393. Birth complications and dopamine function in animal models: implications for schizophrenia

Abstract

Schizophrenia is associated with increased birth complications and altered mesocorticolimbic dopamine (DA) transmission, while stress also influences expression of psychotic symptoms. Our laboratory has used animal models to directly test if minor birth complications [Caesarean section (C-section) birth with or without a short period of apoxia] have long-term effects on DA function. At adulthood, Sprague-Dawley rats that had been born by C-section show 1) increased DA levels in nucleus accumbens (NAcc) and decreased DA in prefrontal cortex, 2) increased amphetamine-induced locomotion, 3) increased NAcc DA release in response to repeated stress and 4) increased D1 receptor levels in NAcc and infralimbio cortex, compared to vaginally born controls. Interestingly, stress at adulthood upregulated D3 receptors in vaginally born but not C-sectioned animals, and upregulated D4 receptors with C-section but not vaginal birth. Thus the individual’s previous experience of stress together with other environmental events in their history such as birth complications, are important in determining DA receptor levels. In contrast to C-section alone, rats born by C-section with added anoxia showed increased amphetamine-induced locomotion and stress-induced DA release but no change in brain DA levels or DA receptors, compared to vaginal birth. Overall, these findings highlight the sensitivity of dopaminergic systems to minor changes in birth procedure in the rat. The rat brain is somewhat less mature at birth than is the brain of the term human newborn, but guinea pig brain at birth is, in fact, more mature than the brain of the term human newborn. Similar to rats, guinea pigs born by C-section showed increased amphetamine-induced locomotion at adulthood, compared to vaginally born controls. Thus C-section birth enhances dopaminergic function in both guinea pig and rat, 2 species whose levels of CNS maturity span that of the human at birth insult. To test if genetic factors and birth complications interact to modulate dopaminergic function, we compared 3 genetically diverse strains of rats, born either vaginally or by C-section, for DA-mediated behavior. C-section birth had differing long-term effects on DA-mediated behavior depending on the animal’s genetic composition. This supports the idea that perinatal insults may have more profound effects on genetically susceptible individuals, resulting in DA dysfunction characteristics of schizophrenia. We are currently modelling similar birth complications in several strains of mice, to proceed towards quantitative trait locus analysis for genes conferring enhanced susceptibility of DAergic systems to birth insult. The epidemiology of schizophrenia provides us with leads about which factors might play a role in the etiology of the disorder. The present findings illustrate how animal models can be used to directly test if candidate etiological factors actually produce CNS changes responsible for symptoms of schizophrenia.