Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin2C/2B receptor agonists : a combined in vivo electrophysiological and microdialysis study

Abstract

Electrophysiological and in vivo microdialysis were used to investigate and compare the effect of tonic activation of serotonin2C/2B (5-HT2C/2B) receptors on nigrostriatal and mesolimbic dopaminergic (DA) function. Thus, extracellular single unit recordings of neurochemically-identified DA neurons in the SNc and the VTA, as well as simultaneous monitoring of striatal and accumbal DA release were performed following the administration of the unselective 5-HT2C/2B agonists, mCPP (m-chlorophenylpiperazine) and MK 212 [6-chloro-2-(1-piperazinyl)piperazine]. Both mCPP (5–320 μg/kg i.v.) and MK 212 (5–320 μg/kg i.v.) dose-dependently decreased the firing rate of VTA DA neurons. The maximal effect was reached at the cumulative dose of 320 μg/kg mCPP and MK 212, which caused a decrease of 42.6 ± 12.8% and 56.4 ± 12.6%, respectively. In addition, the total number of events in bursts and the number of bursts of VTA DA cells were significantly reduced by both mCPP and MK 212. On the other hand, mCPP (5–320 μg/kg i.v.) and MK 212 (5–320 μg/kg i.v.) induced a slight decrease in the basal firing rate, but not in bursting activity of SNc DA neurons. Consistent with electrophysiological data, dialysate DA levels in the nucleus accumbens decreased significantly, reaching the maximum of 26.6 ± 9.6% below baseline levels 120 min after mCPP (1 mg/kg i.p.) administration, and of 25.2 ± 5.5% 140 min after MK 212 (1 mg/kg i.p.) injection. DA outflow in the striatum was unaffected by both drugs. The inhibitory effect of both mCPP and MK 212 on VTA DA cell activity was blocked completely by pretreatment with the selective 5-HT2C antagonist SB 242084 {6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline} (200 μg/kg), given intravenously 10 min before the first injection of the 5-HT2C/2B agonists. SB 242084 (2.5 mg/kg i.p.) antagonized also the decrease in DA release induced by mCPP and MK 212 in the nucleus accumbens. Taken together, these data indicate that mCPP and MK 212 selectively inhibit mesolimbic dopaminergic function by acting on 5-HT2C receptors. Therefore, selective 5-HT2C receptor agonists might be useful in clinical conditions where it is necessary to reduce the mesolimbic dopaminergic activity without affecting the nigrostriatal function.