Serotonin 5-HT_2A and 5-HT_2C receptors as potential targets for modulation of psychostimulant use and dependence

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 psychstimulants. Two key modulators of DA output are the serotonin (5-HT)_2A receptor (5-HT_2AR) and the 5-HT_2CR. 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-HT_2AR antagonists and/or 5-HT_2CR agonists may effectively reduce craving and/or relapse, and likewise, enhance abstinence, while 5-HT_2CR agonists may also effectively reduce cocaine intake in active cocaine users. At present the progression of studies to probe the effectiveness of 5-HT₂AR and 5-HT_2CR ligands in the clinical setting is hindered by a lack of available selective 5-HT_2AR antagonists or 5-HT_2CR agonists for use in human cocaine abusers. However, a number of selective 5-HT₂R 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.