Several studies have shown that the ventral tegmental area (VTA) is innervated serotonin (5- hydroxytryptamine, 5-HT)-containing axon terminals originating in the midbrain raphe nuclei, Electrophysiological experiments have shown that 5-HT inhibits the spontaneous activity of dopamine (DA)- containing neurons in the VTA through the 5-HT2C/2B receptor subtype. Thus mixed 5-HT2C/2B receptor agonists, such as 1-(m-trifluoromethylphenyl)piperazine (TFMPP) and 1-(m-chlorophenyl)piperazine (mCPP) reduce the basal firing rate of DA neurons in the VTA, whereas these neurons are stimulated by the 5-HT2C/2B receptor antagonist mesulergine. Prisco and Esposito have shown that fluoxetine and citalopram, two selective serotonin reuptake inhibitors (SSRIs), inhibit the activity of DA cells in the VTA but not in the substantia nigra pars compacta (SNc). The effect of fluoxetine on VTA DA neurons is mediated through an enhancement of 5-HT neurotransmission, in that it is abolished by selective lesions of 5-HT neurons by the neurotoxin 5,7- dihydroxytryptamine. Moreover, pretreatment with mesulergine blocks the inhibitory effect of fluoxetine, thus indicating an involvement of 5-HT2C/2B receptor subtypes in fluoxetine’s action. More recently, it has been found that administration of SB 206553, a poten and selective 5-HT2C/2B antagonist, causes a dose-dependent increase in the basal firing rate of VTA DA neurons. On the other hand, injection of the selective 5-HT2A antagonist SR 46349B and ritanserin, a blocker of 5-HT2A/2C receptors, do not cause any significant change in the basal activity of these neurons. Moreover, SB 206553 significant increases DA outflow in the nucleus accumbens, whereas SR 46349B and ritanserin do not have any effect. Taken together, these data indicate that the mesocorticolimbic dopaminergic function is under tonic control by 5-HT, which acts through the 5-HT2C/2B receptors, and that the selective blockade of 5-HT2C/2B receptors disinhibits this neuronal system. In addition, several studies indicate that 5-HT3 receptor antagonists reduce raised mesolimbic DA activity. These findings might open new possibilities for the employment of 5-HT2C/2B receptor antagonists in the treatment of depression and negative symptoms of schizophrenia. Moreover, the selective action of 5-HT3 receptor antagonists on the overactivity of mesocorticolimbic DA transmission raises the possibility of developing such drugs as potentially antipsychotic agents, and in preventing ethanol-induced reward behavior and drug abuse.
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