Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse

Abstract

The serotonin (5-HT) neurotransmitter system provides fundamental modulatory regulation of the limbic-corticostriatal circuitry known to be vital in the development of addiction as well as the aspects of addiction that hinder recovery and contribute to relapse. Thus, components of the 5-HT system may provide novel targets for the development of pharmacological treatments for psychostimulant dependence, which is associated with significant aberrations in dopamine (DA) neurotransmission. Two key modulators of DA signalling within the limbic-corticostriatal circuit are the 5-HT(2A) receptor (5-HT(2A)R) and the 5-HT(2C)R. These receptors are known to control the neurochemical and behavioural effects of psychostimulants, and in particular the in vivo effects of cocaine. Pre-clinical studies indicate that 5-HT(2A)R antagonists and/or 5-HT(2C)R agonists may effectively reduce craving and/or relapse, and likewise, enhance abstinence, while 5-HT(2C)R agonists may also effectively reduce cocaine intake in active cocaine users. At present, the progression of studies to probe the effectiveness of 5-HT(2A)R and 5-HT(2C)R ligands in the clinical setting is hindered by a lack of available, selective 5-HT(2A)R antagonists or 5-HT(2C)R agonists for use in human cocaine abusers. However, a number of selective 5-HT(2)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.