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 mM) led to a slight decrease in extracellular dopamine in the nucleus accumbens. This effect was absent in MAMexposed 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.

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

“…Lesions of the prefrontal cortex have been shown to selectively increase perseveration to a previously learned dimension in non-human primates (Dias et al, 1996) and humans (Elliott et al, 1995;Owen et al, 1993). Given the likelihood that MAM disrupts prefrontal cortex function (Flagstad et al, 2004;Lavin et al, 2005) it would be expected that MAM-treated animals would likewise show increases in perseveration, and that this might serve as the basis for the deficit observed in the present study. In addition to an impairment in EDS learning, MAM-treated animals were impaired when required to make a simple reversal of a previously acquired discrimination (for two out of three reversals).…”

“…For example, Flagstad et al (2004) reported brain weight decreases in the HI and prefrontal cortex of 17 and 22 percent, respectively.…”

“…Neonatal methylazoxymethanol acetate (MAM) treatment induces brain abnormalities that may be similar to the types of changes seen in schizophrenia, including abnormalities in hippocampal (Chen and Hillman, 1986;Ferguson and Holson, 1997;Flagstad et al, 2004;Gourevitch et al, 2004;Shimizu et al, 1991;Virgili et al, 1997) and cortical (Lavin et al, 2005;Talamini et al, 1999) function and morphology. These changes are accompanied by changes in mesolimbic dopamine function, as indicated by an increased sensitivity to the behavioral and neurochemical effects of amphetamine (Ferguson and Holson, 1997;Flagstad et al, 2004).…”

“…These changes are accompanied by changes in mesolimbic dopamine function, as indicated by an increased sensitivity to the behavioral and neurochemical effects of amphetamine (Ferguson and Holson, 1997;Flagstad et al, 2004). Animals exposed to MAM during gestation show impairments within cognitive domains known to be disrupted in schizophrenia, such as attention (Flagstad et al, 2005;Mohammed et al, 1986a, b;Talamini et al, 2000), long-term memory (Fiore et al, 2001(Fiore et al, , 2002Gourevitch et al, 2004;Lee and Rabe, 1992;Shimizu et al, 1991), working memory (Gourevitch et al, 2004), and behavioral flexibility (Fiore et al, 2002;Flagstad et al, 2005;Leng et al, 2005), although negative findings have also been reported in many of these domains (Flagstad et al, 2005;Jongen-Relo et al, 2004).…”

“…Treatment occurring on or before gestational day 15 produces widespread disruptions of brain morphology and behavior (Gourevitch et al, 2004) and it is likely that these changes are too nonspecific to serve as a useful model of schizophrenia. Treatment at gestational day 17 produces much less intense changes in brain and behavior (Gourevitch et al, 2004), and treatment at this time produces deficits within many cognitive domains known to be impaired in schizophrenia (Flagstad et al, 2004(Flagstad et al, , 2005Gourevitch et al, 2004;Moore et al, 2006).…”