The objective of the proposed research is to establish how prenatal exposure to opiates (morphine) alters neural development in such a way that adult neuroendocrine functions are permanently altered. Previous work demonstrated that the female offspring of rats given morphine during mid to late gestation are impaired in the ability to exhibit reproductive (estrous) behavior in response to appropriate ovarian steroids administered in adulthood. It is known that steroid facilitation of hypothalamic norepinephrine (NE) neurotransmission plays a critical role in hormonal regulation of estrous behavior. In addition, morphine can inhibit estrous behavior when administered acutely to adult female rats, and preliminary data suggest that the behavioral inhibition may be related to morphine suppression of hypothalamic NE release. Thus the proposed research tests two related hypotheses: Hypothesis 1. Morphine inhibits female reproductive behavior when given acutely to adult rats by interfering with hypothalamic NE transmission. Specific experiments will ask: (1) Is morphine inhibition of steroid-dependent estrous behavior correlated with depressed hypothalamic NE release? (2) Does the opiate antagonist naloxone restore both the behavior and NE release to normal levels? (3) Does infusion of NE directly into the hypothalamus reverse morphine inhibition of female reproductive behavior. Hypothesis 2. The attenuation of estrous behavior in female rats exposed to morphine during development is a consequence of long-term opiate depression of NE transmission in the hypothalamus. Specific experiments will ask: (1) Does prenatal morphine treatment alter NE content, NE turnover and/or NE receptors in the hypothalamus? (2) Do prenatally morphine-treated females show deficits in ovarian steroid enhancement of both reproductive behavior and hypothalamic NE release? (3) Does naloxone restore hormonal activation of behavior and hypothalamic NE release? (3) Does naloxone restore hormonal activation of behavior and hypothalamic NE release in prenatally morphine-exposed animals? (4) Does infusion of NE directly into the hypothalamus of prenatally morphine-treated females restore estrous behavior? These experiments will provide new information regarding mechanisms by which opiates act in adult and developing brains to produce neuroendocrine and behavioral dysfunctions.
