The role of 5-HT3 receptors in drug dependence

Since the discovery of serotonin receptor subtypes in 1957, the classification of serotonin receptors now includes 5-HT1 through 5-HT7 receptors, with further subtypes of receptors in each family. Unique among this expanding group of 5-HT receptor subtypes is the 5-HT3 receptor, which is the only known 5-HT receptor that directly gates an ion channel. The channel conducts primarily Na+ and K+, resulting in rapid depolarization followed by a rapid desensitization. The immediate consequence of neuronal depolarization resulting from 5-HT3 receptor activation is the release of stored neurotransmitter. The subsequent release of stored neurotransmitter, particularly dopamine in the mesolimbic pathways, suggest a potentially important role for this receptor system in neuronal circuitry involved in drug abuse. The following review broadly covers the structure, function and distribution of the 5-HT3 receptor system in the CNS and data addressing the potential role of this receptor system in modulating the effects of a wide variety of abused drugs. Most of the evidence indicates an association between the ability of 5-HT3 antagonists to decrease mesolimbic dopamine levels and to attenuate the psychomotor stimulant effects of drugs. However 5-HT3 receptor antagonists are less robust at attenuating other drug effects that are believed to be related to their abuse liability, such as discriminative stimulus and reinforcing effects. The one exception may be ethanol, which directly potentiates the effects of 5-HT at the 5-HT3 receptor channel complex. In addition to the implications of an interaction with the mesolimbic dopaminergic system, the ability of 5-HT3 receptor antagonists to function as anxiolytics suggest they could be useful pharmacotherapies during drug withdrawal. However, further studies are needed since currently available 5-HT3 receptor antagonists do not have uniform behavioral effects, may interact with other receptor systems, and have atypical dose-response effects.