Electrophysiological effects of E-5842, a sigma1 receptor ligand and potential atypical antipsychotic, on A9 and A10 dopamine neurons.
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)bu tyl]pyridine citrate), a preferential sigma1 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) x 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.
Sánchez-Arroyos
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R
Department of Neuropharmacology, Research Center, Laboratorios Esteve, Barcelona, Spain.
Guitart
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X
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D008024:Ligands; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000097605:Sigma-1 Receptor
D014150:Antipsychotic Agents; D004298:Dopamine; D008024:Ligands; D011725:Pyridines; D017480:Receptors, sigma; D014230:Triazoles; D000097605:Sigma-1 Receptor; C117757:E 5842