Lack of a role for the D3 receptor in clozapine induction of c-fos demonstrated in D3 dopamine receptor-deficient mice.
The role of the D3 dopamine receptor in mediating the effects of clozapine was analysed using in situ hybridization histochemistry to measure the induction of the immediate early gene c-fos in different brain areas of mice lacking a functional D3 dopamine receptor compared to wild type mice. Clozapine treatment (15 and 30 mg/kg, s.c.) resulted in a dose-dependent pattern of induction of c-fos messenger RNA in the striatum, accumbens and septal area, with a non-significant increase in the prefrontal cortex. There was no difference detected in any of these areas in the level of induction between mice lacking the D3 receptor (D3-/-) and wild type (D3+/+). To determine which types of neurons in the striatum and accumbens displayed clozapine (30 mg/kg) induction of c-fos messenger RNA, a double-labeling experiment was performed using a radioactive c-fos messenger RNA probe and a digoxigenin-labeled enkephalin messenger RNA probe, the latter used as a marker of D2-containing neurons. Clozapine-induced c-fos was detected in 20% of enkephalin-positive striatal neurons and 15% of enkephalin-positive accumbens neurons, and in both areas in about 10% of enkephalin-negative, putative D1 neurons, in both D3+/+ and D3-/- mice. These results demonstrate that clozapine induction of c-fos messenger RNA is not dependent on the D3 dopamine receptor subtype in the striatum or nucleus accumbens.
Carta
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AR
Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD 20892, USA.
Gerfen
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CR
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D016762:Genes, fos / Q000235:genetics*; D051379:Mice; D009474:Neurons / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000502:physiology*; D050637:Receptors, Dopamine D3
D014150:Antipsychotic Agents; C493594:Drd3 protein, mouse; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D003024:Clozapine