Histamine H3 and doparnine D2 receptor-mediated [35S]GTP-γ[S] binding in rat striatum:: Evidence for additive effects but lack of interactions

The interactions in the rat striatum between H-3 receptors (H(3)Rs) and D-2 receptors (D(2)Rs) were investigated with the [S-35]GTP-gamma[S] binding assay. The H3R agonist (R)alpha-methylhistamine increased [S-35]GTP gamma[S] binding to striatal membranes with an EC50 = 14 5 nM and a maximal effect of +19 +/- 1%. This effect was inhibited by the H3R antagonist ciproxifan with a K-i = 1.0 +/- 0.3 nM. The D2R agonist quinpirole increased [S-35]GTP-gamma[S] binding to the same membranes with an EC50 = 1.5 +/- 0.5 mu M and a maximal effect of +28 +/- 2%. Its effect was blocked by haloperidol with a K-i = 0.3 +/- 0.1 nM. The maximal effects of the H3R and D2R agonists were additive (+46 +/- 3%). However, D2R ligands did not modify the effects of H3R ligands and vice versa. Ciproxifan behaved as an H3R inverse agonist and decreased [S-35]GTP-gamma[S] binding. Haloperidol had no effect and did not change the inverse agonist effect of ciproxifan. Administrations for 10 days of ciproxifan (1.5 mg/kg/day) or haloperidol (0.5 mg/kg/day) did not change the effects of quinpirole and (R)alpha-methylhistamine, respectively. These data suggest that striatal H(3)Rs and D(2)Rs do not interact through their coupling to G-proteins. However, a hyperactivity of histaminergic and dopaminergic neurons being observed in schizophrenia, the additive activations of H(3)Rs and D(2)Rs suggest that they cooperate to generate some schizophrenic symptoms. Such a postsynaptic mechanism may underlie the antipsychotic-like effects of H3R inverse agonists and supports their therapeutic interest, alone or as adjunctive treatment with neuroleptics. (c) 2007 Elsevier Inc. All rights reserved.