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5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Salsolinol (SAL), the condensation product of acetaldehyde and dopamine, may be a factor contributing to alcohol abuse. Previous research indicated that both ethanol and acetaldehyde are self-administered into the posterior ventral tegmental area (VTA). The current study examined SAL self-infusions into the VTA, and determined the involvement of dopamine neurons and 5-HT3 receptors in this process., Methods: The intracranial self-administration technique was used to determine the self-infusion of SAL into the VTA of adult, male Wistar rats. The rats were placed in 2-lever (active and inactive) experimental chambers, and allowed to respond for the self-infusion of 0, 0.03, 0.1, 0.3, 1.0 or 3.0 microM SAL into the posterior or anterior VTA. In a second experiment, rats self-administered 0.3 microM SAL for the initial 4 sessions, co-administered SAL with ICS-205,930 (a 5-HT3 receptor antagonist) or quinpirole (a D(2,3) receptor agonist) for sessions 5 and 6, and then only 0.3 microM SAL for session 7., Results: Wistar rats, given 0.03 to 0.3 microM SAL, received more infusions per session than did the group given artificial cerebrospinal fluid (aCSF) alone (e.g., 41 infusions for 0.1 microM SAL versus 9 infusions for the aCSF group), and responded more on the active than inactive lever. These effects were observed in the posterior but not in anterior VTA. Co-infusion of 100 microM ICS-205,930, or quinpirole significantly reduced self-infusions and active lever responding., Conclusions: SAL produces reinforcing effects in the posterior VTA of Wistar rats, and these effects are mediated by activation of DA neurons and local 5-HT3 receptors.

Background: Red chili has been reported to modulate visceral hypersensitivity, probably by the action of its active ingredient, capsaicin. The role of 5HT-3 receptors on capsaicin-sensitive visceral nociceptive pathways is unknown., Aim: To test the hypothesis that capsaicin-containing red chili induces rectal hypersensitivity in healthy humans and 5HT-3 receptors participate in this effect., Methods: Eighteen healthy volunteers, each underwent three rectal barostat studies under three conditions: (i) oral placebo; (ii) oral chili (5 g daily x 3 days); and (iii) oral chili with 1-mg intravenous (i.v.) granisetron, in randomized, double-blinded, cross-over fashions. Rectal sensation was evaluated by using a 5-point Likert scale., Results: Chili ingestion significantly decreased rectal threshold for first, moderate and severe urgency (18 +/- 0.9, 24 +/- 1.2, and 38 +/- 1.5 mmHg, respectively) compared with placebo (22 +/- 0.9, 31 +/- 1.3, and 45 +/- 1.4 mmHg, respectively, P < 0.01). The threshold for first, moderate and severe urgency after chili with i.v. granisetron was 20 +/- 0.9, 28 +/- 1.2 and 44 +/- 1.3 mmHg, respectively. This is a significant increase compared with chili ingestion without granisetron (P < 0.05). After placebo ingestion, i.v. granisetron produced no effect on rectal sensation compared with i.v. placebo in 10 healthy volunteers (P > 0.05)., Conclusions: Low-dose granisetron, a 5HT-3 receptor antagonist, partially reversed chili-induced rectal hypersensitivity but had no effect on rectal perception induced only by mechanical balloon distention. This study suggests that 5HT-3 receptors may be involved in chili-induced rectal hypersensitivity and potentially participate in the capsaicin-sensitive nociceptive pathways of the human gut.

The 5-HT(3) receptor is a member of the superfamily of neurotransmitter-gated ion channels involved in fast synaptic signalling and in modulation of neurotransmitter release. As for many other channel receptors, the electrophysiological properties and the functions of the 5-HT(3) receptor are determined by subunit composition of the pentameric channel. Because in situ hybridization did not allow the detection of mRNA encoding the 5-HT(3B) subunit in the rodent central nervous system, or in nearly half of the neurons expressing the 5-HT(3A) subunit in peripheral ganglia, it has been suggested that subunit composition could define at least two 5-HT(3) receptor-expressing neuronal populations. In order to challenge this hypothesis, we have developed polyclonal antibodies directed against a portion of the second intracytoplasmic loop of the mouse 5-HT(3B) subunit. Immunohistochemical analysis in the mouse and the rat revealed that immunolabelling was most prominent in peripheral ganglia, particularly in trigeminal ganglia (TG). In rats, transection or ligature of the infraorbital nerve resulted in a pronounced accumulation of immunoreactive material at the proximal side of the lesioned nerve, and an up-regulation of both subunits in 5-HT(3) receptor-expressing TG neurons. Surprisingly, nearly 100% of neurons expressing 5-HT(3A) subunits were also labelled by anti-5-HT(3B) antibodies. We also detected 5-HT(3B) immunoreactivity in the rat hippocampal CA1 layer and in scattered cortical neurons, indicating that detection of 5-HT(3) subunit mRNA by in situ hybridization might not provide really complete mapping of heteromeric 5-HT(3A/B) vs. homomeric 5-HT(3A) receptors in the peripheral and central nervous systems in rodents.

Many neurological pathologies are related to misfolded proteins. During folding and assembly in the endoplasmic reticulum, the nicotinic acetylcholine receptor (nAChR) subunits undergo several conformational changes to acquire the ability to bind ligands. After folding and maturation, by mechanisms largely unknown, receptors are exported to the cell surface. We investigated the maturational role of the extracellular C-terminal segment located at the boundary between the extracellular and the transmembrane domains. In the functional chimeric alpha7-5HT3A receptor used as a model system, amino acids from the C-terminal segment were successively deleted or mutated. Upon progressive shortening of the peptide we observed less and less alpha-bungarotoxin binding sites until no sites could be detected when the entire peptide had been deleted (chimera Del 5). Protein synthesis and pentameric assembly were not altered. In Del 5 transfected cells, pentameric receptors present in the endoplasmic reticulum were not detected on the cell surface where Del 5 proteins appeared as patches. With the Del 5 chimera, export of proteins to the cell surface diminished to about half that of wild-type. We propose that the C-terminal segment plays a double role: (i) through an interaction between the penultimate tyrosine residue of the C-terminal segment and the Cys loop of the N-terminal domain, it locks the receptor in a mature alpha-bungarotoxin binding conformation; (ii) this mature conformation, in turn, masks a retention signal present in the first transmembrane segment allowing properly assembled and matured receptors to escape to the cell surface.

Background: Drug discrimination studies using selective antagonists and agonists have suggested that 5-HT3 receptors may modulate ethanol's discriminative stimulus effects. However, conflicting data between laboratories leaves the issue of 5-HT3 receptor involvement in ethanol's discriminative stimulus effects in question. The present study utilized transgenic mice that over-express 5-HT3 receptors in conjunction with traditional pharmacological techniques to examine the contribution of 5-HT3 receptors to ethanol's discriminative stimulus., Methods: Ten 5-HT3 over-expressing (5-HT3 OE) and 18 B6SJL wild-type (WT) mice were trained to discriminate 1.5 g/kg ethanol from saline in daily 15 min, milk reinforced operant sessions. After training, ethanol substitution and response-rate suppression dose response curves were determined for ethanol, midazolam, dizocilpine, cocaine, mCPP, MD-354, YC-30 and MDL-72222. Antagonism tests combining ethanol with MDL-72222 and ondansetron were also conducted., Results: The 5-HT3 OE and WT mice learned the ethanol discrimination in a comparable number of training sessions. Similar patterns of substitution were generated in both groups of mice for most test drugs. 5-HT3 OE mice were more sensitive to the rate suppressing effects of dizocilpine and MDL-72222 than were WT mice. Neither of the 5-HT3 antagonist tested significantly attenuated ethanol's discriminative stimulus effects in either 5-HT3 OE or WT mice., Conclusions: The results of the present study are consistent with a minimal role of 5-HT3 receptors in transducing ethanol's discriminative stimulus effects. Over-expression of 5-HT3 receptors does not alter the relative efficacy of GABAA positive modulators or NMDA antagonists for producing ethanol-like discriminative stimulus effects. However, 5-HT3 receptor over-expression does appear to modulate the response-rate altering effects of the uncompetitive NMDA antagonist, dizocilpine, and the 5-HT3 antagonist, MDL-72222., (Copyright 2004 Research Society on Alcoholism)