(-)-Stepholidine acts as a D1 partial agonist on firing activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine-lesioned rats.

(-)-Stepholidine (SPD), a novel dopamine (DA) D1 and/or D2 receptor antagonist in normosensitive animals, shows agonistic effects on D1 receptors in rotational behavior of 6-hydroxydopamine (6-OHDA)-lesioned rats. To further characterize the pharmacological properties of SPD, we investigated the effects of SPD on firing activity of substantia nigra pars reticulata (SNR) neurons in different sensitive models. In control rats, the selective D1 agonist SKF38393 (4 mg/kg, i.v.) induced inconsistent changes (i.e. increase, decrease or no change) in firing of SNR neurons. These effects were completely antagonized by SPD (i.v.), regardless of the changes induced by SKF38393. SPD (4 mg/kg), per se, increased firing by 30.9 +/- 14.4%. In reserpinized rats, SKF38393 also induced SPD-reversible inconsistent changes as in control rats. Nevertheless, SPD per se produced no alteration in firing of SNR neurons. In 6-OHDA-lesioned rats, 5/6 SNR neurons were inhibited by SKF38393. The inhibition was completely abolished by Sch23390, a selective D1 antagonist (0.5-2 mg/kg), but partially reversed by SPD (1-16 mg/kg). Moreover, SPD (4 mg/kg) itself caused SNR increased or decreased neuron firing, and these effects were completely reversed by Sch23390 (0.5-2 mg/kg) in 8/12 neurons recorded. These results suggest that SPD acts as a partial agonist to D1 receptors in 6-OHDA-lesioned rats, but as an antagonist to D1 receptors in normal and reserpinized rats.