Dopaminergic D-3 binding sites are not presynaptic autoreceptors

Abstract

Postsynaptic dopamine (DA) receptors have been classified biochemically and pharmacologically into two types: D-1 receptors mediate adenylate cyclase stimulation, demonstrating micromolar affinity for DA and butyrophenone antagonists; D-2 receptors mediate adenylate cyclase inhibition, demonstrating nanomolar affinity for DA and butyrophenone antagonists^1,2. D-1 receptors are labelled by ³H-thioxanthene antagonists^2,3, while D-2 receptors are labelled by both ³H-agonists and all ³H-antagonists^2,4. A third class of dopaminergic binding site, termed D-3, represents high-affinity ³H-agonist binding sites demonstrating low, micromolar, affinity for butyrophenones^5,6. In the rat striatum, D-3 sites were decreased 50% by 6-hydroxy dopamine (6-OHDA) lesions of the nigrostriatal DA pathway^7–9, suggesting that such D-3 binding labels presynaptic DA autoreceptors on nigrostriatal terminals^5,7–9. However, nigrostriatal denervation produces a concomitant depletion of striatal DA^10,11. Here we demonstrate that a reserpine-induced depletion of DA produces a decrease in D-3 binding comparable to that seen with nigrostriatal denervation, independent of presynaptic terminal degeneration. This loss in binding, or that caused by 6-OHDA lesions, is recovered by preincubating the striatal membranes with DA or with the supernatant from control striatal membrane preparations. We therefore suggest that the loss of D-3 binding following 6-OHDA lesions results from the depletion of endogenous DA rather than the degeneration of terminals and their putatively associated autoreceptors.