CATALEPSY, FOS PROTEIN, AND DOPAMINE-RECEPTOR OCCUPANCY AFTER LONG-TERM HALOPERIDOL TREATMENT

During 12-week haloperidol treatment of rats, the cataleptic effect of an additional challenge dose becomes gradually weaker. We studied whe ther such a tolerance phenomenon is related to receptor supersensitivi ty-thus leaving more spare receptors - to a shift in affinity of the r eceptors towards agonist binding or to an attenuation of a postsynapti c response to dopamine (D-2-type) receptor blockade in the rat basal g anglia. Receptor occupancy was studied with the radioactive agonist [H -3]N-propylapomorphine (NPA) and antagonist [H-3]N-methylspiperone (MS PIP) to label free dopamine D-2 receptors in vivo. Fos protein served as an index of the postsynaptic response, which was histochemically qu antified. This study does not support the concept that dopamine recept or supersensitivity may overcome neuroleptic receptor blockade, but th ere may be a shift towards higher agonist binding over time. The atten uation of Fos protein expression in the basal ganglia precedes the dev elopment of behavioral tolerance.