Chronic haloperidol treatment leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum

Stimulation of adenosine A₂ receptors (with the selective adenosine A₂ agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D₂ receptors and the transduction of the signal from the D₂ receptor to the G protein. This intramembrane A₂-D₂ interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A₂-D₂ interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals. The present study was designed to examine if chronic treatment with haloperidol, which also produces dopamine receptor supersensitivity, is also associated with an increase in the intramembrane A₂-D₂ interaction in the neostriatum and with a higher sensitivity to the behavioural effects induced by adenosine antagonists. The data showed that: (i) haloperidol pretreatment causes a higher binding of the D₂ antagonist [³H] raclopride in striatal membrane preparations due to an increase in the number of D₂ receptors without changes in their affinity for the antagonist (increase in B_max without changes in k_d); (ii) GCS 21680 decreases the affinity of dopamine for the D₂ receptor, by increasing the equilibrium dissociation constants of high (K_h) and low affinity (K₁) dopamine D₂ binding sites and increases the proportion of high affinity binding sites (R_h); (iii) a low dose of CGS 21680 (3 nM), which is ineffective in membrane preparations from neostriatum of nontreated animals, is effective in membranes from the striatum of haloperidol-pretreated animals; (iv) the nonselective adenosine antagonist theophylline (20 mg/kg SC) causes a higher motor activation in rats pretreated with haloperidol. The possible relevance of these results for the pathophysiology and treatment of tardive dyskinesias is discussed.