Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: possible implications for schizophrenia and other disorders

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Abstract

Altered subcortical dopaminergic activity is thought to be involved in the pathophysiology of several disorders including schizophrenia, substance abuse and attention deficit hyperactivity disorder. Epidemiological studies have implicated perinatal insults, particularly obstetric complications involving fetal or neonatal hypoxia, as etiological risk factors for schizophrenia. This suggests the possibility that perinatal hypoxia might have lasting effects on dopaminergic function. In animal models, dopaminergic systems appears to be particularly vulnerable to a wide range of perinatal insults, resulting in persistent alterations in function of mesolimbic and mesostriatal pathways. This review summarizes recent work characterizing long-term changes in dopaminergic function and biochemistry in models of Caesarean section (C-section) birth and of C-section birth with added global anoxia in the rat and guinea pig. C-section birth and C-section with anoxia appear to be two distinct hypoxic birth insults, with somewhat differing patterns of lasting effects on dopamine systems. In addition, birth insult alters the manner in which dopaminergic function is regulated by stress at adulthood. The possible relevance of these finding to effects of human birth procedures is discussed.

Section snippets

Introduction to the clinical perspective

There is now substantial evidence that dysregulation of brain dopamine (DA) function plays a critical role in the pathophysiology of several psychiatric disorders, notably schizophrenia [51], [132], substance abuse [31], [101] and attention deficit hyperactivity disorder [23], [129]. As regards schizophrenia, it had long been observed that drugs which enhance dopaminergic transmission, like amphetamine (AMPH), can exacerbate psychotic symptoms in subjects with schizophrenia and induce a

Effects of pre-and perinatal insults on DA function in animal models

Animal modeling provides a convenient system to directly ask if perinatal insults can alter brain DA function. In animal studies, long-term overactivity in mesolimbic (meso-nucleus accumbens) or mesostriatal DA systems, as assessed by increased DA release or increased DA-mediated behavioral responses, has been observed following a wide variety of early insults, including prenatal stress or corticosteroids [30], [57], maternal separation in early life [70], [99], neonatal lesions to the ventral

Obstetric complications, fetal hypoxia and schizophrenia

Among possible perinatal influences, the epidemiological literature on schizophrenia indicates that schizophrenia is associated with an increased incidence of obstetric complications [24], [25], [47], [61], [68], [72], [76], [96], reviewed in Refs. [19], [98]. This finding is well supported by numerous replications, suggesting that obstetric complications may be important candidates as risk factors for development of schizophrenia. Most studies on this topic have included a wide spectrum of

Birth hypoxia, C-section and DA function in animal models

Given the association of schizophrenia with both perinatal hypoxia and altered dopaminergic function, and the susceptibility of DA systems to perinatal influences shown in animal models, it has been of interest to use animal models to test if fetal hypoxia can, in fact, have long-term effects on dopaminergic function. Several types of models have been employed to this end, each with advantages and disadvantages for studying specific issues. Some of the more widely used models can be divided

C-section versus C-section+anoxia as distinct animal models of birth hypoxia; gender differences

These findings raise some intriguing questions. How does C-section birth produce long-term changes in DA function? Why does addition of a period of anoxia to the C-section produce a somewhat different profile of dopaminergic changes, and sometimes appear to reverse changes caused by C-section? In fact, it appears that animals born by C-section, or by C-section + anoxia, both experience neonatal hypoxia but the pattern and severity differs in the two groups. Thus the two groups (C-section,

Interactions between birth insult and stress at adulthood

Another noteworthy feature of the data in Table 1 is the finding that the three birth groups (vaginal birth, C-section and C-section+anoxia) reacted differently to stress at adulthood, with respect to some dopaminergic parameters. For example, repeated tail pinch stress at adulthood upregulated NAcc D3-like receptors only in vaginally born controls, upregulated NAcc D4-like receptors only in the C-sectioned group, and had no effect on DA receptors in the C-section+anoxia group (Fig. 1 and [39]

A guinea pig model of C-section/birth hypoxia

Since rat brain at birth is somewhat less mature than the brain of the human neonate [116], the relevance of a rat C-section/birth hypoxia model might seem to be limited to premature human neonates. To address this issue, our laboratory has also modeled C-section birth±anoxia in the guinea pig, a species whose brain is actually more developmentally mature at birth than is the human, based on neurochemical, anatomical, EEG and behavioral comparisons [136]. As adults, guinea pigs born by

Relevance to humans

A large number of epidemiological studies have now confirmed that obstetric complications clearly associated with fetal or neonatal hypoxia confer increased risk for schizophrenia [20], [21], [25], [68], [76], [117], [149], reviewed in ref. [19]. An obvious further question that arises from the above animal studies is “Is C-section birth a risk factor for schizophrenia?” At present, studies specifically designed to test C-section as a risk factor for schizophrenia have not been done. A

Acknowledgements

Studies on C-section/birth hypoxia models in P. Boksa's laboratory and preparation of this manuscript were financially supported by the Canadian Institutes of Health Research.

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