Vol. 287, Issue 1, 51-57, October 1998

Effects of Acute and Repeated Administration of Amisulpride, a Dopamine D₂/D₃ Receptor Antagonist, on the Electrical Activity of Midbrain Dopaminergic Neurons¹

Giuseppe Di Giovanni, Michele Di Mascio, Vincenzo Di Matteo and Ennio Esposito

Istituto di Ricerche Farmacologiche "Mario Negri," Consorzio "Mario Negri" Sud, Santa Maria Imbaro (Chieti), Italy

Electrophysiological techniques were used to study the effects of amisulpride, a D₂/D₃ dopamine receptor blocker, on the activity of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). Administration of single bolus doses of amisulpride (8-32 mg/kg i.v.) induced a dose-dependent increase in the basal activity of dopaminergic neurons, in both the SNc and the VTA. The effect of amisulpride was more evident in the VTA, where it elicited a maximal excitation of 38.5 ± 12%, whereas in the SNc it caused a peak excitation of only 22.1 ± 9.8%. Amisulpride also increased the bursting activity of dopaminergic neurons in the VTA but not in the SNc. Microiontophoretic application of amisulpride (10-40 nA) into the SNc and the VTA caused an increase in the basal firing rate of the majority of dopaminergic neurons sampled. The excitation induced by 40 nA amisulpride was more marked in the VTA (36.1 ± 21%) than in the SNc (25.0 ± 18%). Moreover, microiontophoretic amisulpride (40 nA) increased the bursting activity of dopaminergic neurons in the VTA only. Repeated administration of amisulpride (20 and 50 mg/kg i.p.) for 21 consecutive days produced a significant decrease in the number of spontaneously active dopaminergic neurons in the VTA but not in the SNc. Repeated admistration of haloperidol (0.5 mg/kg i.p.) decreased the number of dopaminergic cells both in the SNc and the VTA. The effect of repeated admistration of amisulpride on the activity of VTA dopaminergic neurons was reversed by apomorphine, suggesting that these neurons were probably under a state of depolarization block. Taken together, these data confirm previous findings indicating that low doses of amisulpride preferentially increase dopaminergic transmission in the mesolimbic system. Moreover, results obtained from long-term experiments are consistent with clinical data indicating that amisulpride given at high doses is an effective antipsychotic agent, associated with a low incidence of extrapyramidal side effects.