The role of serotoninergic system in psychostimulant effects

PURPOSE: This article discusses the modulatory effects of the serotonergic system on the behavioral and neurochemical effects exerted by psychostimulants, mainly cocaine. VIEWS: The mesocorticolimbic dopaminergic system plays an important role in the rewarding effects of psychostimulants and the long-lasting neuroadaptive changes underlying the development of addiction. Dopaminergic brain regions such as the ventral tegmental area (VTA) and substantia nigra (SN) and their projection fields (prefrontal cortex – PFC, nucleus accumbens – Acb, dorsal striatum) are innervated by serotonergic neurons that can modulate this system. Pharmacological manipulation of the activity of the serotonergic system in rats has shown that lowering or elevating its activity increases and decreases, respectively, most behavioral responses to cocaine. Studies on the role of serotonin receptors have shown that the serotonin 5-HT(1B) receptor agonists administered to the Acb during self-administration increase the reinforcing effects of cocaine, whereas when administered during abstinence they decrease cocaine seeking. Distinct populations of 5-HT(2AR) and 5-HT(2CR) in the PFC, Acb, and VTA differentially affect the output of the mesocorticolimbic dopaminergic pathway. 5-HT(2B) receptors exert independent control over the activity of the three ascending dopamine (DA) pathways through specific tonic excitatory and inhibitory control of DA efflux from the Acb and PFC and do not affect striatal activity. CONCLUSIONS: The serotonergic system exerts modulatory effects on the behavioral and neurochemical effects of psychostimulants. The pharmacological manipulation of serotonergic system activity makes it possible to attenuate the effects of psychostimulants, which gives hope for the development of effective pharmacotherapy. Currently, the main obstacle to this is the excessive side effects shown by potential drugs.