There is an ever-increasing need to understand the neurobiological consequences of maternal substance abuse. Drugs such as opiates can cross the placenta and induce long-term alterations in the developing CNS. Our work demonstrates that exposure to morphine during mid to late gestation induces long-term, sex-specific behavioral and neurochemical alterations in young adult male and female rats. It is noteworthy that these long-lasting, sex-specific changes in NE neurotransmission occur in brain regions known to participate in stress responses. If activation of the stress system in animals exposed prenatally to morphine is maladaptive and/or uncontrolled, the resulting dysphoria could increase drug abuse liability in adult offspring. Therefore, we now propose to test the hypothesis that prenatal morphine exposure alters the development of brain systems mediating endocrine and neural responses to stress and promotes drug abuse liability in both young adult male and female rats.
Specific Aim 1 will test the hypothesis that prenatal morphine exposure increases acute stress-induced activation of the female HPA axis, possibly by reducing the sensitivity to negative feedback of adrenal steroids. RIA will be used to measure plasma ACTH and corticosterone (COR) levels before and several times after an acute stressor. Sensitivity of the brain to glucocorticoid negative feedback will also be evaluated. Binding assays will assess whether alteration in ACTH and COR release correlate with changes in glucocorticoid receptor (GR) binding in the hippocampus and hypothalamus. In situ hybridization experiments will assess the effects of prenatal morphine on GR mRNA in both the hippocampus and hypothalamus.
Specific Aim 2 will test the hypothesis that prenatal morphine exposure enhances the reward-potentiating properties of drugs in young adult animals, using electrical brain-stimulation reward in conjunction with acute systemic administration of cocaine or morphine. Additional experiments will investigate whether prenatal morphine exposure enhances cocaine self-administration, and whether stress-induced relapse to cocaine self-administration is potentiated in prenatally morphine-exposed animals.
Specific Aim 3 will test the hypothesis that prenatal morphine exposure alters NE release in brain structures involved in stress responses. In vivo brain microdialysis will assess basal and stress-induced NE release in the PVN and hippocampus.
Specific Aim 4 will test the hypothesis that prenatal exposure to morphine alters neuronal plasticity in the hippocampus of exposed animals. The hippocampus plays a role in negative feedback inhibition of the HPA axis, and hippocampal GRs regulate the magnitude of long-term potentiation (LTP) in the dentate gyrus (DG). Electrophysiological experiments will investigate the effects of prenatal morphine exposure on basal LTP and on mineralocorticoid receptor (MR) and GR modulation of LTP in the DG and CA1 regions of the hippocampus. We will also evaluate spatial learning and memory in an eight-arm radial maze, a hippocampal-dependent task. This research will provide valuable information regarding the mechanisms by which prenatal morphine exposure alters the sensitivity of the HPA axis, neural plasticity of the hippocampus and the propensity for drug abuse.
