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 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.
Coppens
H J
HJ
Department of Biological Psychiatry, Groningen University, The Netherlands.
Sebens
J B
JB
Korf
J
J
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced* / Q000523:psychology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006220:Haloperidol / Q000494:pharmacology*; D007150:Immunohistochemistry; D007700:Kinetics; D008024:Ligands; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D008024:Ligands; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; D006220:Haloperidol