 33.3% of IE responses were accompanied by time-locked bursts (currents and cell groups combined). It is argued that time-locked bursts during IE responses were produced by rebound activation of a low threshold calcium conductance, whereas time-locked bursts during E responses were produced by excitatory afferents. Since natural bursts in DA neurons also seem to involve cortically induced excitation, the hypothesis that the PFC plays a role in the production of natural bursts in DA neurons is strengthened.
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Affiliation(s)
- Z Y Tong
- Department of Psychology and Centre for Substance Abuse Research, University of Wales, Swansea, United Kingdom
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Charara A, Smith Y, Parent A. Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry. J Comp Neurol 1996; 364:254-66. [PMID: 8788248 DOI: 10.1002/(sici)1096-9861(19960108)364:2<254::aid-cne5>3.0.co;2-4] [Citation(s) in RCA: 205] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
To verify the possibility that the pedunculopontine nucleus is a source of glutamatergic terminals in contact with midbrain dopaminergic neurons in the squirrel monkey, we used the anterograde transport of Phaseolus vulgaris-leucoagglutinin in combination with preembedding immunohistochemistry for tyrosine hydroxylase and for calbindin D-28k and postembedding immunocytochemistry for glutamate and for gamma-aminobutyric acid. Following tracer injections in the pedunculopontine nucleus, numerous anterogradely labeled fibers emerged from the injection sites to innervate densely the pars compacta of the substantia nigra and ventral tegmental area. The major type of labeled fibers were thin with multiple collaterals and varicosities that established intimate contacts with midbrain dopaminergic neurons. At the electron microscopic level, the anterogradely labeled boutons were medium sized (maximum diameter between 0.9 microns and 2.5 microns) and contained numerous round vesicles and mitochondria. Postembedding immunocytochemistry revealed that 40-60% of anterogradely labeled terminals were enriched in glutamate and formed asymmetric synapses with dendritic shafts of substantia nigra and ventral tegmental area neurons. In triple-immunostained sections, some of the postsynaptic targets to these terminals were found to be dopaminergic. In addition, 30-40% of the anterogradely labeled terminals in both regions displayed immunoreactivity for gamma-aminobutyric acid and, in some cases, formed symmetric synapses with dendritic shafts. In conclusion, our results provide the first ultrastructural evidence for the existence of synaptic contacts between glutamate-enriched terminals from the pedunculopontine nucleus and midbrain dopaminergic neurons in primates. Our results also show that the pedunculopontine nucleus is a potential source of gamma-aminobutyric acid input to this region. These findings suggest that the pedunculopontine nucleus may play an important role in the modulation of the activity of midbrain dopaminergic cells by releasing glutamate or gamma-aminobutyric acid as neurotransmitter.
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Affiliation(s)
- A Charara
- Centre de Recherche en Neurobiologie, Hôpital de l'Enfant-Jésus and Université Laval, Québec, Canada
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Hutson PH, Hogg JE. Effects of and interactions between antagonists for different sites on the NMDA receptor complex on hippocampal and striatal acetylcholine efflux in vivo. Eur J Pharmacol 1996; 295:45-52. [PMID: 8925873 DOI: 10.1016/0014-2999(95)00634-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Intraperitoneal administration of the non-competitive NMDA receptor antagonists (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801, 0.25 and 0.5 mg/kg) and 1-(1-phenylcyclohexyl)piperidine (PCP, 5 and 10 mg/kg) increased the extracellular concentration of acetylcholine in rat hippocampus but not striatum. In contrast, R-(+)-3-amino-1-hydroxypyrrolid-2-one (R(+)-HA-966, 30 and 60 mg/kg), an antagonist at the glycine modulatory site of the NMDA receptor, did not affect acetylcholine efflux in either region. (+/-)-3-[2-Carboxypiperazin-4-yl]-propyl-1-phosphonic acid ((+/-)CPP, 10 mg/kg) and cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS19755, 5 mg/kg), competitive antagonists at the glutamate agonist site of the NMDA receptor, marginally increased hippocampal acetylcholine efflux. Pretreatment with R(+)-HA-966 (60 mg/kg) or (+/-)CPP (10 mg/kg) attenuated the increase of hippocampal acetylcholine efflux by MK-801 (0.5 mg/kg). However, prior administration of CGS19755 (5 mg/kg) prolonged the MK-801-induced increase of hippocampal acetylcholine efflux. Results demonstrate differential effects on hippocampal and striatal acetylcholine efflux of antagonists at different sites on the NMDA receptor complex and are discussed in relation to previously described effects of these drugs on mesolimbic dopamine function.
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Affiliation(s)
- P H Hutson
- Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK
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Phillips TJ, Shen EH. Neurochemical bases of locomotion and ethanol stimulant effects. INTERNATIONAL REVIEW OF NEUROBIOLOGY 1996; 39:243-82. [PMID: 8894850 DOI: 10.1016/s0074-7742(08)60669-8] [Citation(s) in RCA: 154] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The locomotor stimulant effect produced by alcohol (ethanol) is one of a large number of measurable ethanol effects. Ethanol-induced euphoria in humans and locomotor stimulation in rodents, a potential animal model of human euphoria, have long been recognized and the latter has been extensively characterized. Since the euphoria produced by ethanol may influence the development of uncontrolled or excessive alcohol use, a solid understanding of the neurochemical substrates underlying such effects is important. Such an understanding for spontaneous locomotion and for ethanol's stimulant effects is beginning to emerge. Herein we review what is known about three neurochemical substrates of locomotion and of ethanol's locomotor stimulant effects. Several lines of research have implicated dopaminergic, GABAergic, and glutamatergic neurotransmitter systems in determining these behaviors. A large collection of work is cited, which strongly implicates the above-mentioned neurotransmitter substances in the control of spontaneous locomotion. A smaller, but persuasive, body of evidence suggests that central nervous system processes utilizing these transmitters are involved in determining the effects of ethanol on locomotion. Particular emphasis has been placed on the mesolimbic ventral tegmental area to nucleus accumbens dopaminergic pathway, and on the ventral pallidum/substantia innominata, where GABA and glutamate have been found to play a role in altering the activity of this dopaminergic pathway. Research on ethanol and drug locomotor sensitization, increased responsiveness to the substance with repeated administration, is also reviewed as a process that may be important in the development of drug addiction.
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Affiliation(s)
- T J Phillips
- Department of Veterans Affairs Medical Center, Oregon Health Sciences University, Portland 97201, USA
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Tong ZY, Overton PG, Clark D. Antagonism of NMDA receptors but not AMPA/kainate receptors blocks bursting in dopaminergic neurons induced by electrical stimulation of the prefrontal cortex. J Neural Transm (Vienna) 1996; 103:889-904. [PMID: 9013383 DOI: 10.1007/bf01291780] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Evidence suggests that the prefrontal cortex (PFC) plays an important role in the burst activity of midbrain dopaminergic (DA) neurons. In particular, electrical stimulation of the PFC elicits patterns of activity in DA neurons, closely time-locked to the stimulation, which resemble natural bursts. Given that natural bursts are produced by the activity of excitatory amino acid (EAA)-ergic afferents, if PFC-induced time-locked bursts are homologues of natural bursts, EAA antagonists should attenuate them. Hence, the NMDA (N-methyl-D-aspartate) antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) and the AMPA (D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid)/kainate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) were applied by iontophoresis to DA neurons exhibiting time-locked bursts during PFC stimulation. CPP produced a significant reduction in time-locked bursting. In contrast, CNQX (at currents which antagonised AMPA responses) did not. These effects of CPP and CNQX on time-locked bursting mirror the effects previously reported for these drugs on natural bursting. Since natural bursting and bursting induced by PFC stimulation are both blocked selectively by CPP, the present results increase the degree of analogy between the two burst phenomena, thereby adding extra support to the contention that the cortex is involved in producing the natural bursting in DA neurons.
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Affiliation(s)
- Z Y Tong
- Department of Psychology, University of Wales, Swansea, United Kingdom
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