title: Chronic administration of haloperidol and clozapine induces differential effects on the expression of Arc and c-Fos in rat brain.
abstract: The modulation of genes implicated in synaptic plasticity following administration of antipsychotic drugs has been instrumental in understanding their possible mode of action. Arc (Arg 3.1) is one such gene closely associated with changes in synaptic plasticity. In this study we have investigated the changes in expression of Arc protein following acute and chronic administration of a typical antipsychotic (haloperidol) and an atypical antipsychotic (clozapine) by means of immunohistochemistry compared to the prototypic gene marker c-Fos. In dorsal striatum haloperidol (1 mg/kg) significantly increased Arc expression following both acute and chronic (21 day) administration with evidence of modulation in induction after repeated dosing. No significant changes were observed following either acute or chronic administration of clozapine (20 mg/kg). In the nucleus accumbens shell both clozapine and haloperidol induced Arc expression following acute administration, again with evidence of modulation after chronic dosing. The pattern of induction of Arc expression following haloperidol and clozapine in both dorsal and ventral striatum was similar to that for c-Fos. In medial prefrontal and cingulate cortex, Arc expression was significantly decreased by clozapine but not haloperidol without any indication of modulation following chronic dosing, whereas no significant changes in c-Fos expression were observed with either drug. Since synaptic modulation mediated by Arc is associated with down-regulation of the AMPA glutamate receptor, this study suggests a mechanism whereby enhanced glutamate receptor efficacy in medial cortical areas may be a component of antipsychotic drug action.
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, UK Current address: Loxbridge Research, Royal Free Hampstead NHS Trust, London, UK.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Collins
authors.affiliation: GlaxoSmithKline, Harlow, UK Current address: CNS Research, UCB S.A., B-1420 Braine -l'Alleud, Belgium.
authors.forename: Martyn D
authors.initials: MD
authors.lastname: Wood
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, UK jme@dmu.ac.uk.
authors.forename: J Martin
authors.initials: JM
authors.lastname: Elliott
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D020665:Septum of Brain / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; C092069:activity regulated cytoskeletal-associated protein; D003024:Clozapine; D006220:Haloperidol
keywords: Brain; antipsychotic; arc; chronic; rat