title: An investigation of the role of 5-HT(2C) receptors in modifying ethanol self-administration behaviour.
abstract: We have previously reported that the 5-HT uptake blocker and releaser, dexfenfluramine, attenuates ethanol intake, and that this may be mediated via a 5-HT(2C) receptor mechanism. Our goals were to further determine the contribution made by this receptor subtype in mediating the reduction in ethanol self-administration induced by dexfenfluramine using the selective 5-HT(2C) antagonist, SB242,084. Additionally, we wanted to compare dexfenfluramine's effects on ethanol motivated responding with those elicited by the 5-HT(2C) receptor agonist Ro60-0175. In male Wistar rats trained to self-administer a 12% w/v ethanol solution on an FR-4 schedule, both dexfenfluramine (0.05--2.5 mg/kg ip) and Ro60-0175 (0.1--1 mg/kg sc) produced a significant dose-dependent reduction in ethanol self-administration, which was reversed by SB242,084 (0.5 mg/kg ip). Interestingly, SB242,084 alone (0.1--1 mg/kg ip) significantly increased ethanol motivated responding in both high and low ethanol drinking animals. While dexfenfluramine had no effect on ethanol's kinetic profile, the selective 5-HT(2C) agents used had opposing effects, with the agonist Ro60-0175 decreasing and the antagonist SB242,084 increasing blood ethanol levels. Since there were incongruent drug effects on ethanol self-administration and blood ethanol levels, these data support a role for 5-HT(2C) receptors in modifying ethanol intake independent of their effects on blood ethanol kinetics. Furthermore, 5-HT(2C) receptors may exert a tonic control over ethanol self-administration behaviour, since agonist and antagonist administration had opposing effects on this behaviour.
authors.affiliation: Biobehavioural Pharmacology, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. denise_tomkins@camh.net
authors.forename: Denise M
authors.initials: DM
authors.lastname: Tomkins
authors.forename: N
authors.initials: N
authors.lastname: Joharchi
authors.forename: M
authors.initials: M
authors.lastname: Tampakeras
authors.forename: J R
authors.initials: JR
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Wichmann
authors.forename: G A
authors.initials: GA
authors.lastname: Higgins
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000523:psychology; D000437:Alcoholism / Q000188:drug therapy* / Q000523:psychology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000097:blood / Q000493:pharmacokinetics; D003216:Conditioning, Operant / Q000187:drug effects; D020372:Dexfenfluramine / Q000494:pharmacology; D000431:Ethanol / Q000097:blood / Q000493:pharmacokinetics; D005021:Ethylamines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D002492:Central Nervous System Depressants; D005021:Ethylamines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; D000431:Ethanol; D020372:Dexfenfluramine