The Role of 5-HT3 Receptors in Drug Abuse and as a Target for Pharmacotherapy

Abstract

Alcohol and drug abuse continue to be a major public health problem in the United States and other industrialized nations. Extensive preclinical research indicates the mesolimbic dopamine (DA) pathway and associated regions mediate the rewarding and reinforcing effects of drugs of abuse and natural rewards, such as food and sex. The serotonergic (5-HT) system, in concert with others neurotransmitter systems, plays a key role in modulating neuronal systems within the mesolimbic pathway. A substantial portion of this modulation is mediated by activity at the 5-HT3 receptor. The 5-HT3 receptor is unique among the 5-HT receptors in that it directly gates an ion channel inducing rapid depolarization that, in turn, causes the release of neurotransmitters and/or peptides. Preclinical findings indicate that antagonism of the 5-HT3 receptor in the ventral tegmental area, nucleus accumbens or amygdala reduces alcohol self-administration and/or alcohol-associated effects. Less is known about the effects of 5-HT3 receptor activity on the self-administration of other drugs of abuse or their associated effects. Clinical findings parallel the preclinical findings such that antagonism of the 5-HT3 receptor reduces alcohol consumption and some of its subjective effects. This review provides an overview of the structure, function, and pharmacology of 5-HT3 receptors, the role of these receptors in regulating DA neurotransmission in mesolimbic brain areas, and discusses data from animal and human studies implicating 5-HT3 receptors as targets for the development of new pharmacological agents to treat addictions.

Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking

“…Within this system, ethanol increases the release of dopamine in the shell of the nucleus accumbens, which is directly associated with the rewarding effects of ethanol consumption (McBride, 2002; McBride and Li, 1998) reviewed in Koob (2013). Serotonin modulates the effect of ethanol on dopamine release via the 5-HT3 receptor (Campbell et al, 1996; Campbell and McBride, 1995; Engleman et al, 2008; Wozniak et al, 1990). …”

The Nonpsychoactive Cannabinoid Cannabidiol Inhibits 5-Hydroxytryptamine3A Receptor-Mediated Currents in Xenopus laevis Oocytes

“…An involvement of 5-HT 3 receptors in pain transmission, mood disorders, and drug abuse has been reported (for reviews, see Riering et al, 2004;Faerber et al, 2007;Engleman et al, 2008). Furthermore, 5-HT 3 receptor antagonists are effective therapeutic agents for the treatment of chemotherapy-induced nausea and vomiting (Slatkin 2007;Thompson and Lummis, 2007).…”

MU314, a novel selective estrogen receptor modulator (SERM), improves estrogen-dependent depressive behaviors

“…Thus, estrogen and the amygdala are closely related [8]. Furthermore, the amygdala expresses 5-HT receptors (5-HT1-7) and receives serotonergic input from the raphe [2,[16][17][18][19][20][21][22][23][24][25][26]. Therefore, estrogen and its moderators may be effective treatment methods for OVX-induced depressive symptoms.…”