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Neuroleptics Up‐Regulate Adenosine A 2a Receptors in Rat Striatum: Implications for the Mechanism and the Treatment of Tardive Dyskinesia
Author(s) -
Parsons Bruce,
Togasaki Daniel M.,
Kassir Suham,
Przedborski Serge
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.65052057.x
Subject(s) - sulpiride , haloperidol , cgs 21680 , fluphenazine , clozapine , adenosine a2a receptor , chemistry , medicine , pharmacology , endocrinology , dopamine receptor , dopamine receptor d2 , dopamine , striatum , receptor , adenosine receptor , agonist , dopaminergic , schizophrenia (object oriented programming) , psychiatry
Neuroleptics, which are potent dopamine receptor antagonists, are used to treat psychosis. In the striatum, dopamine subtype‐2 (D 2 ) receptors 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 intraperitoneal injections of these drugs. Haloperidol (1.5 mg/kg/day) increased the density of striatal D 2 receptors by 24% without changing their affinity for [ 3 H]sulpiride. Haloperidol increased the density of 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) without changing their affinity for [ 3 H]CGS‐21680 (control, 19.2 ± 2.2 n M ; haloperidol, 21.4 ± 2.3 n M ). In contrast, haloperidol had no such effect on striatal dopamine subtype‐1 (D 1 ) and adenosine subtype‐1 (A 1 ) receptors. Binding characteristics and the pharmacological displacement profile of the increased [ 3 H]CGS‐21680 binding sites confirmed them as A 2a receptors. Comparing different classes of neuroleptics 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) did 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 protein; sulpiride, 319.8 ± 18.9 fmol/mg of protein; clozapine, 309.2 ± 13.7 fmol/mg of protein). Similarly, the typical neuroleptics increased 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 of protein; fluphenazine, 701.1 ± 31.6 fmol/mg of protein; 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 [ 3 H]CGS‐21680 or [ 3 H]sulpiride among the various treatment groups. This study demonstrates that typical neuroleptics induce comparable up‐regulation in both striatal D 2 and A 2a receptors. Thus, A 2a receptors might be a pharmacologic target for the development of novel therapeutic strategies to minimize the adverse effects of antipsychotic treatment.