Electrophysiological effects of E-5842, a σ 1 receptor ligand and potential atypical antipsychotic, on A9 and A10 dopamine neurons

Abstract

Extracellular single unit recording techniques were used to study the effects of the novel potential atypical antipsychotic E-5842, (4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-[4-(1,2,4-triazol-1-il)butyl]pyridine citrate), a preferential σ 1 receptor ligand, on the activity of dopamine cells in substantia nigra pars compacta (A9) and ventral tegmental area (A10) in anesthetized rats. Acute i.v. administration of E-5842 (up to 3.2 mg kg −1) did not change the spontaneous activity of the dopamine neurons, which still responded to the inhibitory effect of a subsequent administration of high dose of apomorphine. Acute administration of E-5842 (20 mg kg −1, i.p.) did not change the number of spontaneously active A9 or A10 dopamine cells. Chronic administration of E-5842 (20 mg kg −1 day −1×21 days, s.c.) decreased the number of spontaneously active A10, but not A9, dopamine neurons. This effect was reversed by the administration of apomorphine, thus, indicating a possible depolarization inactivation phenomenon. Our results suggest an influence of E-5842 on dopaminergic neurotransmission, although the exact mechanism remains unknown. The effect of E-5842 on A10 is similar, in some ways, to the effects observed with several atypical antipsychotics and suggest the atypicality of the compound and that E-5842 may exert its antipsychotic effects without causing significant extrapyramidal side effects.