Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain.
Long-term administration of the atypical neuroleptic clozapine (CLZ) poses a much lower risk of extrapyramidal side effects (EPS) than does the use of typical neuroleptics such as haloperidol (HAL). To investigate the neural mechanisms of the differing CNS activities of these two drugs, we used quantitative autoradiography to measure changes in dopamine and serotonin receptors in rats after injection with CLZ or HAL for 21 days at clinically relevant dose ratios. Levels of D1, D2, and 5-HT2 receptors were determined in frontal cortex, caudate-putamen, and nucleus accumbens. Rats that received CLZ chronically showed CNS receptor changes markedly different from those in chronic HAL-treated animals. Whereas rats treated chronically with HAL showed enhanced striatal D2 binding (average increase of 42%), those treated with CLZ did not. In contrast, chronic CLZ, but not chronic HAL, induced enhanced striatal D1 binding (average increase of 43%). Finally, CLZ treatment decreased 5-HT2 receptor binding by an average of 37%, while HAL had no significant effect. The effects of chronic HAL or CLZ treatment on receptors were similar in all forebrain areas examined. However, since D1 and 5-HT2 receptors are more abundant than D2 sites in limbic and neocortical areas, the preferential modulation of D1 and 5-HT2 receptors by CLZ suggests a greater impact of this atypical neuroleptic on activity of the limbic system than that achieved by the typical neuroleptic, HAL. These findings suggest that the clinical profile of atypical neuroleptics such as CLZ may be attributed to their effects on a receptor profile differing in pharmacological characteristics and anatomical distribution from that affected by typical neuroleptics.
O'Dell
S J
SJ
Department of Psychobiology, University of California, Irvine 92717.
La Hoste
G J
GJ
Widmark
C B
CB
Shapiro
R M
RM
Potkin
S G
SG
Marshall
J F
JF
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*
D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D003024:Clozapine; D006220:Haloperidol