Atypical neuroleptic properties ofl-stepholidine : Electrophysiological and behavioral studies

Intravenous administration ofl-stepholidine (SPD), a dopamine (DA) receptor antagonist, increased the firing rate of DA neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) in both anaesthetized and paralyzed rats. However, with the increase of dose, SPD selectively inhibited the firing activity of DA neurons in the VTA but not in the SNC. The inhibition was reversed by the DA agonist apomorphine (APO), suggesting that it may be via the mechanism of depolarization inactivation (DI). In rats, chronic adrninistration of SPD for 21 d dose-dependently decreased the number of spontaneously active DA neurons in the VTA, of which effect was reversed by APO (i. v.). In contrast, the same treatment failed to affect the population of DA neurons in the SNC. Similarly, the acute treatment of SPD also decreased the number of spontaneously firing DA neurons in the VTA, but not in the SNC. SPD per se only induced very weak catalepsy. Its catalepsy which was not in proportion to dosage was only observed in the dose range of 10-40 mg/kg and lasted 15 min. SPD effectively antagonized the APO (2 mg/kg, i. p.)-induced stereotypy.The above-mentioned results suggest that SPD selectively inactivates the DA neurons in the VTA not in the SNC. SPD may associate with a low incidence of extrapyramidal side-effects and may be ranked as a promising compound for searching for a new kind of atypical neuroleptics.