Characteristics of (-)-stepholidine on the firing activity of substantia nigral dopamine neurons after repeated reserpine treatment.

Although (-)-stepholidine [(-)-SPD] exhibits antagonistic effects to normosensitive dopamine (DA) receptors, it shows agonistic effect (probably D1) on rotational behavior in rats with unilateral 6-OHDA lesions of substantia nigra pars compacta (SNC). In this study, another supersensitive model, reserpinized rats (1 mg/kg x 6 days, s.c.), were used to investigate the properties of (-)-SPD. In reserpinized rats, (-)-SPD reversed and/or significantly attenuated the firing inhibition caused by the mixed DA receptor agonist apomorphine (APO). After reserpinization, the selective D1 and D2 receptor agonists separately inhibited the firing rate of SNC DA neurons, and (-)-SPD reversed both D2 receptor agonist N-0437- and D1 receptor agonist SKF 38393-induced inhibition of the SNC DA cell firing. These results suggest that (-)-SPD shows D1 and D2 receptor antagonistic action and does not possess the same DA receptor agonistic effect on SNC DA cell firing activity in reserpinized supersensitive rats as it does in unilateral 6-OHDA-lesioned rotational behavior. Also, large doses of (-)-SPD inhibited the firing rate of SNC DA cells in reserpinized rats, but the inhibition was not reversed by D1 receptor antagonist SCH 23390 but was reversed by N-0437 or APO. This inhibition, thus, could be interpreted as depolarization inactivation (DI) due to blockade of DA receptors. Interestingly, in control (nonreserpinized) rats, (-)-SPD did not produce DI of SNC DA cells as it did on ventral tegmental area DA cells. These results imply that reserpinization modulates the onset of DI of SNC DA cells and that (-)-SPD may serve as a leading compound for exploring new types of atypical neuroleptics.