Histamine H3 and dopamine D2 receptor-mediated [35S]GTPgamma[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 [(35)S]GTPgamma[S] binding assay. The H(3)R agonist (R)alpha-methylhistamine increased [(35)S]GTPgamma[S] binding to striatal membranes with an EC(50)=14+/-5 nM and a maximal effect of +19+/-1%. This effect was inhibited by the H(3)R antagonist ciproxifan with a K(i)=1.0+/-0.3 nM. The D(2)R agonist quinpirole increased [(35)S]GTPgamma[S] binding to the same membranes with an EC(50)=1.5+/-0.5 microM 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 H(3)R and D(2)R agonists were additive (+46+/-3%). However, D(2)R ligands did not modify the effects of H(3)R ligands and vice versa. Ciproxifan behaved as an H(3)R inverse agonist and decreased [(35)S]GTPgamma[S] binding. Haloperidol had no effect and did not change the inverse agonist effect of ciproxifan. Administrations for 10 days of ciproxifan (1.5mg/kg/day) or haloperidol (0.5mg/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 H(3)R inverse agonists and supports their therapeutic interest, alone or as adjunctive treatment with neuroleptics.
Humbert-Claude
Marie
M
INSERM, Unité de Neurobiologie et Pharmacologie Moléculaire (U573), Centre Paul Broca, 75014 Paris, France.
Morisset
Séverine
S
Gbahou
Florence
F
Arrang
Jean-Michel
JM
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism* / Q000502:physiology; D018100:Receptors, Histamine H3 / Q000378:metabolism* / Q000502:physiology; D013462:Sulfur Radioisotopes
D007093:Imidazoles; D017448:Receptors, Dopamine D2; D018100:Receptors, Histamine H3; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C115705:ciproxifan; D006220:Haloperidol