Dopamine receptors in canine caudate nucleus.

Abstract

Physiological, pharmacological, histochemical and biochemical studies indicate that dopamine receptors are heterogenous in the central nervous system with each individual functions. This review describes pharmacological and biochemical characteristics of dopamine receptors, particularly in canine caudate nucleus, which have been studied in our laboratory with a brief comparison to the current studies by other workers in similar research fields. Two distinct dopamine receptors have been characterized by means of [3H]dopamine binding to the synaptic membranes from canine caudate nucleus. One of the receptors with a Kd of about 3 muM for dopamine may be associated with adenylate cyclase and referred to as D2 receptor. The other receptor with a Kd of about 10 nM for dopamine is independent of adenylate cyclase and referred to as D2. A photochemical irreversible association of [3H]dopamine with the membraneous receptors makes it possible to separate D1 and D2 receptors from one another by gel filtration on a Sephadex G-200 column after solubilization with Lubrol PX. On the basis of selective inhibition of [3H]dopamine binding to D1 and D2 receptors, dopamine antagonists can be classified into three classes: D1-selective (YM-09151-2), D2-selective (sulpiride) and nonselective (haloperidol, chlorpromazine). Effects of these typical antagonists on the metabolism of rat brain dopamine suggest that D1 receptor is more closely associated with the neuroleptic-induced increase in dopamine turnover. Studies with 28 benzamide derivatives and some classical neuroleptics reveal that apomorphine-induced stereotypy displays a greater association with D1 than with D2 receptors. Dopamine-sensitive adenylate cyclase in canine caudate nucleus can be solubilized with Lubrol PX in a sensitive form to either dopamine. Gpp(NH)p or fluoride Sephadex G-200 gel filtration separates adenylate cyclase from D1 receptors with a concomitant loss of dopamine sensitivity. Addition of the D1 receptor fraction to the adenylate cyclase restores the responsiveness to dopamine. The solubilized dopamine-unresponsive adenylate cyclase can be further separated into two distinct fractions by a batch-wise treatment with GTP-sepharose: a catalytic unit which does not respond to fluoride, and a guanine nucleotide regulatory protein. The regulatory protein confers distinct responsiveness to Gpp(NH)p and fluoride upon adenylate cyclase. These results indicate that dopamine-sensitive adenylate cyclase is composed of at least three distinct units; D1 receptor, guanine nucleotide regulatory protein and adenylate cyclase.