title: Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens.
abstract: Gestational disruption of neurodevelopment has been proposed to lead to pathophysiological changes similar to those underlying schizophrenia. We induced such disruption by treating pregnant rat dams with methylazoxymethanol acetate (MAM) on gestational day 17 (GD17). Total brain size and that of the prefrontal cortex and hippocampus were reduced in adult rats exposed prenatally to MAM. When locomotor activity was assessed in an open field, MAM-exposed rats were hyper-responsive to a mild stress and to amphetamine (2 mg/kg, s.c.). They also engaged in less social interaction than controls. We studied, by microdialysis, the effect of amphetamine on extracellular dopamine in the nucleus accumbens and the medial prefrontal cortex of freely moving control and MAM-exposed rats. Amphetamine (2 mg/kg, s.c.) induced an increase in dopamine release that was larger in the nucleus accumbens of MAM-exposed rats than in controls, whereas no difference was seen in the medial prefrontal cortex. In controls, amphetamine infused into the medial prefrontal cortex (50 microM) led to a slight decrease in extracellular dopamine in the nucleus accumbens. This effect was absent in MAM-exposed rats, where a transient increase in nucleus accumbens dopamine levels was seen after amphetamine infusion. These results show that the late gestational disruption of neurogenesis in the rat leads to behavioral changes that mimic positive and negative schizophrenia symptoms, and also to a dysregulation of subcortical dopamine neurotransmission. This study contributes to the evaluation of the validity of the prenatal MAM GD17 treatment in rats as an animal model for schizophrenia.
authors.affiliation: Department of Psychopharmacology, H Lundbeck A/S, Copenhagen-Valby, Denmark. PFLA@Lundbeck.com
authors.forename: Peter
authors.initials: P
authors.lastname: Flagstad
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.forename: Birte Y
authors.initials: BY
authors.lastname: Glenthøj
authors.forename: Johan
authors.initials: J
authors.lastname: van Beek
authors.forename: Adina T
authors.initials: AT
authors.lastname: Michael-Titus
authors.forename: Michael
authors.initials: M
authors.lastname: Didriksen
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D000661:Amphetamine; D004298:Dopamine