SB 242 084, a selective serotonin 2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system

Abstract

Electrophysiological techniques and in vivo microdialysis were used to investigate the effect of SB 242 084, a potent and selective 5-HT 2C receptor antagonist in the control of nigro-striatal and mesolimbic dopaminergic function. Thus, extracellular single unit recordings were performed from neurochemically-identified dopamine (DA) neurons in the substantia nigra, pars compacta (SNc) and the ventral tegmental area (VTA), as well as monitoring of striatal and accumbal basal DA release in anesthetized rats following the administration of SB 242 084 and RO 60-0175. Administration of SB 242 084 (160–640 μg/kg, i.v.) caused a dose-dependent increase in the basal firing rate of VTA DA neurons, reaching its maximum (27.8±6%, above baseline) after 640 μg/kg. Moreover, bursting activity was significantly enhanced by SB 242 084 in the VTA. On the other hand, SB 242 084 (160–640 μg/kg, i.v.) did not cause any significant change in the basal firing rate and bursting activity of DA neurons in the SNc. Injection of the 5-HT 2C receptor agonist RO 60-0175 (80–320% μg/kg, i.v.) dose-dependently decreased the basal firing of DA neurons in the VTA but not in the SNc. RO 60-0175 exerted its maximal inhibitory effect (53.9±15.1%, below baseline) in the VTA at the dose of 320 μg/kg. Basal DA release (34.8±9%, above baseline) and dihydroxyphenylacetic acid (DOPAC) efflux (19.7±7%, above baseline) were significantly enhanced in the nucleus accumbens following the intraperitoneal administration of 10 mg/kg SB 242 084. Intraperitoneal injection of 5 mg/kg SB 242 084 significantly increased DA release (16.4±6%, above baseline) in the nucleus accumbens, but did not affect DOPAC efflux. In the striatum, SB 242 084 (5 and 10 mg/kg, i.p.) only slightly increased DA release above baseline (3.5±4 and 11.2±6%, respectively), without affecting DOPAC efflux in this area. However, the effect of SB 242 084 in the striatum was rendered more evident by the fact that injection of the vehicle used to dissolve the drug in a group of control rats, significantly reduced basal DA output by 19.6±7%. Stimulation of 5-HT 2C receptors by RO 60-0175 (1 mg/kg, i.p.) significantly decreased DA release in the nucleus accumbens by 26.1±4% (below baseline) 60 min after injection. On the other hand, RO 60-0175 (1 mg/kg, i.p.) did not cause any significant change of DA release in the striatum. However, DOPAC efflux was reduced by RO 60-0175 (1 mg/kg, i.p.) both in the striatum and the nucleus accumbens. Taken together, these data indicate that the central 5-HT system exerts a tonic and phasic inhibitory control on mesolimbic DA neuron activity and that 5-HT 2C receptor subtypes are involved in this effect. Moreover, these findings might open new possibilities for the employment of 5-HT 2C receptor antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central DA neurons.