An electrophysiological analysis of the actions of the 3-PPP enantiomers on the nigrostriatal dopamine system.

Abstract

Extracellular single unit recording and microiontophoretic studies were carried out in chloral hydrate-anesthetized gallamine-paralyzed rats to investigate the actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, on the nigrostriatal DA system. Intravenously administered (+)- or (-)-3-PPP consistently inhibited nigral DA neuronal activity; these actions were readily antagonized by haloperidol but were not affected by a pretreatment of reserpine plus alpha-methyltyrosine. In contrast to (+)-3-PPP, the (-)-enantiomer produced only partial inhibition of the majority of cells studied and was also capable of partially reversing the inhibitory action of apomorphine. A prior hemitransection of the brain did not alter the inhibitory action of either enantiomer. Whereas iontophoretically ejected (+)-3-PPP consistently reduced DA cell firing rate, similarly applied (-)-3-PPP reduced the activity of only some DA cells, while the majority were not influenced. In addition, iontophoresis of (-)-3-PPP could reduce the inhibitory effect of similarly applied DA or (+)-3-PPP. The (+)-enantiomer reduced caudate neuronal activity both after intravenous administration and iontophoresis. Intravenously administered (-)-3-PPP failed to influence or increased the activity of these neurons and reversed the inhibitory action of apomorphine. However, iontophoretically ejected drug reduced caudate cell activity and did not influence the inhibitory action of DA. The activity of non-DA zona reticulata neurons was inconsistently influenced by the 3-PPP enantiomers. It is concluded that (+)-3-PPP is a directly acting DA agonist, stimulating both DA autoreceptors and postsynaptic DA receptors. In contrast, (-)-3-PPP appears to be a partial agonist at nigral DA autoreceptors, whereas the action of the drug at putative postsynaptic DA receptors in the caudate remains to clarified.