Transforming youth mental health: a Canadian perspective.

In most mental illnesses, onset occurs before the age of 25 and the earliest stages are critical. The youth bear a large share of the burden of disease associated with mental illnesses. Yet, Canadian youths with mental health difficulties face delayed detection; long waiting lists; inaccessible, unengaging services; abrupt transitions between services; and, especially in remoter regions, even a complete lack of services. Responding to this crisis, the Canadian Institutes of Health Research announced a 5-year grant that was awarded to ACCESS, a pan-Canadian network of youths, families, clinicians, researchers, policymakers, community organisations and Indigenous communities. Using strategies developed collaboratively by all stakeholders, ACCESS will execute a youth mental healthcare transformation via early detection, rapid access and appropriate, high-quality care. The project includes an innovative, mixed-methods service research component. Similar in many respects to other national youth mental health initiatives, ACCESS also exhibits important differences of scale, scope and approach.

Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats.

Febrile responses to bacterial pathogens are attenuated near term of pregnancy in several mammalian species. It is unknown, however, whether this reflects a fundamental physiological adaptation of female rats or whether it is specific to pregnancy. The aims of this study therefore were 1) to determine whether febrile responses to the bacterial endotoxin lipopolysaccharide (LPS) are attenuated in female vs. male rats and, if so, to identify possible mechanisms involved in modulating this and 2) to assess whether plasma concentrations of the anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), an important regulator of fever, are dependent on the physiological state of the female and could therefore be involved in modulating febrile responses. We found febrile responses were attenuated in cycling female vs. male rats and also in near-term pregnant dams vs. cycling females after intraperitoneal injection of LPS (0.05 mg/kg). Plasma levels of IL-1ra were significantly greater in female rats after injection of LPS, particularly during pregnancy, than in males. This was accompanied by attenuated levels of hypothalamic IL-1beta and cyclooxygenase-2 mRNA, two key mediators of the febrile response, in female rats. Furthermore, increasing plasma levels of IL-1ra in male rats by intraperitoneal administration of the recombinant antagonist attenuated hypothalamic mRNA levels of these mediators after LPS. These data suggest that there is a fundamental difference in febrile response to LPS between the genders that is likely regulated by IL-1ra. This may be an important mechanism that protects the developing fetus from potentially deleterious consequences of maternal fever during pregnancy.

Birth insults involving hypoxia produce long-term increases in hippocampal [125I]insulin-like growth factor-I and -II receptor binding in the rat.

Insulin-like growth factors-I and -II and insulin are structurally related mitogenic growth factors with multiple actions in the developing nervous system and adult CNS. Previous studies have demonstrated acute induction of insulin-like growth factors and their receptors, over a time course of several days, in response to hypoxic/ischemic insult to developing or adult brain. The current study tested whether birth insults involving hypoxia may produce long term changes in brain insulin-like growth factor or insulin receptor levels, lasting into adulthood. For this, rats were born vaginally (controls), by cesarean section, or by cesarean section with 15 min of added global anoxia (cesarean section+anoxia), and brain [125I]insulin-like growth factor-I, [125I]insulin-like growth factor-II and [125I]insulin receptor binding sites were assessed autoradiographically at adulthood. [125I]Insulin-like growth factor-I receptor binding sites were increased in all hippocampal subfields (CA1-CA3, dentate gyrus) in rats born either by cesarean section or by cesarean section+anoxia, compared with vaginal birth. [125I]Insulin-like growth factor-II binding was increased in all hippocampal subfields only in rats born by cesarean section+anoxia compared with either vaginal birth or cesarean section groups. [125I]Insulin-like growth factor-I and [125I]insulin-like growth factor-II binding in frontal cortex, striatum and cerebellum were unaffected by birth group, except for increased [125I]insulin-like growth factor-I binding in the cerebellar molecular layer of cesarean-sectioned animals. Birth group had no significant effect on [125I]insulin binding in any brain region. Affinity cross-linking experiments performed with hippocampal membranes from the three birth groups showed that i) [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II recognized bands of molecular weights characteristic of insulin-like growth factor-I and insulin-like growth factor-II receptors, respectively, and ii) [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II were displaced more potently by their respective unlabeled ligands than by related molecules. It is concluded that birth insults involving hypoxia can induce lasting increases in insulin-like growth factor-I and -II receptors in the CNS. There is specificity with respect to the subtype of insulin-like growth factor receptor affected by the particular birth insult and the brain region affected. It is suggested that enduring increases in levels of insulin-like growth factor receptors consequent to hypoxic birth insult may help to maintain hippocampal function at adulthood, and could modulate responsiveness to insulin-like growth factor administration.

The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia.

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

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

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.

Caesarean section birth produces long term changes in dopamine D1 receptors and in stress-induced regulation of D3 and D4 receptors in the rat brain.

Schizophrenia is associated with increased birth complications and altered mesocorticolimbic dopaminergic (DA) transmission, whereas stress also influences psychotic symptoms. Given this, the present study tested effects of two birth complications, Caesarean section (C-section) birth with or without acute global anoxia, on brain DA receptors in rats at adulthood. Effects of repeated stress at adulthood were also tested. Before stress, C-sectioned rats showed increased D1-like receptor binding in limbic areas, compared to vaginally born controls. There were no differences between birth groups in D2-like, D3, or D4-like receptor binding before stress. After stress, C-sectioned animals showed decreased D3 receptors in accumbens and increased D4-like receptors in dorsal striatum, accumbens, and olfactory tubercles, compared to vaginal birth. This occurred because stress upregulated D3 receptors only with vaginal birth and upregulated D4-like receptors only with C-section. Animals born by C-section + anoxia showed no change in DA receptors relative to vaginal birth, before or after stress. It is concluded that interactions between an individual's experience of stress at adulthood, together with other environmental events in their history, such as birth complications, can be important determinants of brain DA receptor levels.

Birth insult alters dopamine-mediated behavior in a precocial species, the guinea pig. Implications for schizophrenia.

Schizophrenia is associated with increased birth complications, suggesting that birth complications might alter CNS dopaminergic activity later in life. In rats, Caesarean section (C-section) birth can produce long term changes in dopaminergic biochemistry and behavior. However rat brain is somewhat immature compared to human brain at birth. The current study tested if mild birth complications also alter dopamine-mediated function in a species with a more mature CNS at birth, the guinea pig. As adults, guinea pigs born by C-section showed increased amphetamine-induced locomotion and disruption of prepulse inhibition (PPI) of acoustic startle, compared to vaginally born controls. Guinea pigs born by C-section with 1 min of added global anoxia showed reduced amphetamine-induced locomotion and disrupted PPI, while a C-section plus 2 min anoxia group showed no change in amphetamine-induced locomotion but increased amphetamine-induced startle. No group differences in effects of amphetamine or apomorphine on PPI were observed. Taken with previous findings, these results indicate that mild birth complications can cause long term changes in dopamine-mediated behavior in both guinea pig and rat, two species spanning the level of human brain maturity at birth.

Interactive effects of anoxia and general anesthesia during birth on the degree of CNS and systemic hypoxia produced in neonatal rats.

A model of global hypoxia during Caesarean-section (C-section) birth has been widely used to study long-term effects of birth hypoxia on central nervous system (CNS) function. However, the actual degree of CNS and systemic hypoxia produced by the birth insult in this model has never been characterised. Additionally, the way in which the dam is anaesthetised during the C-section procedure may impinge on the degree of hypoxia experienced by the neonate. This study examined how a period of global birth anoxia and isoflurane/N2O anaesthesia interact to affect measures of CNS and systemic hypoxia in neonatal rats born by C-section compared with control, vaginally born animals. A 10-min period of global anoxia just before birth increased blood lactate, a metabolic indicator of systemic hypoxia, increased brain lactate and decreased brain ATP to a similar extent in pups born by C-section from either decapitated, unanaesthetised dams or dams anaesthetised with 2.5% isoflurane. Thus, this model does produce systemic and CNS hypoxia in the neonate. Pups born by C-section with a higher concentration of isoflurane (3.5%), in the absence of added global anoxia, also showed reductions in brain ATP at birth. In addition, 10 min of global anoxia produced greater increases in blood lactate in pups born from dams anaesthetised with the higher concentration of isoflurane. Thus, the concentration of anaesthetic used in this model may affect the degree of CNS or systemic hypoxia experienced by the neonate. Compared with vaginal birth, pups born by C-section with 2.5% or 3.5% isoflurane (and no added global anoxia) showed decreased PO2 and pH, and increased pCO2 in systemic blood taken <30 s after birth. Exposure to global anoxia during C-section birth actually increased systemic PO2 at <30 s after birth, presumably due to ventilatory responses to hypoxemia and hypercapnia; this effect of anoxia was reduced in anaesthetised compared with unanaesthetised pups. Thus, global anoxia acts as a stimulus for rapid recovery of systemic PO2 at birth, and this stimulus is dampened by isoflurane/N2O anaesthesia. These results should aid in understanding how CNS and systemic hypoxia at birth contribute to long-term changes in brain biochemistry and behaviour in this model.

Genetic factors modulate effects of C-section birth on dopaminergic function in the rat.

Genetic predisposition and environmental factors such as perinatal complications are believed to contribute to the etiology of schizophrenia, a disorder involving enhanced CNS dopaminergic activity. This study used a rat model to test whether genetic factors and a minor birth complication, i.e. Caesarean section (C-section) birth, interact in producing longterm effects on dopamine-mediated behavior. For this, we compared the effects of vaginal and C-section birth on amphetamine (AMPT)-induced locomotor activity in strains of rats differing in genetic composition. In Sprague-Dawley rats, C-section birth increased AMPT-induced locomotion compared with vaginal birth. By contrast in Lewis rats, C-section birth reduced AMPT-induced locomotion compared with vaginal birth. In Fischer rats, AMPT-induced locomotion was increased by C-section under maternal anesthesia but decreased by C-section after maternal decapitation, compared with vaginal birth. It is concluded that a minor birth complication like C-section can have differing long-term effects on dopaminergic function in the rat, depending on the genetic composition of the individual.

Transient birth hypoxia increases behavioral responses to repeated stress in the adult rat.

The aim of this study was to test if two birth complications, namely, transient global hypoxia during Caesarean section (C-section) birth or C-section birth per se, produce long-term changes in behavioral responses to repeated stress. Adult rats, that had been born vaginally, by C-section or by C-section with 10 min of global anoxia, were stressed for 8 days (15 min tail pinch daily) followed by challenge with the same stressor 2 weeks later. The main finding is that adult rats born by C-section + 10 min of anoxia showed enhanced locomotor activity on days 5 and 6 of the repeated stress period and at stress challenge 2 weeks later, compared to animals born vaginally or by C-section. It is concluded that transient global birth hypoxia can render the adult rat behaviorally hyper-responsive to repeated stress.

Effects of vaginal birth versus caesarean section birth with general anesthesia on blood gases and brain energy metabolism in neonatal rats.

Using a rat model, several laboratories have demonstrated long-term effects of Caesarean section (C-section) birth or of global hypoxia during C-section birth on a variety of central nervous system (CNS) parameters. These studies used C-section delivery from rapidly decapitated dams, to avoid confounding anesthetic effects, or from dams anesthetized with halothane or ether under unspecified conditions. Systemic oxygenation or cerebral energy metabolites in the pups at birth have not been systematically measured in this model. To develop and characterize a C-section model with relevance to the human situation, the present study measured arterial/venous blood gases and pH and brain ATP and lactate, a widely accepted measure of CNS hypoxia, in pups born either vaginally, by C-section from decapitated dams, or by C-section from dams anesthetized with nitrous oxide (N2O) and increasing concentrations of isoflurane under well-defined conditions. Immediately after birth, pups born vaginally, by C-section with maternal decapitation, or by C-section with 2.5% isoflurane showed no group differences in systemic pO2 or pH or brain ATP levels, but pCO2 was elevated in the C-section/2.5% isoflurane group. Pups born by C-section with 3.0, 3.5, or 4.0% isoflurane, showed progressive reductions in blood pO2 and increases in pCO2 and blood pH was reduced with 3.5% isoflurane. Relative to vaginal birth, brain lactate levels were unchanged in pups born by C-section with any concentration (2.5-4.0%) of isoflurane, but reduced in pups born by C-section from decapitated dams. At 1 h (and 4 h) after birth, in both vaginally born controls and the 2.5% isoflurane group, brain lactate fell while blood pO2 and brain ATP remained stable. In the 3.0, 3.5, or 4.0% isoflurane groups, blood gases and pH and brain lactate also normalized to control values. In conclusion, rat neonates show minimal signs of systemic or CNS hypoxia following C-section birth under 2.5% isoflurane with N2O. However, there is a rather narrow window of isoflurane concentrations which produces effective maternal anesthesia without producing respiratory compromise in the neonate. Thus the results indicate that the level of maternal anesthesia employed is an important factor influencing neonatal systemic and CNS oxygenation during C-section birth.

Caesarean section birth with general anesthesia increases dopamine-mediated behavior in the adult rat.

Schizophrenia is associated with both increased dopaminergic activity and perinatal complications. To test whether dopamine-mediated behavior can be altered by birth complications, we investigated effects of amphetamine (AMPT) on activity levels in adult rats that had been born vaginally or by Caesarean section (C-section) from isoflurane-anesthetized dams with or without addition of 10 min global anoxia. For comparison with our previous results, we also included rats born by C-section from decapitated dams. The main finding is that rats born by C-section from isoflurane-anesthetized dams, either with or without added anoxia, showed greater AMPT-induced activity as adults compared to vaginally born controls. C-section from decapitated dams also enhanced AMPT-induced activity, however the time course differed from that following maternal anesthesia. Thus subtle alterations in birth procedure can produce long-lasting increases in dopamine-mediated behavior, supporting a role for birth complications in the pathophysiology of schizophrenia.

Birth insult increases amphetamine-induced behavioral responses in the adult rat.

We have previously reported that an apparently uncomplicated Caesarean section birth produces long-term alterations in steady-state levels of dopamine in the central nervous system of the rat. In addition, adult rats that had been born by Caesarean section, either with or without acute global anoxia, showed markedly greater dopamine release from the nucleus accumbens in response to repeated stress, in comparison to vaginally born controls. The aim of the present study was to test whether these birth complications also result in long-term changes in behavior mediated by dopamine systems. For this, we investigated effects of a low dose (0.5 mg/kg) of amphetamine on activity levels in three-month-old rats that had been born vaginally (control), by rapid Caesarean section, or by Caesarean section with 15 min of global anoxia. Amphetamine induced a significantly greater increase in locomotor activity in animals born by Caesarean section or by Caesarean section+ 15 min anoxia, in comparison to the drug's effects in vaginally born controls. Behavioral responses were further analysed from video recordings of the animals' behavior. In confirmation of automated activity counts, both animals born by Caesarean section and by Caesarean section + 15 min anoxia showed a significant increase in the duration and frequency of moving and a decrease in the duration and frequency of standing, in comparison to vaginally born controls. Animals delivered by Caesarean section showed a significant increase in the duration of sniffing and a decrease in the duration and frequency of grooming when compared to vaginally born controls. Animals delivered by Caesarean section + 15 min anoxia showed a significant increase in the duration and frequency of rearing, in comparison to controls. The pattern of behavioral changes observed indicates that, as adults, animals born by Caesarean section and by Caesarean section with added global anoxia both show heightened behavioral responses to amphetamine, in comparison to vaginally born animals. These findings highlight the sensitivity of dopamine pathways to variations in birth procedure and add experimental support to epidemiological evidence implicating birth complications in the pathophysiology of disorders involving central dopaminergic neurons, such as schizophrenia.

Responses to stress and novelty in adult rats born vaginally, by cesarean section or by cesarean section with acute anoxia.

The aim of this study was to test the hypothesis that alterations in birth conditions, specifically vaginal birth vs. birth by Cesarean section (C-section) vs. birth by C-section with an added period of acute global anoxia, produces long-term differences in behavioral responses to stress or novelty in the rat at adulthood. In comparison to animals born by rapid C-section alone, animals born by C-section with 10 or 15 min of added anoxia were significantly more immobile during forced swim stress administered for 6 trials over several weeks. In a step-down passive avoidance task, there were no group differences in acquisition or retention of the avoidance response. However, when initially placed in the passive avoidance apparatus before delivery of shock, animals born by C-section with 15 min of anoxia required significantly more pretrials to step down from the wooden platform, than did vaginally born or C-sectioned animals. No group differences were observed on measures of exploratory behavior in an elevated plus-maze or of approach behavior either to food or to a novel object in an open field. These findings suggest that birth conditions which include a degree of perinatal hypoxia can contribute to variability in selective responses to stress and novelty in the adult rat.

Birth insult alters ethanol preference in the adult rat.

While genetic factors clearly play a role in regulating ethanol intake, the present study considered the possibility that early environmental factors which influence central nervous system development and long-term function might also alter ethanol intake. The specific aim of the study was to test whether alterations in birth condition, namely Caesarean section (C-section) birth and C-section birth with an added period of global anoxia, can affect subsequent ethanol preference in the adult rat. At 5 months of age, groups of experimental and vaginally born control rats were offered free choice between drinking water or various concentrations of ethanol (1-10% v/v) in water across 36 days of testing. Rats that had been born by C-section with 10 or 15 min of added global anoxia showed significant reductions in ethanol preference scores, in comparison to vaginally born controls. For the 10-min anoxia group, ethanol intake was decreased, water intake was increased and total fluid intake remained unchanged relative to values for vaginally born controls, across the entire test period. Although total fluid intake by the 15-min anoxia group also did not differ from that of vaginally born controls, the decreased ethanol preference scores in the 15-min anoxia group were mainly due to increased water intake during some test periods and a combination of reduced ethanol intake and increased water intake during others. Animals born by rapid C-section alone, with no added period of global anoxia, showed reduced ethanol preference only during a few early periods of testing, a much less pronounced effect than that observed for animals with added global anoxia. When animals were given the choice between drinking water vs. solutions of sucrose or NaCl, no group differences due to birth condition were found on measures of sucrose or NaCl preference. Together with reduced ethanol preference, the 10-min anoxia group showed a transient depression of locomotor activity in response to a low dose (0.25 g/kg) of intraperitoneal ethanol, which had no effect on locomotion in vaginally born controls. These results indicate that a relatively subtle alteration in birth condition, compatible with grossly normal development and behavior, is sufficient to alter ethanol preference in the adult rat.

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.

Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood: an electrochemical study in the rat.

Evidence from animal studies suggests that a period of anoxia to the fetus, a consequence common to many birth complications, results in long-term alterations in ventral mesencephalic dopamine function. Long-term functional changes in these dopamine neurons, in particular those that innervate the nucleus accumbens, also occur when animals are repeatedly stressed. In the present study, we examined the possibility that a period of anoxia during a Cesarean section birth can later alter the development of stress-induced sensitization of dopamine transmission in the nucleus accumbens. Dams were decapitated on the last day of gestation and the entire uterus was removed by Cesarean section. Pups were then delivered either immediately (Cesarean section group) or were immersed in a 37 degrees C saline bath for 3.5 or 13.5 min (Cesarean section+anoxia groups) before delivery of the pups. A fourth group of pups that were born vaginally served as controls (Vaginal group). Three to four months postnatally, animals from each group were implanted with monoamine-selective carbon-fiber electrodes into the nucleus accumbens. Voltammetry was used to monitor the dopamine response to each of five consecutive, once daily, 15-min exposures to tail-pinch stress. The results show that the first exposure to stress elicited dopamine signal increases of comparable amplitudes and durations in all animals. However, when compared to the initial stress response, the fourth and fifth exposures to tail-pinch elicited significantly longer-lasting dopamine responses in animals born by Cesarean section, either with or without added anoxia. In contrast, there was no significant day-to-day enhancement of the stress response in control, vaginally born animals. The findings reported here provide experimental support for the idea that birth complications may contribute to the pathophysiology of psychiatric disorders, in particular those that involve central dopamine dysfunction, such as schizophrenia. Specifically, our results suggest that subtle alterations in birth procedure may be sufficient to increase the sensitivity of mesolimbic dopamine neurons to the effects of repeated stress in the adult animal.

Early developmental profiles of plasma corticosterone are altered by birth condition in the rat: a comparison of vaginal birth, cesarean section, and cesarean section with added anoxia.

Circulating glucocorticoids play a role during the immediate postnatal period in adapting the neonate to extrauterine life and are also thought to influence tissue development and function in the later postnatal period. In the present study we have used a rat model to test whether birth by cesarean section (C-section), either alone or with an added period of acute anoxia, affects the development profile of basal corticosterone secretion during the first 5 wk of life. Plasma levels of total corticosterone and of corticosteroid-binding globulin were measured at various times after birth in rats born vaginally, by C-section, or by C-section with 15 min of added anoxia. These measures allowed for calculation of levels of free, biologically active, corticosterone. Under all conditions, total corticosterone appeared to accurately reflect levels of free corticosterone. Plasma corticosterone levels measured immediately (< 5 min) after birth were similar in male rat pups born vaginally, by C-section, or by C-section with added anoxia, whereas female pups born by C-section showed a significant increase in free corticosterone at birth, in comparison with vaginally born females. Both male and female animals born by C-section showed a reduction in plasma corticosterone at 1 h (male: 31% of control, p < 0.01; female: 45% of control, p < 0.05) and at 7 d (male: 61% of control, p < 0.01; female: 55% of control, p < 0.05) after birth, in comparison with vaginally born controls. In animals born by C-section with added anoxia, significant reductions in plasma corticosterone were observed for males at 1 h (58% of control; p < 0.05) and for females at 7 d (62% of control; p < 0.05) after birth. At 14 d of age, corticosterone levels were higher in male rats born by C-section either with (227% of control; p < 0.05) or without (239% of control; p < 0.05) added anoxia, in comparison with vaginally born controls. Thus C-section birth produces an early rise in plasma corticosterone on d 14 away from the low values associated with the adrenal quiescent period in the first 1-2 wk in the rat. By 35 d of age, there were no differences in plasma corticosterone attributable to C-section birth and/or acute birth anoxia, in either male or female rats. It is concluded that, in a rat model, birth by C-section has significant effects on the profile of plasma corticosterone during the early weeks of development, a period though to be critical for effects of corticosteroids on developing tissues. Because the rat at birth is developmentally less mature than is the term human neonate, these findings may have implications for development of the premature human neonate.

Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats.

We examined the possibility that anoxia at birth can alter behavioral sensitization to amphetamine during adulthood. Male rats born either vaginally or by Cesarean section with or without an additional 15-min period of anoxia received five once-daily injections of either d-amphetamine (2.0 mg/kg, i.p.) or vehicle or no pretreatment. One week later, all animals received a challenge injection of amphetamine (0.5 mg/kg, i.p.). The data indicate that all three birth groups of animals pretreated with amphetamine had sensitized equally to the drug's behavioral effect. Of animals pretreated with saline, however, only those born by Cesarean section with added anoxia displayed a sensitized response to amphetamine, suggesting that the stress of daily injection was sufficient to sensitize these animals to amphetamine. These findings provide experimental support for clinical evidence implicating obstetric complications, such as perinatal anoxia, in the pathophysiology of schizophrenia.