title: Double activity imaging reveals distinct cellular targets of haloperidol, clozapine and dopamine D(3) receptor selective RGH-1756.
abstract: Acute administration of typical (haloperidol) and atypical (clozapine) antipsychotics results in distinct and overlapping regions of immediate-early gene expression in the rat brain. RGH-1756 is a recently developed atypical antipsychotic with high affinity to dopamine D(3) receptors that results in a unique pattern of c-Fos induction. A single injection of either antipsychotic results in c-fos mRNA expression that peaks around 30 min after drug administration, while the maximum of c-Fos protein induction is seen 2 h after challenge. The transient and distinct temporal inducibility of c-fos mRNA and c-Fos protein was exploited to reveal and compare cellular targets of different antipsychotic drugs by concomitant localization of c-fos mRNA and c-Fos immunoreactivity in brain sections of rats that were timely challenged with two different antipsychotics. Double activity imaging revealed that haloperidol, clozapine and RGH-1756 share cellular targets in the nucleus accumbens, where 40% of all labeled neurons displayed both c-fos mRNA and c-Fos protein. Haloperidol activates cells in the caudate putamen, while clozapine-responsive, single labeled neurons were dominant in the prefrontal cortex and major island of Calleja. RGH-1756 targets haloperidol-sensitive cells in the caudate putamen, but cells that are activated by clozapine and RGH-1756 in the major island of Calleja are different.
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kovács
authors.forename: M
authors.initials: M
authors.lastname: Csejtei
authors.forename: I
authors.initials: I
authors.lastname: Laszlovszky
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D002452:Cell Count / Q000706:statistics & numerical data; D003024:Clozapine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003720:Densitometry; D017781:Genes, Immediate-Early / Q000187:drug effects; D006220:Haloperidol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D013844:Thiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C427703:1-(2-methoxy-phenyl)-4-(4-(4-(6-imidazol(2,1-b) thiazolyl)-phenoxy)-butyl-4-(14)C)-piperazine dimethane; D014150:Antipsychotic Agents; C493595:Drd3 protein, rat; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D003024:Clozapine; D006220:Haloperidol