Atypical neuroleptic properties of l-stepholidine -Electrophysiological and behavioral studies

Intravenous administration of l-stepholidine (SPD), a dopamine (DA) receptor antagonist, in-creased 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 fir-ing activity of DA neurons in the VTA but not in the SNC. The inhibition was reversed by the DA agonist apomor-phine (APO), suggesting that it may be via the mechanism of depolarization inactivation (DI). In rats, chronic admin-istration 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 neu-rons 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 pro-portion to dosage was only observed in the dose range of 10-40 mg/kg and lasted 15 min. SPD effectively antago-nized the APO (2 mg/kg, i.p. )-induced stereotypy. The above-mentioned results suggest that SPD selectively inacti-vates the DA neurons in the VTA not in the SNC. SPD may associate with a low incidence of extrapyramidal side-ef-fects and may be ranked as a promising compound for searching for a new kind of atypical neuroleptics.

Intravenous administration of l-stepholidine (SPD), a dopamine (DA) receptor antagonist, in-creased 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 fir-ing activity of DA neurons in the VTA but not in the SNC. The inhibition was reversed by the DA agonist apomor-phine (APO), suggesting that it may be via the mechanism of depolarization inactivation (DI). In rats, chronic admin-istration 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 neu-rons 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