Induction of c-fos mRNA in rat medial prefrontal cortex by antipsychotic drugs: role of dopamine D2 and D3 receptors.
The present studies compared the effects of acute and chronic administration of haloperidol or clozapine on c-fos mRNA expression in the rat medial prefrontal cortex. Acute administration of clozapine, but not haloperidol robustly increased c-fos mRNA expression in the infralimbic and prelimbic cortex of the rat. Even though most c-fos mRNA-expressing neurons in the clozapine- treated animals were localized in deep cortical layers, labeled neurons were found organized into several cell bridges connecting the superficial and deep layers of the cortex. After chronic treatment with clozapine, c-fos mRNA was reduced by approximately 60% of that seen acutely; however, the columns of c-fos mRNA expressing neurons did not show the same magnitude of tolerance. Haloperidol had no significant effect even after chronic treatment. We examined further the role of dopamine D2 versus D3 receptors in c-fos gene induction in the infralimbic cortex by studying the acute effects of remoxipride and U-99194A. Remoxipride, a selective D2 antagonist in vitro, induced c-fos mRNA at very low doses and lost its ability to alter c-fos mRNA at higher doses. Interestingly, U-99194A, an antagonist with 20-fold selectivity for D3 over D2 receptors, also produced greater induction of c-fos mRNA at lower doses. We hypothesize that blockade of D3 receptors may enhance c-fos gene expression in the medial prefrontal cortex but that of D2 receptors may prevent the same.
Merchant
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KM
CNS Diseases Research, Upjohn Laboratories, 301 Henrietta Street, Kalamazoo, MI 49001, USA.
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D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D002375:Catalepsy / Q000139:chemically induced; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D017403:In Situ Hybridization; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; D007189:Indans; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C086335:(5,6-dimethoxyindan-2-yl)dipropylamine