During 12-week haloperidol treatment of rats, the cataleptic effect of an additional challenge dose becomes gradually weaker. We studied whether such a tolerance phenomenon is related to receptor supersensitivity--thus leaving more spare receptors--to a shift in affinity of the receptors towards agonist binding or to an attenuation of a postsynaptic response to dopamine (D2-type) receptor blockade in the rat basal ganglia. Receptor occupancy was studied with the radioactive agonist [3H]N-propylapomorphine (NPA) and antagonist [3H]N-methylspiperone (MSPIP) to label free dopamine D2 receptors in vivo. Fos protein served as an index of the postsynaptic response, which was histochemically quantified. This study does not support the concept that dopamine receptor supersensitivity may overcome neuroleptic receptor blockade, but there may be a shift towards higher agonist binding over time. The attenuation of Fos protein expression in the basal ganglia precedes the development of behavioral tolerance.
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