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Keller BN, Hajnal A, Browning KN, Arnold AC, Silberman Y. Involvement of the Dorsal Vagal Complex in Alcohol-Related Behaviors. Front Behav Neurosci 2022; 16:801825. [PMID: 35330845 PMCID: PMC8940294 DOI: 10.3389/fnbeh.2022.801825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/19/2022] [Indexed: 12/20/2022] Open
Abstract
The neurobiological mechanisms that regulate the development and maintenance of alcohol use disorder (AUD) are complex and involve a wide variety of within and between systems neuroadaptations. While classic reward, preoccupation, and withdrawal neurocircuits have been heavily studied in terms of AUD, viable treatment targets from this established literature have not proven clinically effective as of yet. Therefore, examination of additional neurocircuitries not classically studied in the context of AUD may provide novel therapeutic targets. Recent studies demonstrate that various neuropeptides systems are important modulators of alcohol reward, seeking, and intake behaviors. This includes neurocircuitry within the dorsal vagal complex (DVC), which is involved in the control of the autonomic nervous system, control of intake of natural rewards like food, and acts as a relay of interoceptive sensory information via interactions of numerous gut-brain peptides and neurotransmitter systems with DVC projections to central and peripheral targets. DVC neuron subtypes produce a variety of neuropeptides and transmitters and project to target brain regions critical for reward such as the mesolimbic dopamine system as well as other limbic areas important for the negative reinforcing and aversive properties of alcohol withdrawal such as the extended amygdala. This suggests the DVC may play a role in the modulation of various aspects of AUD. This review summarizes the current literature on neurotransmitters and neuropeptides systems in the DVC (e.g., norepinephrine, glucagon-like peptide 1, neurotensin, cholecystokinin, thyrotropin-releasing hormone), and their potential relevance to alcohol-related behaviors in humans and rodent models for AUD research. A better understanding of the role of the DVC in modulating alcohol related behaviors may lead to the elucidation of novel therapeutic targets for drug development in AUD.
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Ballaz S, Espinosa N, Bourin M. Does endogenous cholecystokinin modulate alcohol intake? Neuropharmacology 2021; 193:108539. [PMID: 33794246 DOI: 10.1016/j.neuropharm.2021.108539] [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: 12/07/2020] [Revised: 02/06/2021] [Accepted: 03/22/2021] [Indexed: 02/08/2023]
Abstract
Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK1 and CCK2. Genetic evidence relates CCK1 receptors to alcoholism in humans. CCK2 activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT3 receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the "dimmer-switch" function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.
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Affiliation(s)
- Santiago Ballaz
- School of Biological Sciences & Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí, Ecuador; School of Medicine, Universidad Espíritu Santo, Samborondón, Ecuador.
| | - Nicole Espinosa
- School of Biological Sciences & Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí, Ecuador.
| | - Michel Bourin
- Neurobiology of Anxiety and Mood Disorders, University of Nantes, 98, Rue Joseph Blanchart, 44100 Nantes, France.
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Voigt JP, Fink H. Serotonin controlling feeding and satiety. Behav Brain Res 2015; 277:14-31. [PMID: 25217810 DOI: 10.1016/j.bbr.2014.08.065] [Citation(s) in RCA: 192] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 08/14/2014] [Accepted: 08/19/2014] [Indexed: 02/06/2023]
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Engster KM, Frommelt L, Hofmann T, Nolte S, Fischer F, Rose M, Stengel A, Kobelt P. Peripheral injected cholecystokinin-8S modulates the concentration of serotonin in nerve fibers of the rat brainstem. Peptides 2014; 59:25-33. [PMID: 25017242 DOI: 10.1016/j.peptides.2014.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/02/2014] [Accepted: 07/02/2014] [Indexed: 02/05/2023]
Abstract
Serotonin and cholecystokinin (CCK) play a role in the short-term inhibition of food intake. It is known that peripheral injection of CCK increases c-Fos-immunoreactivity (Fos-IR) in the nucleus of the solitary tract (NTS) in rats, and injection of the serotonin antagonist ondansetron decreases the number of c-Fos-IR cells in the NTS. This supports the idea of serotonin contributing to the effects of CCK. The aim of the present study was to elucidate whether peripherally injected CCK-8S modulates the concentration of serotonin in brain feeding-regulatory nuclei. Ad libitum fed male Sprague-Dawley rats received 5.2 and 8.7 nmol/kg CCK-8S (n=3/group) or 0.15M NaCl (n=3-5/group) injected intraperitoneally (ip). The number of c-Fos-IR neurons, and the fluorescence intensity of serotonin in nerve fibers were assessed in the paraventricular nucleus (PVN), arcuate nucleus (ARC), NTS and dorsal motor nucleus of the vagus (DMV). CCK-8S increased the number of c-Fos-ir neurons in the NTS (mean±SEM: 72±4, and 112±5 neurons/section, respectively) compared to vehicle-treated rats (7±2 neurons/section, P<0.05), but did not modulate c-Fos expression in the DMV or ARC. Additionally, CCK-8S dose-dependently increased the number of c-Fos-positive neurons in the PVN (218±15 and 128±14, respectively vs. 19±5, P<0.05). In the NTS and DMV we observed a decrease of serotonin-immunoreactivity 90 min after injection of CCK-8S (46±2 and 49±8 pixel/section, respectively) compared to vehicle (81±8 pixel/section, P<0.05). No changes of serotonin-immunoreactivity were observed in the PVN and ARC. Our results suggest that serotonin is involved in the mediation of CCK-8's effects in the brainstem.
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Affiliation(s)
- Kim-Marie Engster
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany
| | - Lisa Frommelt
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany
| | - Tobias Hofmann
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany
| | - Sandra Nolte
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany
| | - Felix Fischer
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany
| | - Matthias Rose
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany
| | - Andreas Stengel
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany
| | - Peter Kobelt
- Medical Clinic, Department of Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Germany.
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Asarian L. Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors. Am J Physiol Regul Integr Comp Physiol 2009; 296:R51-6. [DOI: 10.1152/ajpregu.90655.2008] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
To investigate the role of serotonin 2C receptors (2CR), which are expressed only in the central nervous system, in the satiating actions of the gut peptides CCK and glucagon-like peptide 1 (GLP-1), we examined 1) the effect of null mutations of serotonin 2CR (2CR KO) on the eating-inhibitory potencies of dark-onset intraperitoneal injections of 0.9, 1.7, or 3.5 nmol/kg (1, 2, or 4 μg/kg) CCK and 100, 200, and 400 nmol/kg (33, 66, or 132 μg/kg) GLP-1, and 2) the effects of intraperitoneal injections of 1.7 nmol//kg CCK and 100 nmol/kg GLP-1 on neuronal activation in the brain, as measured by c-Fos expression. All CCK and GLP-1 doses decreased 30-min food intake in wild-type (WT) mice, but none of them did in 2CR KO mice. CCK increased the number of cells expressing c-Fos in the nucleus tractus solitarii (NTS) of WT, but not 2CR KO mice. CCK induced similar degrees of c-Fos expression in the paraventricular (PVN) and arcuate (Arc) nuclei of the hypothalamus of both genotypes. GLP-1, on the other hand, increased c-Fos expression similarly in the NTS of both genotypes and increased c-Fos expression more in the PVN and Arc of 2CR KO mice, but not WT mice. These results indicate that serotonin signaling via serotonin 2CR is necessary for the full satiating effects of CCK and GLP-1. In addition, they suggest that the satiating effects of the two peptides are mediated by different neural mechanisms.
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White CL, Ishihara Y, York DA, Bray GA. Effect of meta-chlorophenylpiperazine and cholecystokinin on food intake of Osborne-Mendel and S5B/P1 rats. Obesity (Silver Spring) 2007; 15:624-31. [PMID: 17372312 DOI: 10.1038/oby.2007.579] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To investigate whether there is a difference in sensitivity to a serotonin agonist, meta-chlorophenylpiperazine (mCPP), or cholecystokinin (CCK-8), an intestinal hormone that inhibits food intake, between the Osborne-Mendel (OM) rat, which becomes obese eating a high-fat diet, and the S5B/Pl (S5B) rat, which is resistant to dietary-induced obesity. RESEARCH METHODS AND PROCEDURES OM and S5B rats were adapted to either a high-saturated-fat diet (56% energy as fat) or a low-fat diet (10% energy as fat) or to both for 14 days and then treated with several doses of mCPP or CCK-8. RESULTS Treatment with mCPP reduced food intake in both strains of rats. The dose-response curve showed that the OM rats had an increased sensitivity to the serotonergic agonist. Animals eating the high-fat diet had less response to mCPP; and in the S5B rats, the response was significantly reduced. After treatment with CCK-8, there was a similar dose-related suppression of food intake in both the OM and S5B rats. DISCUSSION These data are consistent with the hypothesis that the serotonin system in the S5B rat has a greater activity that could act to inhibit fat intake. The response to CCK was not significantly affected by strain or diet.
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Affiliation(s)
- Christy L White
- Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
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Chua ASB, Keeling PWN, Dinan TG. Role of cholecystokinin and central serotonergic receptors in functional dyspepsia. World J Gastroenterol 2006; 12:1329-35. [PMID: 16552797 PMCID: PMC4124306 DOI: 10.3748/wjg.v12.i9.1329] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Symptoms of functional dyspepsia are characterized by upper abdominal discomfort or pain, early satiety, postprandial fullness, bloating, nausea and vomiting. It is a chronic disorder, with symptoms more than 3 mo per year, and no evidence of organic diseases. Dysfunctional motility, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. It is believed that these pathophysiological mechanisms interact to produce the observed symptoms. Dyspepsia has been categorized into three subgroups based on dominant symptoms. Dysmotility-like dyspepsia describes a subgroup of patients whose symptom complex is usually related to a gastric sensorimotor dysfunction. The brain-gut peptide cholecystokinin (CCK) and serotonin (5-HT) share certain physiological effects. Both have been shown to decrease gastric emptying and affect satiety. Furthermore the CCK induced anorexia depended on serotonergic functions probably acting via central pathways. We believe that abnormalities of central serotonergic receptors functioning together with a hyper responsiveness to CCK or their interactions may be responsible for the genesis of symptoms in functional dyspepsia (FD).
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Hayes MR, Savastano DM, Covasa M. Cholecystokinin-induced satiety is mediated through interdependent cooperation of CCK-A and 5-HT3 receptors. Physiol Behav 2004; 82:663-9. [PMID: 15327914 DOI: 10.1016/j.physbeh.2004.06.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2003] [Revised: 04/15/2004] [Accepted: 06/01/2004] [Indexed: 10/26/2022]
Abstract
Recent evidence supports a role for the serotonin-3 (5-HT3) receptors in the modulation of cholecystokinin (CCK)-induced satiation. Likewise, 5-HT's anorectic response has been linked to recruitment of peripheral CCK-A receptors. Evidence to date, however, does not elucidate whether there is a concomitant interaction between CCK-A and 5-HT3 receptors or whether each receptor functions independently in the negative feedback control of food intake elicited by CCK. In the present study, we used selective receptor antagonists to investigate the roles of CCK-A and 5-HT3 receptors in CCK-induced satiation. Intraperitoneal administration of CCK-8 reduced 30-min 15% sucrose intake in a dose-responsive manner. Prior treatment with ondansetron (1.0 mg/kg ip), a highly selective 5-HT3 receptor antagonist, attenuated CCK-induced suppression of food intake in a dose-responsive manner. Pretreatment with lorglumide (1.0 mg/kg ip), a selective CCK-A receptor antagonist, reversed CCK-induced inhibition of sucrose intake. Finally, simultaneous blockade of CCK-A and 5-HT3 receptors by lorglumide and ondansetron, as well as concomitant administration of the two antagonists with CCK, produced a significant synergistic increase in sucrose intake compared with intakes after administration of saline, CCK, or either antagonist alone. These findings support evidence that CCK-A and 5-HT3 receptors cooperate interdependently in control of short-term food intake. Most likely, this interconnection exists through a feed-forward parallel model arising from CCK-A and 5-HT3 receptors, where activation of one system engages the other to intensify the overall satiety signal.
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Affiliation(s)
- Matthew R Hayes
- Department of Nutritional Sciences, College of Health and Human Development, The Pennsylvania State University, 126 South Henderson, University Park, PA 16802-6504, USA.
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Zittel TT, Glatzle J, Weimar T, Kless S, Becker HD, Jehle EC. Serotonin receptor blockade increases food intake and body weight after total gastrectomy in rats. J Surg Res 2002; 106:273-81. [PMID: 12175978 DOI: 10.1006/jsre.2002.6463] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Total gastrectomy often results in early satiety and loss of body weight. Serotonin inhibits food intake, and postprandial serotonin release is increased after total gastrectomy. Serotonin might contribute to early satiety and loss of body weight after total gastrectomy. METHODS AND MATERIALS Food intake and body weight were investigated with an automated recording system in gastrectomized rats 1-12 months postoperatively. Rats were treated with metergoline, a 5-hydroxytryptamine (5-HT)(1/2) receptor antagonist, two different 5-HT(3) receptor antagonists, a combination of metergoline and devazepide, a cholecystokinin (CCK) a receptor antagonist, or vehicle. In addition, metergoline or vehicle was applied continuously by an intraperitoneal osmotic minipump for 7, 28, or 84 days after total gastrectomy. RESULTS Metergoline treatment resulted in a dose-dependent increase in food intake in gastrectomized rats. 5-HT(3) receptor antagonist treatment had no effect, and devazepide in addition to metergoline did not further stimulate food intake. Metergoline increased food intake at 1, 3, and 6 months postoperatively by up to 45% (24-h cumulative food intake [FI], 6 months: vehicle 3.83 +/- 0.10, metergoline 5.52 +/- 0.15 g/100 g body weight (BW), P < 0.0001). Chronic metergoline treatment for 7, 28, or 84 days significantly increased food intake after total gastrectomy compared to vehicle treatment (FI 7 days: vehicle 30.83 +/- 0.71, metergoline 36.27 +/- 0.85 g/100 g BW; P < 0.0002; average weekly FI during 28 days; vehicle 31.23 +/- 0.22, metergoline 36.83 +/- 0.33 g/100 g BW, P < 0.0001; average weekly FI during 84 days: vehicle 33.02 +/- 0.59, metergoline 35.07 +/- 0.48 g/100g BW, P < 0.008), and there was a significant body weight increase compared to vehicle treatment (7 days: DeltaBW vehicle -0.7 +/- 1.2 g vs DeltaBW metergoline 9.0 +/- 2.1 g, P < 0.001; 28 days: DeltaBW vehicle 0.3 +/- 2.2 vs DeltaBW metergoline 13.0 +/- 2.3, P < 0.001; 84 days: DeltaBW vehicle 25.7 +/- 10.2 vs DeltaBW metergoline 49.5 +/- 7.2, P < 0.04). Treatment for 84 days resulted in a significant body weight gain, while vehicle treatment had no effect (vehicle: 438 +/- 11 g vs 464 +/- 12 g, P < 0.2, n.s.; metergoline: 448 +/- 9 g vs 498 +/- 10 g, P < 0.007). CONCLUSIONS Inhibition of food intake by serotonin might contribute to early satiety and loss of body weight after total gastrectomy.
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Affiliation(s)
- Tilman T Zittel
- University Hospital, Department of General and Transplantation Surgery, University of Tübingen, 72076 Tübingen, Germany
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Abstract
Catecholamine, dopamine, serotonine (5HT) and neuronal histamine are anorectic monoamines and act as anorectic neurotransmitters. The anorectic agents as modulators of these monoamines inhibit appetite by activating release together with suppressing reuptake of those monoamines. The anorectic agents were classified in clinical use into either alpha 1, beta-adrenergic receptor agonists or 5HT-receptor agonist. Dexfenfluramine, a 5HT-receptor agonist, was inhibited in clinical use because of its cardiac complications including pulmonary hypertension and valvelar disease. Mazindol is an adrenergic agonist and the solitary anti-obesity drug used clinically in Japan. Sibutramine shows the effects of both beta-adrenergic and serotonergic receptor agonists. Sibutramine induces not only appetite suppression but also acceleration of peripheral energy expenditure. No histaminergic anorectics have been employed in the clinical situation to date. L-Histizine, precursor amino acid of endogenous neuronal histamine, is useful for suppression of food intake, lipolytic acceleration of peripheral adipose tissues and enhanced energy expenditure in both animals and humans. L-Histizine thus inspires development of more effective and safer anorectics that can be used without suffering from the rebound phenomenon of body weight.
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Affiliation(s)
- K Fukagawa
- 1st Department of Internal Medicine, Oita Medical University, Idaiga-oka, Hazama-cho, Hazama-gun, Oita 879-5593, Japan.
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Fratucci De Gobbi JI, De Luca LA, Johnson AK, Menani JV. Interaction of serotonin and cholecystokinin in the lateral parabrachial nucleus to control sodium intake. Am J Physiol Regul Integr Comp Physiol 2001; 280:R1301-7. [PMID: 11294747 DOI: 10.1152/ajpregu.2001.280.5.r1301] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Serotonin [5-hydroxytryptamine (5-HT)] and CCK injected into the lateral parabrachial nucleus (LPBN) inhibit NaCl and water intake. In this study, we investigated interactions between 5-HT and CCK into the LPBN to control water and NaCl intake. Male Holtzman rats with cannulas implanted bilaterally in the LPBN were treated with furosemide + captopril to induce water and NaCl intake. Bilateral LPBN injections of high doses of the 5-HT antagonist methysergide (4 microg) or the CCK antagonist proglumide (50 microg), alone or combined, produced similar increases in water and 1.8% NaCl intake. Low doses of methysergide (0.5 microg) + proglumide (20 microg) produced greater increases in NaCl intake than when they were injected alone. The 5-HT(2a/2c) agonist 2,5-dimetoxy-4-iodoamphetamine hydrobromide (DOI; 5 microg) into the LPBN reduced water and NaCl intake. After proglumide (50 microg) + DOI treatment, the intake was not different from vehicle treatment. CCK-8 (1 microg) alone produced no effect. CCK-8 combined with methysergide (4 microg) reduced the effect of methysergide on NaCl intake. The data suggest that functional interactions between 5-HT and CCK in the LPBN may be important for exerting inhibitory control of NaCl intake.
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Affiliation(s)
- J I Fratucci De Gobbi
- Department of Physiology and Pathology, School of Dentistry, Paulista State University (UNESP), 14801 - 903 Araraquara, São Paulo, Brazil
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Abstract
The present study was aimed to test the hypothesis that increased endogenous CCK may interact with the anorectic serotonergic agent dl-fenfluramine to reduce food intake in rats. Previous studies, using selective CCK receptor antagonists, could demonstrate CCK-dependent 5-HT-induced anorexia. In the present approach, we used protease inhibitors to increase levels of endogenous CCK instead of blocking CCK receptors by antagonists. The protease inhibitors we used were soybean trypsin inhibitor (STI) and camostate. We hypothesized that combining the anorectic serotonergic drug dl-fenfluramine with either STI or camostate should result in an enhanced hypophagic effect when compared to single drug treatment. All feeding experiments were performed in non-deprived rats during night time feeding. Given alone, STI (500 mg/kg, po), camostate (200 mg/kg po) and also fenfluramine (1-9 mg/kg ip) reduced significantly food intake, with a more pronounced effect following fenfluramine. However, the experiments do not provide evidence for any additive or synergistic action between camostate or STI and the anorectic serotonergic drug dl-fenfluramine on food intake.
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Affiliation(s)
- J P Voigt
- Institute of Pharmacology and Toxicology, Charité, Humboldt University, D-10098 Berlin, Germany.
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Affiliation(s)
- J E Blundell
- Department of Psychology, University of Leeds, United Kingdom
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Francis J, Dourish CT, Cooper SJ. Lack of interaction between devazepide and 8-OH-DPAT-induced hyperphagia in the rat. Physiol Behav 1996; 60:1337-40. [PMID: 8916191 DOI: 10.1016/s0031-9384(96)00223-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Recently, a number of studies have provided evidence suggesting that CCK and 5-HT interact in the control of food intake. However, the majority of these studies have relied on the administration of exogenous CCK to investigate potential interactions. The aim of the present study was to focus on the potential role of endogenous CCK in 5-HT-CCK interactions. Our prediction was that the CCKA antagonist, devazepide, alone would potentiate the hyperphagic effect of the 5-HT1A agonist, 8-OH-DPAT, in free-feeding rats. The results showed that devazepide, at a dose that had no intrinsic effect (1.0 mg/kg), did not enhance the hyperphagic effect of 8-OH-DPAT (100 and 300 micrograms/kg). This suggests that when serotonergic inhibitory activity is reduced by 5-HT1A-receptor stimulation, there is no compensatory increase of endogenous CCK activity to excite 5-HT neurons and thereby inhibit food intake.
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Affiliation(s)
- J Francis
- Centre for Human Nutrition, University of Sheffield, Northern General Hospital, UK
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Borisenko SA, Meng QH, Rauhala P, Männistö PT. Neurochemical mediators of anxiety have inconsistent effects on hypothalamic self-stimulation in rats. PHARMACOLOGY & TOXICOLOGY 1996; 78:354-60. [PMID: 8737973 DOI: 10.1111/j.1600-0773.1996.tb01388.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
We studied effects of anxiogenic and anxiolytic compounds on the electric self-stimulation of the medial fore-brain bundle in male rats to find out if there is a link between reward and anxiety-related behaviours. The cholecystokinin agonist, caerulein (25-100 micrograms/kg) and the 5-HT agonist 1-(3-chlorophenyl)piperazine (0.2-1 mg/kg) dose-dependently inhibited the electric self-stimulation. The 5-HT2A antagonist, ketanserin, at 2.5 mg/kg, increased the self-stimulation at high currents but not at threshold current. The 5-HT3 antagonist ondansetron (10 and 100 micrograms/kg). The alpha 1-adrenergic antagonist, prazosin (0.125 and 0.5 mg/kg), the beta-adrenergic antagonist, propranolol (5 and 10 mg/kg) and the alpha 2-adreno-receptor antagonist, atipamezole (4 mg/kg), did not affect the self-stimulation. Nor did the benzodiazepine agonist, diazepam (5-15 mg/kg), a benzodiazepine receptor antagonist flumazenil (at 10 and 25 mg/kg) or the inverse agonist of benzodiazepine receptors, N-methyl-beta-carboline-3-carboxamide (10 and 20 mg/kg), cause any substantial changes of the self-stimulation. We conclude that only two anxiolytic drugs (caerulein and 1-(3-chlorophenyl)piperazine) suppress the electric self-stimulation. These findings indicate that anxiogenicity as such is not able to weaken the hypothalamic electric self-stimulation. Anxiety and reward are apparently mediated through separate neural pathways.
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Affiliation(s)
- S A Borisenko
- Department of Pharmacology and Toxicology, University of Helsinki, Finland
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Fuller RW. Mechanisms and functions of serotonin neuronal systems: opportunities for neuropeptide interactions. Ann N Y Acad Sci 1996; 780:176-84. [PMID: 8602731 DOI: 10.1111/j.1749-6632.1996.tb15122.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- R W Fuller
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
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Affiliation(s)
- S J Cooper
- Department of Psychology, University of Durham, Science Laboratories, Durham, United Kingdom
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Blundell JE, Lawton CL, Halford JC. Serotonin, eating behavior, and fat intake. OBESITY RESEARCH 1995; 3 Suppl 4:471S-476S. [PMID: 8697045 DOI: 10.1002/j.1550-8528.1995.tb00214.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
There is an intimate relationship between nutritional intake (eating) and serotonin activity. Experimental manipulations (mainly neuropharmacological) of serotonin influence the pattern of eating behavior, subjective feelings of appetite motivation, and the response to nutritional challenges. Similarly, nutritional manipulations (food restriction, dieting, or altered nutrient supply) change the sensitivity of the serotonin network. Traditionally, serotonin has been linked to the macronutrient carbohydrate via the intermediary step of plasma amino acid ratios. However, it has also been demonstrated that 5-HT drugs will reduce energy intake and reverse body weight gain in rats exposed to weight increasing high fat diets. 5-HT drugs can also reduce food intake and block weight gain of rats on a high fat cafeteria diet. Some diet selection studies in rats indicate that the most prominent reduction of macronutrient intake is for fat. These data indicate that 5-HT activity can bring about a reduction in fat consumption. In turn, different types of dietary fat can alter brain 5-HT activity. In human studies the methodology of food choice experiments has often precluded the detection of an effect of 5-HT manipulation on fat intake. However, there is evidence that in obese and lean subjects some 5-HT drugs can readily reduce the intake of high fat foods. Data also suggest that 5-HT activation can lead to a selective avoidance of fat in the diet. These effects of 5-HT on the intake of dietary fat may involve a pre-absorptive mechanism and there is evidence that 5-HT is linked to cholecystokinin and enterostatin. These proposals have theoretical and practical implications and suggest possible strategies to intensify or advance fat-induced satiety signals.
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Li BH, Rowland NE. Effects of vagotomy on cholecystokinin- and dexfenfluramine-induced Fos-like immunoreactivity in the rat brain. Brain Res Bull 1995; 37:589-93. [PMID: 7670882 DOI: 10.1016/0361-9230(95)00045-g] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
This study compared the effects of bilateral subdiaphragmatic vagotomy on the Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat brain induced by two anorectic agents, cholecystokinin (CCK) and the serotonin agonist, dexfenfluramine (DFEN). In the nonvagotomized rats, both CCK (5 micrograms/kg, IP) and DFEN (2 mg/kg, IP) induced FLI in the nucleus of the solitary tract (NST), the external subdivision of the lateral parabrachial nuclei (LPBE), the lateral subdivision of the central amygdaloid nucleus (CeL), and the bed nucleus of the stria terminalis (BST). However, subregional distribution of the FLI induced by the two agents was different in most of these regions. Additionally, the area postrema and the medial subdivision of the hypothalamic paraventricular nucleus were preferentially activated by CCK but not DFEN, while the caudate-putamen was activated by DFEN but not CCK. Bilateral subdiaphragmatic vagotomy completely abolished CCK-induced FLI in all the brain regions but did not attenuate DFEN-induced FLI in any of these regions, including the NST. The results of the present study suggest that DFEN-activation of the NST-LPBE-CeL/BST neuraxis is not mediated by the vagus nerve. On the other hand, and consistent with a variety of other data, activation of various parts of the brain by peripherally administered CCK depends on a vagal pathway. These data are discussed in relation to a previously proposed interaction between CCK and serotonin in mediating satiety.
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Affiliation(s)
- B H Li
- Department of Psychology, University of Florida, Gainesville 32611-2250, USA
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Abstract
The reduction in growth resulting from lead (PB) exposure in weanling rats is consistent with a lowering of the biological set-point for food intake. In this study the effects of lead on the patterns of food intake were examined. For 10 days (from ages 26 to 36 days), female rats were provided with drinking water containing 250 ppm lead as the acetate (n = 6) or equivalent acetate as sodium acetate (n = 6). A computerized system was used to monitor daily food intake at 5-min intervals over 10 successive 23-h periods (each period consisting of 12 h dark, 11 h light). Control rats consumed approximately 75% to 85% of their food intake during the dark phase. Exposure to lead resulted in decreased body weight, tail length, and cumulative food intake. Decreased food intake associated with lead during the first 6 days of exposure was due to a decrease in the size of each meal during the dark phase, which reflected a decrease in the duration of each meal. These results suggest that lead, at least initially, was affecting food-satiety signals to produce a premature termination of food intake during a meal. After 6 days, the lead-exposed rats appear to have adjusted their meal size and meal duration to approximately control values. However, this compensation appears to have occurred at the expense of the daily (nocturnal) number of meals, which decreased slightly (although not significantly) in lead-exposed animals. Thus, the total daily intake of food in lead-treated animals remained depressed relative to control animals.
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Affiliation(s)
- D J Minnema
- Department of Environmental Health, University of Cincinnati, College of Medicine 45267-0056
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Blundell JE, Halford JC. Regulation of nutrient supply: the brain and appetite control. Proc Nutr Soc 1994; 53:407-18. [PMID: 7972155 DOI: 10.1079/pns19940046] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Li BH, Rowland NE. Cholecystokinin- and dexfenfluramine-induced anorexia compared using devazepide and c-fos expression in the rat brain. REGULATORY PEPTIDES 1994; 50:223-33. [PMID: 8016407 DOI: 10.1016/0167-0115(94)90003-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK in most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.
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Affiliation(s)
- B H Li
- Department of Psychology, University of Florida, Gainesville 32611-2065
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Abstract
Cholecystokinin (CCK) has emerged as an important mammalian neuropeptide, localized in peripheral organs and in the central nervous system. This review presents an overview of the molecular aspects of CCK peptides and CCK receptors, the anatomical distribution of CCK, the neurophysiological actions of CCK, release of CCK and effects of CCK on release of other neurotransmitters, and the actions of CCK on digestion, feeding, cardiovascular function, respiratory function, neurotoxicity and seizures, cancer cell proliferation, analgesia, sleep, sexual and reproductive behaviors, memory, anxiety, and dopamine-mediated exploratory and rewarded behaviors. Human clinical studies of CCK in feeding disorders and panic disorders are described. New findings are presented on potent, nonpeptide CCK antagonists, selective for the two CCK receptor subtypes, which demonstrate that endogenous CCK has biologically important effects on physiology and behavior.
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Affiliation(s)
- J N Crawley
- Section on Behavioral Neuropharmacology, National Institute of Mental Health, Bethesda, MD 20892
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Abstract
Studies with dexfenfluramine, an anorectic agent which releases 5-hydroxytryptamine (5-HT) from nerve terminals and inhibits its reuptake, have considerably increased our knowledge of the role of 5-HT in feeding control. 5-HT1B receptors mediate the satiating effect of dexfenfluramine, whereas the mechanism by which 5-HT uptake inhibitors such as fluoxetine and sertraline cause anorexia is not clear. Anorexia induced by (+)-amphetamine, phentermine, diethylpropion and phenylpropanolamine seems to be the result of their ability to increase the release of noradrenaline and/or dopamine from nerve terminals and inhibit their reuptake or, in the case of phenylpropanolamine, to stimulate directly alpha 1-adrenoceptors. It has been suggested that beta- and alpha 1-adrenoceptors and D1 dopamine receptors are involved in their effect on food intake. The difficulties of extrapolation across species limit our knowledge of the mechanism of the anorectic action in humans. Significant advances in the treatment of feeding pathology will be linked to identifying new receptor types and subtypes for neurotransmitters and quantifying and modelling eating disorders such as binge-eating and food craving.
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Affiliation(s)
- R Samanin
- Mario Negri Institute of Pharmacological Research, Milano, Italy
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