Catalepsy, Fos protein, and dopamine receptor occupancy after long-term haloperidol treatment

• Published in: Pharmacology, biochemistry and behavior Vol. 51; no. 2; pp. 175 - 182
• Main Authors: Coppens, Hubert J., Sebens, Jantiena B., Korf, Jakob
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-06-1995; Elsevier Science
• Subjects: Animals; Basal Ganglia - drug effects; Basal Ganglia - metabolism; Behavior, Animal - drug effects; Biological and medical sciences; Brain Chemistry - drug effects; Catalepsy; Catalepsy - chemically induced; Catalepsy - psychology; Chronic treatment; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; Dopamine receptor occupancy; Dose-Response Relationship, Drug; Drug Tolerance; Drug toxicity and drugs side effects treatment; Fos protein; Haloperidol; Haloperidol - pharmacology; Immunohistochemistry; Kinetics; Ligands; Male; Medical sciences; N-Propyl-apomorphine; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-fos - biosynthesis; Rats; Rats, Wistar; Receptor supersensitivity; Receptors, Dopamine D2 - drug effects; Spiperone; Toxicity: nervous system and muscle; Spiperone; Fos protein; Catalepsy; Chronic treatment; Receptor supersensitivity; Haloperidol; N-Propyl-apomorphine; Dopamine receptor occupancy; Intraperitoneal administration; Rat; Neuroleptic; Psychotropic; Toxicity; Dopamine antagonist; Rodentia; Muscle tonus alteration; Long term; Proteins; Vertebrata; Biological fixation; Mammalia; D2 Dopamine receptor; Animal; Psychomotor disorder; Acquired tolerance
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/0091-3057(94)00397-2

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 (D
2-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 D
2 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.