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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has long been postulated that an interaction between ethanol and stress may play an important role in the etiology of alcoholism. In the present review, we focused on an interaction between ethanol and stress in the mechanism of psychological dependence on ethanol. Ethanol with conditioned fear stress (CFS), but not without the stress, induced a significant place preference. These results suggest that psychological stress may play an important role in the rewarding effect of ethanol. It has been hypothesized that activation of the mesolimbic dopamine system mediated by the endogenous opioid system may be particularly important in the rewarding mechanism of ethanol. It appeared that mu- and delta-opioid receptors might play critical roles in the development of the rewarding effect of ethanol under the stress. Under psychological stress, the rewarding effect of ethanol through the activation of mu- and/or delta-opioid receptors was found to results the activation of dopamine D1 and/or D2 receptors. Additionally, a subtype of serotonin (5-HT) receptors, 5-HT3 receptor, was shown to be involved in the rewarding mechanism of ethanol through the activation of mu- and delta-opioid receptors. In conclusion, psychological stress may be an important factor in the development of the rewarding effect of ethanol and may potentiate the rewarding mechanism. 5-HT3 receptor, is likely to be involved in the rewarding mechanism of ethanol under stress. Dopamine D1 and D2 receptors may also be implicated in the rewarding mechanism of ethanol under stress.
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PMID:[Psychological stress and rewarding effect of alcohol]. 1213 20

This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The organizers and chairs were William J. McBride and David M. Lovinger. The presentations were (1) Mechanisms of alcohol potentiation of 5-HT3 receptor function, by David M. Lovinger and Tina Machu; (2) Chronic alcohol drinking alters 5-HT3 receptors regulating the mesolimbic dopamine system, by Richard J. Thielen; (3) 5-HT3 receptors in the VTA regulate alcohol drinking and the reinforcing effects of alcohol, by Zachary A. Rodd and James M. Murphy; and (4) Ondansetron as a treatment for "biological" alcoholism, by John D. Roache and Bankole A. Johnson.
Alcohol Clin Exp Res 2004 Feb
PMID:Serotonin-3 receptors in the actions of alcohol, alcohol reinforcement, and alcoholism. 1511 33

Opioid receptor antagonist naltrexone has shown some efficacy in decreasing ethanol consumption in humans. However, naltrexone treatment is not always efficacious and produces several aversive effects such as nausea, anxiety and weight loss. Serotonin-3 (5-HT3) receptor antagonists also modulate some of the behavioral effects of alcohol and may decrease alcohol consumption. We examined the effects of the combination of 5-HT3 receptor antagonist ICS 205-930 ((3-tropanyl-indole-1-carboxylate, tropisetron) and naltrexone on ethanol and food intake in Sprague-Dawley rats. Both naltrexone (0.56-10 mg/kg) and ICS 205-930 (5.6 mg/kg), when administered intraperitoneally 30 min before the scheduled 3-h access to ethanol, significantly suppressed ethanol intake. Naltrexone (1 mg/kg) when given in combination with ICS 205-930 (5.6 mg/kg) was significantly more efficacious in suppressing ethanol intake in comparison with naltrexone (1 mg/kg) administered alone. The drug combination did not affect the food intake. These data suggest that 5-HT3 receptor antagonist ICS 205-930 may be used as an effective adjunct for pharmacotherapy of alcoholism.
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PMID:5-HT3 antagonist ICS 205-930 enhances naltrexone's effects on ethanol intake. 1514 Jun 31

The ionotropic serotonin subtype-3 (5-HT3) receptor has emerged as a potential therapeutic target in the treatment of alcohol abuse and alcoholism because selective pharmacological antagonists reduce alcohol consumption in preclinical and clinical models. 5-HT binds to the extracellular N-terminus of the 5-HT(3A) receptor subunit but receptor activation is also enhanced by distinct allosteric sites, which indicates the presence of other receptor subunits. It is not known if specific molecular subunits of the 5-HT3 receptor modulate alcohol drinking. To address this issue, we characterized acute locomotor response to alcohol and alcohol consumption in a two-bottle home-cage procedure by congenic C57BL/6J mice with a targeted deletion of the 5-HT(3A) receptor subunit gene. 5-HT(3A)-null mice did not differ from wild-type littermate controls on measures of spontaneous locomotor activity, habituation to a novel environment, or locomotor response to ethanol (0, 0.5, 1, or 2 g/kg). Moreover, null mice did not differ from controls on measures of ethanol (2-10%) intake and preference during or after a two-bottle home-cage sucrose fading procedure. Systemic administration of the 5-HT3 antagonist LY-278,584 (0-10 mg/kg) decreased intake of both sweetened (2% sucrose+10% ethanol) and unsweetened (10% ethanol) ethanol in wild-type mice only. These findings indicate that reduction of alcohol drinking produced by 5-HT3 antagonism is dependent on the presence of 5-HT(3A)-containing receptors.
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PMID:5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking. 1516 58

The meso-limbic dopamine (DA) system has an important role in regulating alcohol drinking. Previous findings from our laboratory indicated that Wistar rats self-administered ethanol (EtOH) directly into the posterior, but not anterior, ventral tegmental area (VTA), and that coadministration of a DA D(2,3) receptor agonist or a serotonin-3 (5-HT3) receptor antagonist blocked EtOH self-administration. In addition, we reported that alcohol-preferring (P) rats self-administered acetaldehyde (ACD), the first metabolite of EtOH, into the posterior VTA. The objectives of this study were to compare the reinforcing effects of EtOH and ACD within the VTA of P rats to examine the possibility that the reinforcing effects of EtOH within the VTA may be mediated by its conversion to ACD. Adult female P rats were stereotaxically implanted with guide cannulae aimed at either the posterior or anterior VTA. At 1 week after surgery, rats were placed in standard two-lever (active and inactive) experimental chambers for a total of seven to eight sessions. The 4-h sessions were conducted every other day. The results indicated that (a) 75-300 mg% (17-66 mM) EtOH and 6-90 microM ACD were self-administered into the posterior, but not anterior, VTA; (b) the self-administration of 150 mg% EtOH was not altered by coinfusion of a catalase inhibitor; (c) coadministration of the D(2/3) agonist quinpirole (100 microM) blocked the self-infusions of 150 mg% EtOH and 23 microM ACD into the posterior VTA; and (d) coadministration of 200 microM ICS205,930 (5-HT3 receptor antagonist) prevented the self-infusion of 150 mg% EtOH, whereas concentrations of ICS 205,930 up to 400 microM had no effect on the self-infusion of 23 microM ACD into the posterior VTA. Overall, the results of this study indicate that EtOH and ACD can independently produce reinforcing effects within the posterior VTA, and that activation of DA neurons mediates these effects. Furthermore, activation of 5-HT3 receptors within the posterior VTA is involved in the self-infusion of EtOH, but not ACD.
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PMID:Regional heterogeneity for the intracranial self-administration of ethanol and acetaldehyde within the ventral tegmental area of alcohol-preferring (P) rats: involvement of dopamine and serotonin. 1538 30

This report of the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism highlights the actions of ethanol on purinergic (P2XRs) and 5-hydroxytryptamine3 (5-HT3Rs) receptors. Both P2XRs and 5-HT3Rs, are modulated by pharmacologically relevant concentrations of ethanol, with inhibition or stimulation of P2XR subtypes and stimulation of 5-HT3Rs, respectively. With regard to ethanol-modulatory actions, these 2 distinctly different receptor classes have been studied to a much lesser extent than other LGICs. The organizers and chairs were Daryl L. Davies and Tina K. Machu. John J. Woodward discusses the molecular pharmacology and physiology of P2XRs and 5-HT3Rs and sets the stage for a detailed investigation into the ethanol sensitivity of these channels by the invited speakers. Daryl L. Davies discusses the results from recent electrophysiological studies conducted in his and Dr. Woodward's laboratories, highlighting the actions of ethanol on P2XR subtypes. Jiang-Hong Ye discusses results from recent studies using loose-patch and whole-cell recordings on purinergic receptors expressed on neurons from the ventral tegmental area (VTA) in rats. Tina K. Machu discusses electrophysiological studies conducted in her and Dr. David Lovinger's laboratories on nonpore lining residues of the second transmembrane domain (TM2) of the 5-HT3A receptor. Li Zhang presents data demonstrating that F-actin cytoskeletons play a critical role in 5-HT3 receptor clustering in hippocampal neurons. Collectively, the presentations provided strong evidence that P2X and 5-HT3 receptors are important targets for ethanol action.
Alcohol Clin Exp Res 2006 Feb
PMID:Effects of ethanol on adenosine 5'-triphosphate-gated purinergic and 5-hydroxytryptamine receptors. 1644 Dec 84

Behavioral effects of genetic manipulations are influenced by the background genetics of mouse strains used for the creation of transgenic mice. One strategy to address whether background genes may compromise interpretation of phenotype is the production of congenics. 5-HT3 receptor over-expressing mice have been behaviorally characterized on a B6SJL/F2 background (B6SJL/F2-OE mice), and were found to consume less ethanol failed to develop conditioned place preference to moderate doses of cocaine and demonstrate improved hippocampal-dependent learning. To assess the contribution of parental strain genetics to these behaviors, we bred the transgene onto two well-defined backgrounds that differ in ethanol consumption and contextual fear conditioning, C57Bl/6J (B6) and DBA/2J (D2) strains. The behavioral phenotype of B6SJL/F2-OE was recapitulated in C57Bl/6J-OE mice. However, the effect of transgene over-expression on behavior was only apparent for one aspect of the novelty test using DBA/2J-OE mice. Results underscore the need to consider the genetic environment conferred by strain selection on the effects of genetic manipulation in mice.
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PMID:Influence of genetic background on alcohol drinking and behavioral phenotypes of 5-HT3 receptor over-expressing mice. 1676 27

A previous study indicated that pretreatment with repeated daily injections of serotonin-3 (5-HT3) receptor antagonists subsequently reduced the effectiveness of the 5-HT3 antagonists to attenuate ethanol intake under 24-h free-choice conditions; one possibility to account for this is that the functional activity of the 5-HT3 receptor may have been altered by prior treatment with the antagonists. The present experiments were conducted to examine the effects of local perfusion of the 5-HT3 agonist 1-(m-chlorophenyl)-biguanide (CPBG) on the extracellular levels of dopamine (DA) in the nucleus accumbens (ACB) and ventral tegmental area (VTA) of adult male Wistar rats that had received repeated daily injections of the 5-HT3 antagonist, MDL 72222 (MDL). In vivo microdialysis was used to test the hypothesis that alterations in 5-HT3 receptor function have occurred with repeated antagonist injections. One group was given daily injections of MDL (1 mg/kg, s.c.) for 10 consecutive days (MDL group), and the other group was administered saline for 10 days (saline group). On the day after the last treatment, rats were implanted with a unilateral guide cannula aimed at either the ACB or VTA. Two days later, the microdialysis probe was inserted into the guide cannula; on the next day, microdialysis experiments were conducted to determine the extracellular levels of DA in the ACB or VTA. Local perfusion of CPBG (17.5, 35, 70 microM) in the ACB significantly stimulated DA release in the saline- and MDL-treated animals. In terms of percent baseline, the CPBG-stimulated DA release was higher in the MDL-treated group than in the saline-treated group in both the ACB and VTA; however, on the basis of the extracellular concentration, there were no significant differences in the ACB between the two groups. Using the no-net-flux microdialysis, it was determine that the basal extracellular concentration of DA in the ACB was approximately 60% lower in the MDL group than saline group; there was no difference between the groups in the extraction fraction (clearance). Overall, the results suggest that repeated daily treatments with MDL decreased basal DA neurotransmission in the ACB and did not have a clear effect on functional activity of 5-HT3 receptors in the ACB.
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PMID:Effects of repeated daily treatments with a 5-HT3 receptor antagonist on dopamine neurotransmission and functional activity of 5-HT3 receptors within the nucleus accumbens of Wistar rats. 1682 50

Alcohols and volatile anesthetics modulate the function of cys-loop ligand-gated ion channels, binding to a putative site between transmembrane domains two and three. The extracellular linker between these two domains is important in the transduction of the gating signal from the glycine binding site to the channel gate. Although the anesthetic binding site is proposed to be in the same region throughout the cys-loop receptor family, the modulatory effects of these compounds depend on the receptor. A sequence comparison revealed an extra proline in the TM2-TM3 loop of the 5-HT3A receptor (5-HT3AR) that is not found in the glycine receptor (GlyR). We hypothesized that this proline residue could affect the size and orientation of the putative alcohol and anesthetic binding pocket and perhaps explain some of the differences in alcohol and anesthetic effects seen in this family of receptors. A lysine to proline mutation was introduced into the TM2-TM3 linker region at position 281 (K281P) of the alpha1 GlyR. Mutation at this residue did not affect thiol binding to residues in TM2 or TM3 and it does not appear that residue 281 constitutes part of the alcohol binding site. The K281P receptors displayed constitutive activity in the absence of glycine, and unlike wild-type receptors, this channel opening was antagonized by application of either volatile anesthetics or another GlyR modulator, zinc. Our data suggest that the TM2-TM3 extracellular loop plays a role in the transduction of signals generated by allosteric modulators in addition to gating signals that follow glycine binding.
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PMID:Effects of a mutation in the TM2-TM3 linker region of the glycine receptor alpha1 subunit on gating and allosteric modulation. 1743 60

Manipulation of the serotonergic system has been shown to alter ethanol sensitization. Ondansetron is a 5-HT3 receptor antagonist, reported to attenuate cocaine and methamphetamine-induced behavioral sensitization, but no reports are available on its role in ethanol-induced behavioral sensitization. Therefore, an attempt has been made to assess this issue by using an earlier used animal model of ethanol-induced locomotor sensitization. Results indicated that ondansetron (0.25-1.0 mg/kg, subcutaneously) given before the challenge dose of ethanol (2.4 g/kg, intraperitoneally) injection, significantly and dose dependently attenuated the expression of sensitization. In addition, ondansetron (1.0 mg/kg, subcutaneously) given before ethanol injection on days 1, 4, 7, and 10 significantly blocked the development (days 1, 4, 7, and 10), and expression (day 15) of sensitization to the locomotor stimulant effect of ethanol injection. Ondansetron had no effect per se on locomotor activity and did not affect blood ethanol levels. Therefore, the results raise the possibility that ondansetron blocked the development and expression of ethanol-induced locomotor sensitization by acting on 5-HT3 receptors.
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PMID:The 5-HT3 receptor antagonist, ondansetron, blocks the development and expression of ethanol-induced locomotor sensitization in mice. 1910 64


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