title: Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation.
abstract: Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has been associated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypical antipsychotics such as olanzapine. In rodents, early life exposure to stressful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg s.c.), olanzapine (5 mg/kg s.c.), and haloperidol (0.5 mg/kg s.c.) on dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of the mPFC in group- and isolation-reared rats. Rats reared in isolation showed significant and robust deficits in prepulse inhibition of the acoustic startle. In group-reared animals, both clozapine and olanzapine produced a significant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics compared with group-reared animals. In contrast, the administration of haloperidol failed to modify dialysate DA levels in mPFC in either group- or isolation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D2 or D3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate, GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA responsiveness to the atypical antipsychotic drugs clozapine and olanzapine may explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, namely hyperactivity and attention deficit.
authors.affiliation: Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK. Christian_A_Heidbreder@sbphrd.com
authors.forename: C A
authors.initials: CA
authors.lastname: Heidbreder
authors.forename: R
authors.initials: R
authors.lastname: Foxton
authors.forename: J
authors.initials: J
authors.lastname: Cilia
authors.forename: Z A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: A J
authors.initials: AJ
authors.lastname: Shah
authors.forename: A
authors.initials: A
authors.lastname: Atkins
authors.forename: A J
authors.initials: AJ
authors.lastname: Hunter
authors.forename: J J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: D N
authors.initials: DN
authors.lastname: Jones
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018846:Excitatory Amino Acids / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D017551:Microdialysis; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects; D012934:Social Isolation
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D018846:Excitatory Amino Acids; D007202:Indicators and Reagents; D001569:Benzodiazepines; D010890:Pirenzepine; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine; D004298:Dopamine