Receptor Binding Autoradiography With Pramipexole, A Clinically Useful D3-Preferring Dopamine Agonist

Abstract

Because it most potently stimulates dopamine (DA) autoreceptors, pramipexole (PPX) (EJPharmacol 215:161, 1992) can depress DA tone. PPX is currently being evaluated as a novel autoreceptor agonist antipsychotic. At higher doses, PPX also stimulates DA postsynaptic receptors belonging to the D2 receptor subfamily. It is also useful for treating Parkinson's disease (Neurol 43:879P, 1993). The D2 receptor subfamily is composed of the broadly-distributed D2, the mesolimbic-preferring D3, and the mesocortical-preferring D4 receptor subtypes. We report that, in studies with cloned subtypes of the D2 receptor subfamily, PPX has higher affinity for the D3 as compared to the D2 and D4 subtypes. Receptor binding autoradiography with 3H-PPX (5 nM, 62 Ci/mmole) was used to evaluate the distribution of PPX binding sites within the rat brain. Talipexole, 10 μM, was used to evaluate nonspecific binding. Consistent with its preference for D3 binding sites, the highest concentrations of 3H-PPX binding sites were found in the islets of Calleja, previously reported to contain D3 but not D2 or D4 receptors (PNAS 89:8155, 1992). 3H-PPX binding was also high in other mesolimbic areas such as the nucleus accumbens, olfactory tubercle and amygdala. However, 3H-PPX binding was also high in caudate, a DA postsynaptic area thought to be high in D2 receptors, but in which some D3 pharmacological effects have also been described (Neurosci Abs 19:80, 1993). Fewer 3H-PPX binding sites were found in VTA and substantia nigra, areas rich in cell bodies for DA neurons. Although PPX most potently stimulates DA autoreceptors, PPX binding sites have their highest concentrations in projection areas containing both DA terminal and postsynaptic receptors. PPX's preferential affinity for the D3 receptor subtype could render it less likely to produce adverse affects than D2 subfamily agonists non-selectively interacting with D2, D3 and D4 receptor subtypes.