Effect of guanine nucleotides on striatal dopamine receptors

Abstract

GUANINE NUCLEOTIDES have been shown to regulate the sensitivity of adenylate cyclase to hormones in several systems^1–5, including the dopamine-sensitive adenylate cyclase in the caudate nucleus^2,4. It has also been reported that in the presence of GTP the affinities of glucagon receptors⁶, β-adrenergic receptors^7,8, prostaglandin E₁ receptors⁹ and opiate receptors¹⁰ for agonists are decreased. For β-adrenergic receptors this effect of GTP has been described as ‘agonist-specific’, as it is seen with agonists but not with antagonists^7,8. We report here a similar effect of GTP on the ability of dopamine-receptor agonists to compete for ³H-spiroperidol binding sites on rat striatal membranes. The presence of 0.3 mM GTP led to a four-to-fivefold increase in the K_d values for the inhibition of ³H-spiroperidol binding by dopamine-receptor agonists. No changes in K_d values were observed for antagonists. Dopamine-receptor agonists and antagonists have been defined by the stimulation or inhibition of dopamine-sensitive adenylate cyclase in the neostriatum^11,12 or by their effects on the canine renal artery¹³. Controversy exists, however, as to whether binding studies using labelled neuroleptics such as spiroperidol actually measure dopamine receptors. Our finding of an agonist-specific effect of GTP supports the conclusion that ³H-spiroperidol is binding to functional dopamine receptors in the caudate nucleus.