Contrasting effects of chronic clozapine, Seroquel(TM) (ICI 204,636) and haloperidol administration of deltaFosB-like immunoreactivity in the rodent forebrain.
We have recently demonstrated that specific neuroanatomical patterns of Fos-like immunoreactivity are predictive of atypical antipsychotic activity. However, the fact that neuroleptics must be administered chronically in order to generate both extrapyramidal side effects and an optimal therapeutic response calls into question the relevance of acute changes in Fos-like immunoreactivity for these slowly developing events. Fos-like immunoreactivity cannot be used to identify neurons activated by chronic neuroleptic administration because the increase in Fos-like immunoreactivity produced by an acute antipsychotic injection is dramatically reduced following repeated neuroleptic administration. In contrast, expression of the immediate-early gene product deltaFosB is persistently elevated in the striatum by chronic haloperidol administration. This suggests that deltaFosB-like immunoreactivity may be used to identify neurons activated by chronic antipsychotic administration. Since typical and atypical neuroleptics elevate Fos-like immunoreactivity in different regions of the forebrain acutely, the purpose of the present study was to determine whether typical (haloperidol) and atypical (clozapine, ICI 204,636) antipsychotics produce distinct patterns of elevated deltaFosB-like immunoreactivity in the forebrain after chronic administration. Administration of haloperidol (2 mg/kg/day) to rats for 19 days induced a homogeneous elevation of neurons which displayed deltaFosB-like immunoreactivity in the ventral, medial and dorsolateral aspects of the striatum. Chronic haloperidol administration did not enhance the deltaFos-like immunoreactivity in the prefrontal cortex and lateral septal nucleus. Repeated administration of clozapine (20 mg/kg/day) and ICI 204,636 (20 mg/kg/day) for 19 days elevated deltaFosB-like immunoreactivity not only in the ventral striatum but also in the prefrontal cortex and lateral septal nucleus. However, these compounds had weak effects on deltaFosB-like immunoreactivity in the dorsolateral striatum. These results suggest that a preferential action on limbic structures such as the prefrontal cortex, ventral striatum and lateral septal nucleus may account for the ability of chronic clozapine and ICI 204, 636 administration to reduce the symptoms of schizophrenia without generating extrapyramidal side effects.
Vahid-Ansari
F
F
Department of Pharmacology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
Nakabeppu
Y
Y
Robertson
G S
GS
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects; D003987:Dibenzothiazepines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009419:Nerve Tissue Proteins / Q000032:analysis*; D009474:Neurons / Q000737:chemistry / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects; D016548:Prosencephalon / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis*; D000069348:Quetiapine Fumarate; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D000069348:Quetiapine Fumarate; D003024:Clozapine; D006220:Haloperidol