title: Influence of prenatal undernutrition on the effects of clozapine and aripiprazole in the adult male rats: relevance to a neurodevelopmental origin of schizophrenia?
abstract: Epidemiological and experimental data indicate that maternal undernutrition may sensitize the offspring to the apparition of chronic diseases such as metabolic syndrome and schizophrenia, suggesting that these pathologies may have a developmental origin. To test this hypothesis, we have compared the effects of a 4 weeks treatment of clozapine (30 mg/kg once daily, p.o.) or aripiprazole (10 mg/kg once daily, p.o.) on metabolic and hormonal parameters in 4-month-old male animals from control or 70% prenatally food-restricted mothers (FR30 model). Both neuroleptics did not markedly modify body weight gain and food intake in both controls and FR30 rats. Clozapine decreased insulin secretion in both groups but significantly diminished leptin, corticosterone and glucose plasma levels only in FR30 animals. Aripiprazole decreased corticosterone plasma levels only in FR30 animals. Using quantitative RT-PCR array containing 84 obesity-related genes, we identified several genes involved in energy metabolism regulation whose expression was modified by clozapine or aripiprazole in adult male rat hypothalami. In addition, we demonstrated that expression of some of these genes was differentially affected by each neuroleptic in the hypothalamus of both FR30 and control animals. Although no marked metabolic alterations were observed in both control and FR30 animals after clozapine or aripiprazole treatment, our data indicate that offspring from undernourished mothers exhibit a modified sensitivity to atypical neuroleptics. Our results do not rule out a putative developmental origin of schizophrenia and may help to understand the way by which atypical neuroleptics, such as clozapine, sensitize schizophrenic patients to the development of metabolic disorders.
authors.affiliation: Equipe Dénutritions Maternelles Périnatales (Unité Environnement Périnatal et Croissance, EA4489), Bâtiment SN4, 2(ème) étage, Université des Sciences et Technologies de Lille, Université Lille-Nord de France, 59 655 Villeneuve d'Ascq cedex, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Guillemot
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Lukaszewski
authors.forename: Valérie
authors.initials: V
authors.lastname: Montel
authors.forename: Fabien
authors.initials: F
authors.lastname: Delahaye
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mayeur
authors.forename: Christine
authors.initials: C
authors.lastname: Laborie
authors.forename: Anne
authors.initials: A
authors.lastname: Dickes-Coopman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dutriez-Casteloot
authors.forename: Jean
authors.initials: J
authors.lastname: Lesage
authors.forename: Christophe
authors.initials: C
authors.lastname: Breton
authors.forename: Didier
authors.initials: D
authors.lastname: Vieau
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001835:Body Weight / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D004198:Disease Susceptibility / Q000139:chemically induced; D004435:Eating / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006728:Hormones / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D044342:Malnutrition; D009420:Nervous System / Q000187:drug effects / Q000254:growth & development*; D009765:Obesity / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; D006728:Hormones; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D003024:Clozapine