NEUROLEPTICS UP-REGULATE ADENOSINE A(2A) RECEPTORS IN RAT STRIATUM - IMPLICATIONS FOR THE MECHANISM AND THE TREATMENT OF TARDIVE-DYSKINESIA

Neuroleptics, which are potent dopamine receptor antagonists, are used to treat psychosis. In the striatum, dopamine subtype-2 (D-2) recepto rs interact with high-affinity adenosine subtype-2 (A(2a)) receptors. To examine the effect of various neuroleptics on the major subtypes of striatal dopamine and adenosine receptors, rats received 28 daily int raperitoneal injections of these drugs. Haloperidol (1.5 mg/kg/day) in creased the density of striatal D-2 receptors by 24% without changing their affinity for [H-3]sulpiride. Haloperidol increased the density o f striatal A(2a) receptors by 33% (control, 522.4 +/- 20.7 fmol/mg of protein; haloperidol, 694.6 +/- 23.6 fmol/mg of protein; p < 0.001) wi thout changing their affinity for [H-3]CGS-21680 (control, 19.2 +/- 2. 2 nM; haloperidol, 21.4 +/- 2.3 nM). In contrast, haloperidol had no s uch effect on striatal dopamine subtype-1 (D-1) and adenosine subtype- 1 (A(1)) receptors. Binding characteristics and the pharmacological di splacement profile of the increased [H-3]CGS-21680 binding sites confi rmed them as A(2a) receptors, Comparing different classes of neurolept ics showed that the typical neuroleptics haloperidol and fluphenazine (1.5 mg/kg/day) increased D-2 receptor densities, whereas the atypical neuroleptics sulpiride (100 mg/kg/day) and clozapine (20 mg/kg/day) d id not (control, 290.3 +/- 8.7 fmol/mg of protein; haloperidol, 358.1 +/- 6.9 fmol/mg of protein; fluphenazine, 381.3 +/- 13,6 fmol/mg of pr otein; sulpiride, 319.8 +/- 18.9 fmol/mg of protein; clozapine, 309.2 +/- 13.7 fmol/mg of protein). Similarly, the typical neuroleptics incr eased A(2a) receptor densities, whereas the atypical neuroleptics did not (control, 536.9 +/- 8.7 fmol/mg of protein; haloperidol, 687.9 +/- 28.0 fmol/mg mg of protein; fluphenazine, 701.1 +/- 31.6 fmol/mg of p rotein; sulpiride, 563.3 +/- 27.2 fmol/mg of protein; clozapine, 550.9 +/- 40.9 fmol/mg of protein). There were no differences in affinities for [H-3]CGS-21680 or [H-3]-sulpiride among the various treatment gro ups, This study demonstrates that typical neuroleptics induce comparab le up-regulation in both striatal D-2 and A(2a) receptors. Thus, A(2a) receptors might be a pharmacologic target for the development of nove l therapeutic strategies to minimize the adverse effects of antipsycho tic treatment.