Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats born by Caesarean section compared to vaginal birth.
Epidemiological evidence indicates a higher incidence of pregnancy and birth complications among individuals who later develop schizophrenia, a disorder linked to alterations in mesolimbic dopamine (DA) function. Two birth complications usually included in these epidemiological studies, and still frequently encountered in the general population, are birth by Caesarean section (C-section) and fetal asphyxia. To test the hypothesis that birth complications can produce long-lasting changes in DA systems, the present study examined the effects of Caesarean birth, with or without an added period of anoxia, on steady state monoamine levels and metabolism in various brain regions in a rat model. Pups born vaginally served as controls. At 2 months of age, in animals born by rapid C-section, steady state levels of DA were decreased by 53% in the prefrontal cortex and increased by 40% in both the nucleus accumbens and striatum, in comparison to the vaginally born group. DA turnover increased in the prefrontal cortex, decreased in the nucleus accumbens, and showed no significant change in the striatum, in the C-section group. Thus, birth by a Caesarean procedure produces long-term reciprocal changes in DA levels and metabolism in the nucleus accumbens and prefrontal cortex. This is consistent with the known inhibitory effect of increased prefrontal cortex DA activity on DA release in the nucleus accumbens. By contrast to birth by rapid C-section alone, young adult animals, that had been born by C-section with 15 min of added anoxia, showed no change in steady state DA levels in the prefrontal cortex, nucleus accumbens, or striatum and a significant decrease in DA turnover only in the nucleus accumbens, in comparison to the vaginally born group. Levels of norepinephrine, serotonin, and its metabolite, 5-hydroxyindole acetic acid, were unchanged in all groups, indicating relatively specific effects on DA systems. Although appearing robust at birth on gross observation, more subtle measurements revealed that rat pups born by C-section show altered respiratory rates and activity levels and increased levels of whole brain lactate, suggestive of low grade brain hypoxia, during the first 24 h of life, in comparison to vaginally born controls. Pups born by C-section with 15 min of added acute anoxia were pale, hypotonic, and inactive at birth and showed reduced respiration and high brain lactate levels. However, these alterations resolved by 1-5 h after birth and, with few exceptions, animals in the anoxic group remained normal with respect to these parameters during the remainder of the first 24 h of life. Immediately after birth, levels of plasma epinephrine, a hormone known to play a role in neonatal adaptation to extrauterine life and protection against hypoxia, were decreased in pups born by C-section but increased in pups born by C-section with 15 min added anoxia, in comparison to levels measured in vaginally born controls. These early developmental alterations could contribute to long-term alterations in dopaminergic parameters observed in rats born by C-section, with or without added anoxia. It is concluded that C-section birth is sufficient perturbation to produce long-lasting effects on DA levels and metabolism in the central nervous system of the rat. These findings highlight the sensitivity of DA pathways to variations in birth procedure and support the notion that birth complications might contribute to the pathophysiology of disorders involving central dopaminergic neurons, such as schizophrenia.
El-Khodor
B F
BF
Department of Psychiatry, McGill University, Douglas Hospital Research Centre, Montreal, Quebec, Canada.
Boksa
P
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D002585:Cesarean Section; D004298:Dopamine / Q000378:metabolism*; D004837:Epinephrine / Q000097:blood; D005260:Female; D005311:Fetal Hypoxia / Q000378:metabolism / Q000503:physiopathology; D007743:Labor, Obstetric; D007773:Lactates / Q000378:metabolism; D017072:Neostriatum / Q000737:chemistry / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D009714:Nucleus Accumbens / Q000737:chemistry / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000737:chemistry / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration; D013997:Time Factors
D007773:Lactates; D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine