Serotonin 5-HT2A and 5-HT2C Receptors as Potential Targets for Modulation of Psychostimulant Use and Dependence

Abstract

The development of novel pharmacological agents for the treatment of psychostimulant use disorders is an important research imperative. One potential target system that has been largely overlooked is the serotonin (5-HT) neurotransmitter system. Preclinical studies indicate that 5-HT may be important in modulating the reinforcing properties of various drugs of abuse. While the potential sites of action of 5-HT within the brain are extensive, the natural starting point to examine the mechanisms by which 5-HT may be useful in treatment of psychostimulant use disorders is the interaction between 5-HT and dopamine (DA), a primary mediator of the "rewarding" effects of psychostimulants. Two key modulators of DA output are the serotonin (5-HT)2A receptor (5-HT2A R) and the 5-HT2C R. These receptors are known to control the neurochemical and behavioral effects of psychostimulants, and in particular, the in vivo effects of cocaine. Preclinical studies indicate that 5-HT2A R antagonists and/or 5-HT2C R agonists may effectively reduce craving and/or relapse, and likewise, enhance abstinence, while 5-HT2C R agonists may also effectively reduce cocaine intake in active cocaine users. At present, the progression of studies to probe the effectiveness of 5-HT2A R and 5-HT2C R ligands in the clinical setting is hindered by a lack of available selective 5-HT2A R antagonists or 5-HT2C R agonists for use in human cocaine abusers. However, a number of selective 5-HT2 R ligands currently under development, or in early clinical trials for psychiatric and/or neurological disorders, may soon be available for translational studies to explore their effectiveness in modulating drug use and dependence.

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

“…These findings suggest that the net inhibitory effect of central 5-HT 2C Rs on cocaine-induced DA outflow may result from the functional balance between different populations of 5-HT 2C Rs within the VTA and the NAc, and within the mesoaccumbens pathway (VTA vs NAc). Finally, these data provide new insights into the prominent role of the 5-HT 2C R in the regulatory neurochemistry of mesoaccumbens DA function (Higgins and Fletcher, 2003), and then a better understanding of the therapeutic potential of 5-HT 2C R ligands for treating cocaine abuse and dependence (Bubar and Cunningham, 2006;Grottick et al, 2000;Rocha et al, 2002).…”

“…Indeed, GABA neurons in the VTA co-express both the transcript (Eberle-Wang et al, 1997) and the protein for the 5-HT 2C R (Bubar and Cunningham, 2006). Electrophysiological studies suggest that stimulation of the 5-HT 2C R excites the activity of GABA neurons in the VTA (Di Giovanni et al, 2001;Liu et al, 2000), leading to an inhibition of the firing of VTA DA neurons and a subsequent decrease in accumbal DA release (Di Matteo et al, 2000;Gobert et al, 2000;Navailles et al, 2004).…”

“…On the other hand, the failure of the intra-VTA injection of SB 242084 to modulate the effects of cocaine on accumbal DA efflux may result from the massive blockade of the 5-HT 2C R in the VTA, which may preclude any possible stimulation of these receptors by cocaine-induced increase in 5-HT levels (Cameron and Williams, 1994). It is noteworthy that DA neurons in the VTA have been recently shown to co-express the protein for the 5-HT 2C R (Bubar and Cunningham, 2006;Ji et al, 2006). By this finding, and considering that the 5-HT 2C R depolarizes cell membranes by inducing phospholipase C-mediated inositol phosphate accumulation and enhancement of intracellular calcium (Stanford et al, 2005), the stimulation of 5-HT 2C Rs located on DA neurons would lead to an excitation of DA neuron activity.…”

“…During recent years, numerous studies have focused on the role of the serotonergic2C receptor (5-HT 2C R) in the modulation of this DA pathway and its potential to control cocaine dependence (Bubar and Cunningham, 2006;Di Matteo et al, 2002;Higgins and Fletcher, 2003). Indeed, 5-HT 2C Rs are densely localized in brain regions containing DA cell bodies (VTA) and terminals (NAc) (Bubar and Cunningham, 2006;Clemett et al, 2000;Pazos et al, 1985;Pompeiano et al, 1994), and are known to modulate DA-dependent behavioral and neurochemical effects induced by cocaine (Fletcher et al, 2002(Fletcher et al, , 2006Grottick et al, 2000;McCreary and Cunningham, 1999;Navailles et al, 2004). Specifically, the systemic administration of the 5-HT 2C R agonist Ro 60-0175, and the 5-HT 2C R antagonist SB 242084 has been shown to respectively inhibit and potentiate cocaineinduced behaviors including its hypermotive and rewarding effects (Fletcher et al, 2002(Fletcher et al, , 2006Grottick et al, 2000).…”

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

“…On the basis of this evidence there have been a number of recent suggestions that the 5-HT 2C receptor might be a valid target for the development of medications for treating drug abuse (Bubar and Cunningham, 2006;Di Giovanni et al, 2006;Higgins and Fletcher, 2003;Ji et al, 2006). In the present experiments, we have explored further the potential utility of a 5-HT 2C receptor agonist for drug abuse.…”