Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function:: A combined in vivo electrophysiological and microdialysis study

Electrophysiological techniques and in vivo microdialysis were used to investigate the relative contribution of central serotonin-2C/2B and serotonin-2A receptor subtypes in the control of mesolimbic and nigrostriatal dopaminergic function. Thus, extracellular single-unit recordings were performed from neurochemically identified dopamine neurons in the ventral tegmental area and the substantia nigra pars compacta, as well as simultaneous monitoring of accumbal and striatal basal dopamine release in anesthetized rats following the administration of serotonin-2C/2B (SB 206553), serotonin-2A (SR 46349B) or serotonin-2A/2B/2C (ritanserin) antagonists. Administration of SE 206553 (40-160 mu g/kg, i,v.) caused a dose-dependent increase in the basal firing rate of ventral tegmental area and nigral dopamine neurons, reaching its maximum (45.2 and 28.5%, respectively) following 160 mu g/kg. Moreover, burst activity was significantly enhanced by SE 206553 in the ventral tegmental area only. In contrast, injection of SR 46349B (40-160 mu g/kg, i.v.), and ritanserin (40-160 mu g/kg, i.v.) did not cause any significant change in the basal activity of these neurons. Basal dopamine release was significantly enhanced in both the nucleus accumbens (42%) and the striatum (33%) following the intraperitoneal administration of 5 mg/kg SE 206553. In contrast, SR 46349B (0.5 mg/kg, s.c,) and ritanserin (0.63 mg/kg, i.p.) failed to affect basal dopamine output in both regions. Taken together, these data indicate that the central serotonergic system exerts a tonic inhibitory control of mesolimbic and nigrostriatal dopaminergic pathway activity and that the serotonin-2C/2B receptor subtypes are involved in this effect. Moreover, these findings might open new possibilities for the employment of serotonin-2C/2B receptor antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central dopaminergic neurons. (C) 1999 IBRO. Published by Elsevier Science Ltd.