Subchronic haloperidol increases CB(1) receptor binding and G protein coupling in discrete regions of the basal ganglia.

• The present study was designed to test whether chronic neuroleptic treatment, which is known to alter both expression and density of dopamine D(2) receptors in striatal regions, has effects upon function and binding level of the cannabinoid CB(1) receptor in the basal ganglia by using receptor autoradiography. As predicted, subchronic haloperidol treatment resulted in increased binding of (3)H-raclopride and quinpirole-induced guanosine 5'-O-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) in the striatum when compared to that measured in control animals. This increased D(2) receptor binding and function after 3 days washout was normalized after a 2-week washout period. Effect of haloperidol treatment was studied for CB(1) receptor binding and CP55,940-stimulated [(35)S]GTPgammaS in the striatum, globus pallidus, and substantia nigra. (3)[H]CP55,940 binding levels were found in rank order from highest to lowest in substantia nigra > globus pallidus > striatum. Furthermore, subchronic haloperidol treatment resulted in elevated binding levels of (3)[H]CP55,940 in the striatum and the substantia nigra and CB(1) receptor-stimulated [(35)S]GTPgammaS bindings in the substantia nigra after 3 days washout. These increased binding levels were normalized at 1-4 weeks after termination of haloperidol treatment. Haloperidol treatment had no significant effect on CB(1) receptor or [(35)S]GTPgammaS binding levels in globus pallidus. The results help to elucidate the underlying biochemical mechanism of CB(1) receptor supersensitivity after haloperidol treatment.

Nyckelord

Analgesics/metabolism

Animals

Basal Ganglia/*drug effects/metabolism

Binding; Competitive/*drug effects/physiology

Cyclohexanols/metabolism

Dopamine Antagonists/pharmacology

Drug Administration Schedule

Drug Interactions/physiology

Guanosine 5'-O-(3-Thiotriphosphate)/metabolism

Haloperidol/*pharmacology

Male

Raclopride/metabolism

Radioligand Assay

Rats

Rats; Sprague-Dawley

Receptor; Cannabinoid; CB1/*drug effects/metabolism

Receptors; Dopamine D2/drug effects/metabolism

Receptors; G-Protein-Coupled/*drug effects/metabolism

Up-Regulation/drug effects/physiology

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