It has been estimated that one out of every 1000 children born in the U.S. is exposed in utero to heroin or methadone. This represents between 6,000-9,000 births per year exposed prenatally to these two opioids alone. This does not include the number of pregnant women who abuse other opioids or opioids in combination with other illicit substances. Many offspring of mothers addicted to opioids during pregnancy suffer from behavioral abnormalities, withdrawal syndrome, altered sleep patterns, and an increased incidence of Sudden Infant Death Syndrome. Of the three major opioid receptor subtypes (mu, delta, and kappa), our knowledge of the effects of perinatal exposure to opioids comes exclusively from studies of the mu receptor. We know nothing about the effects of chronic perinatal exposure to opioids selective for delta or kappa opioid receptors. The objectives of this study are to test the hypothesis that perinatal exposure to kappa opioids alters dopaminergic neurochemical mechanisms thus resulting in neurological deficits in offspring.
The specific aims are to determine the effects of chronic perinatal exposure to the kappa agonist, U-50,488 on dopamine release and metabolism, the binding characteristics of kappa opioid and dopamine D1 and D2 receptors, and tyrosine hydroxylase enzyme activity in the rat nucleus accumbens and striatum. The effects of chronic perinatal exposure to U-50,488 on locomotor activity and stereotyped behavior will also be determined and compared with results of the neurochemical studies for possible correlations. The effects of chronic exposure to U-50,488 on dopamine release and metabolism will be determined using in vivo microdialysis coupled with HPLC. The behavioral studies will be conducted simultaneously in the same animals as they undergo dialysis. Photobeam-activated activity boxes will be used to determine the drug effects on locomotor activity. A trained observer will monitor stereotyped behavior with the aid of a video camera. The ligand binding and enzyme activity studies will be carried out in tissue homogenates of nucleus accumbens and striatum using standard radioligand procedures. Acute challenges with D1 nd D2 receptor-selective agonists will be used in the dialysis and behavioral studies to determine if changes have occurred in dopamine receptor sensitivity due to chronic perinatal exposure to U-50,488.
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