B. Parsons et al., NEUROLEPTICS UP-REGULATE ADENOSINE A(2A) RECEPTORS IN RAT STRIATUM - IMPLICATIONS FOR THE MECHANISM AND THE TREATMENT OF TARDIVE-DYSKINESIA, Journal of neurochemistry, 65(5), 1995, pp. 2057-2064
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.