Clozapine-, but not haloperidol-, induced increases in deltaFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors.
On the basis of anatomical and pharmacological evidence, we have proposed that D3 receptor antagonism plays a role in the mediation of clozapine-, but not haloperidol-, induced immediate-early gene expression in the striatum. To test this hypothesis directly, we compared the effects of repeated administration of vehicle (8 mL/kg/day), clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) for 17 days on expression of deltaFosB-like immunoreactivity (deltaFosB-Ir) in the island of Calleja major, nucleus accumbens and caudate-putamen of wild-type C57Bl6 (WT) and D3 receptor knockout (D3KO) mice. In vehicle-treated mice, the number of deltaFosB-Ir neurons in the nucleus accumbens was greater in D3KO than in WT mice. This finding is consistent with results implicating D3 receptor activation in the tonic inhibition of this limbic structure. Unlike rats, clozapine significantly increased the number of deltaFosB-Ir neurons in both the nucleus accumbens and the caudate-putamen of WT mice albeit to a lesser extent in the caudate-putamen than nucleus accumbens. Similar to rats, however, deltaFosB-Ir in the island of Calleja major of WT mice was elevated by clozapine but not by haloperidol. In the nucleus accumbens and caudate-putamen, haloperidol produced similar increases in deltaFosB-Ir in WT and D3KO mice. By contrast, clozapine-induced increases in deltaFosB-Ir in the island of Calleja major, nucleus accumbens and caudate-putamen of WT mice were absent in D3KO mice. These findings, which indicate that D3 receptor blockade is essential for clozapine-induced increases in striatal deltaFosB-Ir, suggest that D3 receptor antagonism may contribute to the unique therapeutic profile of this atypical antipsychotic.
Robertson
George S
GS
Department of Psychiatry, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia B3H 1X5, Canada. George.Robertson@dal.ca
Lee
Christopher J
CJ
Sridhar
Kavita
K
Nakabeppu
Yusaku
Y
Cheng
Michael
M
Wang
Yan-Min
YM
Caron
Marc G
MG
D000818:Animals; D002452:Cell Count; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004334:Drug Administration Schedule; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000145:classification / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics; D050637:Receptors, Dopamine D3
D018492:Dopamine Antagonists; C493594:Drd3 protein, mouse; D018756:GABA Antagonists; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D003024:Clozapine; D006220:Haloperidol