Effects of D 1 and D 2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D 1/D 2 coactivation induces potentiated responses

Abstract

Extracellular single unit recording techniques were used to compare the effects of selective and non-selective dopamine agonists on substantia nigra pars reticulata activity in rats with 6-hydroxydopamine induced lesions of the nigrostriatal dopamine pathway. As previously shown, apomorphine (0.32 mg/kg), a dopamine agonist that interacts with both D 1 and D 2 dopamine receptor subtypes, produced consistent inhibitions of substantia nigra pars reticulata activity in these animals. The D 1-receptor agonist, SKF 38393 (RS-SKF 38393, 10 mg/kg), also induced significant inhibitions in the activity of these neurons in 6-hydroxydopamine lesioned rats, although less consistently than did apomorphine. The effects of SKF 38393 were reversed by the D 1-antagonist, SCH 23390. The D 2 selective agonist quinpirole was considerably less effective than apomorphine at inhibiting substantia nigra pars reticulata activity at doses up to 1 mg/kg. Since comparable experiments have shown that quinpirole is as effective as apomorphine at producing dopamine D 2-autoreceptor-mediated effects on dopamine neuron activity, quinpirole's lack of efficacy in the present study relative to that of apomorphine does not appear to be related to differences in relative potency for central D 2-receptors using this route of administration. Rather, the relative effectiveness of SKF 38393 on pars reticulata activity suggests that selective stimulation of D 1-receptors is at least, if not more, efficacious than selective stimulation of D 2-receptors at inducing alterations in the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats. The simultaneous stimulation of both receptors, however, was considerably more effective than selective stimulation of either receptor subtype: doses of SKF 38393 and quinpirole which had no significant effect on nigral activity when administered alone brought about marked inhibition of the firing of these cells when administered simultaneously. No such inhibition was seen when the inactive enantiomer, S-SKF 38393, was substituted for the racemic form of SKF 38393 in this protocol. These observations in 6-hydroxydopamine lesioned rats support other recent findings indicating that the two dopamine receptor sub-types can interact in a synergistic way to affect basal ganglia output.