Differential electrophysiological effects of 3-PPP and its enantiomers on dopamine autoreceptors and postsynaptic receptors.

The activities of substantia nigra pars compacta dopamine and globus pallidus neurons have been examined following the systemic administration of ( +/- )-3-PPP and the enantiomers of 3-PPP to investigate the relative effects of these putative dopamine agonists on dopamine autoreceptors and postsynaptic dopamine receptors. ( +/- )-3-PPP inhibited the firing rates of 7 out of 10 dopamine cells completely (ED50 = 0.18 +/- 0.06 mg/kg) but caused no consistent or significant alterations in the firing rates of globus pallidus neurons, exhibiting an apparent selectivity for the dopamine D-2 autoreceptors. However, (+)-3-PPP effectively inhibited the activity of all dopamine neurons studied (ED50 = 0.09 +/- 0.03 mg/kg) and, like d-amphetamine, apomorphine and other dopamine agonists, significantly stimulated pallidal activity. (-)-3-PPP was less effective at inhibiting dopamine cell activity; it had no effect on firing rates of pallidal cells when given alone, but it reversed the pallidal rate increases induced by (+)-3-PPP and also blocked the rate increases induced by systemically administered apomorphine. The results show that (-)-3-PPP, given systemically, acts as a partial agonist in the substantia nigra pars compacta and as an antagonist on postsynaptic dopamine receptors. These effects of (-)-3-PPP appear to account for the apparent dopamine autoreceptor selectivity demonstrated by racemic 3-PPP and further indicate that the autoreceptors and postsynaptic dopamine receptors may be differentially affected by a drug with mixed agonist/antagonist properties. These conclusions are consistent with those obtained from other techniques and support the idea that the effects of dopamine agonists on the activity of dopamine neurons and globus pallidus cells can provide an indication of the relative selectivity of these drugs for pre- or postsynaptic dopamine receptors.