Prenatal stress, moderate fetal alcohol, and dopamine system function in rhesus monkeys
Introduction
Increased violence and substance abuse in everyday life has led to a growing concern about the effects of psychosocial stress and alcohol exposure during pregnancy on child outcome. While it is well established that consumption of alcohol during pregnancy causes harm to the fetus [39], there are limited data on whether psychosocial stress interacts with these effects [36], [37].
It is not a new idea that if a pregnant woman is exposed to stressful events in everyday life, her offspring might be at risk for learning, behavioral, and/or emotional disorders [31], [42]. An important issue of concern relative to the present study is that maternal stress may contribute to child outcome by interacting with numerous other factors in a complex, mutually interacting process. Moreover, it is thought that exposure to prenatal stress and/or alcohol alters an individual's developmental trajectory through altered early brain development. We employ a primate model because in human studies, causal conclusions are difficult to reach due to the clustering of negative events in humans. Nonhuman primates have the advantage of gestation characteristics and early development similar to the human, and their shorter life span makes longitudinal studies somewhat easier to conduct.
Most animal studies of prenatal stress effects have been conducted in rodents. A variety of stressors have been employed, and they have been administered across a variety of times during pregnancy [35]. A number of rodent studies show that prenatal stress is associated with the abnormal regulation of the hypothalamic–pituitary–adrenal (HPA) axis. The underlying mechanism for the dysregulated HPA axis is not fully understood. Several lines of evidence, however, suggest that glucocorticoids or other substances that the mother produces as a result of the stressful experiences could cross the placenta during stress episodes and influence fetal brain development [15].
Studies have demonstrated that drinking alcohol during pregnancy can be harmful even in the absence of gross morphological defects associated with fetal alcohol syndrome (FAS) [24]. Recent findings from several animal models and from neuroimaging studies with children have indicated that several brain areas may be particularly vulnerable to the adverse effects of fetal alcohol exposure. Magnetic resonance imaging (MRI) studies of children with FAS indicated volume reductions in the basal ganglia after accounting for brain size [25], [26]. Using positron emission tomography (PET), Loock et al. [22] reported reduced metabolic activity in the caudate nucleus of children with FAS. Prenatal alcohol exposure has also been found to result in alterations in a number of neurotransmitter systems, including dopamine [9], [10], [23], [34], [38], [40], [41].
Because prenatal stress can covary with fetal alcohol exposure, how fetal alcohol exposure and prenatal stress together affect fetal development is an issue of concern. Both prenatal stress and fetal alcohol exposure have been associated with altered dopaminergic function. For example, fetal alcohol exposure decreased D1 dopamine receptors in the hypothalamus and striatum in 18- to 35-day-old rodents [9]. Prenatal stress was associated with an increase in dopamine turnover in the right prefrontal cortex and a decrease in turnover in the left striatum in rats of both sexes [13]. In addition, an increase in the density of dopamine D2 receptors in the nucleus accumbens was reported in prenatally stressed male rats [16], while a bilateral decrease in dopamine turnover in the nucleus accumbens was reported in female rats [1].
To date, animal studies investigating how prenatal stress and fetal alcohol exposure together affect fetal development have produced mixed results. For example, restraint stress in mice increased the adverse effects of all-trans-retinoic acid, an essential chemical to which the early CNS is known to be highly sensitive and which is a teratogen in high concentrations [32]. Another study, however, reported that prenatal stress decreased the adverse effects of fetal alcohol exposure on sensorimotor development of rats [43]. We recently reported that prenatal stress in combination with moderate fetal alcohol exposure resulted in lowered birth weights in male rhesus monkey offspring and increased fetal loss [37]. The combination of prenatal stress and fetal alcohol exposure also increased the incidence of stereotypies and hyperactivity observed during cognitive testing in both male and female monkey offspring and increased the number of trials to criterion during the acquisition of non-matching-to-sample (NMS) task performance [36]. How prenatal stress with moderate prenatal alcohol exposure affects neurobiological function in monkeys is a question that remains unaddressed.
Our primary goal in the present study was to examine the consequences of prenatal stress, moderate fetal alcohol exposure, or the combination of both on striatal dopamine system function in adult rhesus monkeys. To assess striatal dopamine system function, we used PET. We chose to examine both D2 binding availability and DA synthesis in the striatum because it is rich in dopaminergic synapses and should therefore be sensitive to any treatment that alters DA function. The methodology for PET studies of these particular dopamine system components is well established, resulting from decades of research into neurodegenerative disease, such as Parkinson's. In addition, we investigated the balance of striatal DA synthesis and postsynaptic receptor density, given the documented compensatory relationship between these parameters. For example, it has been shown that a chronic decrease in dopamine production results in an increase in D2 receptor density [8]. The striatum, which consists of the caudate nucleus and putamen, receives inputs from all cortical areas and the thalamus and projects to frontal lobe areas (prefrontal, premotor, and supplementary motor areas). Those circuits regulate the cortex, play a role in predicting future events, and are involved in shifting attention sets, movement, and spatial working memory [17]. Therefore, alterations in striatal DA function may have widespread effects on behaviors associated with prenatal stress and/or fetal alcohol exposure, such as poor self-regulation, motor hyperactivity, and altered arousal.
A second purpose of our study was to examine the relationship between alterations in striatal dopamine system parameters and behavioral outcomes that were previously measured in these same animals. Recent theories of striatal function suggest that it is involved in inhibitory control, or the execution of a pattern of activity by suppressing another opposing pattern [28]. For example, studies by Ferry et al. [11], [12] have supported the hypothesis that the striatum is involved in inhibitory control by demonstrating that lesions in the ventral striatum of macaque monkeys were associated with impairments in the ability to suppress responses to previously rewarded stimuli in a reversal task. In our prospective longitudinal study, we have conducted repeated observations of behavioral functions related to inhibitory control purported to be associated with striatal dopaminergic function. These include attention and motor function during early development [37] and aspects of learning that require inhibitory control—an NMS task. The NMS task requires rule learning, shifting attention to the nonmatching stimulus, inhibitory control, and working memory—all functions dependent upon dopamine innervations in the basal ganglia, limbic, and prefrontal and frontal cortex [29], [45]. Observers rated key aspects of behavior after each testing session [36].
Section snippets
Maternal stress and/or alcohol treatments
These studies were conducted in accordance with the University of Wisconsin-Madison Animal Care and Use Committee. Healthy adult female rhesus monkeys were identified within the breeding colony that consistently and voluntarily consumed 0.6 g/kg of a 6% v/v alcohol solution sweetened with 300 mg/100 ml NutraSweet (Equal Sweetener, Merisant US, Chicago, IL). Prior to breeding, blood samples that were obtained 60 min after consumption of 0.6 g/kg alcohol showed blood alcohol contents of 20–50
Positron emission tomography
The first four monkeys (two control and two alcohol plus stress) were scanned twice to ascertain that the measurements were reliable [33]. The percentage variation from the first test ranged from 6% to 10% with an average of 7.5%.
Fig. 1 shows the distributions, means, and S.E.M.'s of the DVR for the radiotracers measured by PET imaging that reflect the D2 receptor binding availability (indexed by FAL, Fig. 1a), DA synthesis (indexed by FMT, Fig. 1b), and the FAL–FMT ratio (Fig. 1c) for the four
Discussion
The aim of this study was to determine, under controlled laboratory conditions, whether prenatal stress and/or moderate-level maternal alcohol exposure would influence striatal dopamine function in young adult monkeys, assessed by PET. First, it was found that prenatal stress induced CNS alterations that were detected in measures of striatal dopamine system function. PET scans of the striatum showed an altered balance of D2 receptor binding (FAL) to DA synthesis (FMT) in the prenatal
Acknowledgements
This study was supported by Grants R01AA10079 and R01AA12277 from the National Institute of Alcohol Abuse and Alcoholism to M.L. Schneider and 5T32CA009206 from the National Cancer Institute. Partial facilities support was provided through the UW Health Emotions Research Institute.
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