title: Chronic high-dose haloperidol has qualitatively similar effects to risperidone and clozapine on immediate-early gene and tyrosine hydroxylase expression in the rat locus coeruleus but not medial prefrontal cortex.
abstract: Acute administration of clozapine has been reported to activate the locus coeruleus (LC) and beta-adrenoceptor-dependent Fos immunoreactivity in the medial prefrontal cortex (mPFC) in rodents. Haloperidol is reported to exhibit a similar acute effect on LC firing and beta-adrenoceptor dependent Fos immunoreactivity in the mPFC but only at high doses. We compared the effects of chronic 4-week treatment with risperidone (1mg/kg/day s.c.), clozapine (10mg/kg/day s.c.) or a high dose of haloperidol (4mg/kg/day s.c.) on immediate-early gene protein (c-Fos, Egr-1 and Egr-2) and tyrosine hydroxylase (TH) expression. In the mPFC, haloperidol decreased, whereas clozapine increased, c-Fos immunoreactivity. Only haloperidol increased Egr-1 immunoreactivity. There was no significant effect on Egr-2 immunoreactivity. In the LC, both Egr-1 and Egr-2 expression was down regulated by all three antipsychotics. Clozapine and risperidone increased TH immunoreactivity in both mPFC and LC. Haloperidol caused a smaller increase in TH expression in the LC, but did not alter expression in the mPFC. In conclusion, despite qualitatively similar effects in the LC, chronic treatment with haloperidol had different effects to clozapine and risperidone in the mPFC. This may relate to the reported advantage of clozapine and risperidone over haloperidol against prefrontal cortical-dependent cognitive and negative symptoms.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Building MD2, 18 Medical Drive, Singapore 117597, Singapore.
authors.forename: Vivek
authors.initials: V
authors.lastname: Verma
authors.forename: Ee Peng
authors.initials: EP
authors.lastname: Lim
authors.forename: Siew Ping
authors.initials: SP
authors.lastname: Han
authors.forename: Rajini
authors.initials: R
authors.lastname: Nagarajah
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Dawe
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002452:Cell Count / Q000379:methods; D003024:Clozapine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D017874:Immediate-Early Proteins; D014446:Tyrosine 3-Monooxygenase; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone