Early clinical reports of severe morbidity and mortality in infants born passively addicted to opiates are being reinterpreted in light of recent reports of an improved prognosis in children born to women on methadone maintenance programs who avail themselves of antenatal and well-baby clinics, and in whom illicit polydrug abuse and poor nutrition are kept to a minimum. Most of the preclinical animal literature dealing with effects of methadone during development would suggest that methadone should never have been released for clinical use by people of childbearing age or who are pregnant. However, we believe that there are many flaws in the design and interpretation of these experiments and have completed or are in the process of extending a series of experiments with the opiate 1-alpha-acetylmethadol (LAAM) or its active metabolites in which we can duplicate many effects reported for methadone, but which appear to be preventable or nonexistent, if careful attention is paid to animal modeling and potential epiphenomena. We propose to continue these studies as well as incorporate several new studies to determine the relevance (i.e. generality or specificity) of our observations with LAAM, to study the consequences of hypoxia and hypercapnia equivalent to that produced by (acutely toxic) doses of methadone typically used by other laboratories for such studies. Very little is known about the effects of cocaine on the developing child, when exposed in utero. The dearth of data is more recently being added to by anecdotal, small group or clinical case reports of neonates born to cocaine abusers who also invariably are polydrug abusers. This makes it difficult or impossible to separate direct from indirect effects, as well as effects due solely or primarily to cocaine exposure, except in those instances where clearcut acute toxic manifestations are responsible (e.g. subdural hematoma or other evidence of CVA or seizures). Even then, combinations of multiple drug exposure, poor nutritional or health status (i.e. infectious hepatitis due to i.v. drug self-administration) may be more responsible for morbidity/mortality of cocaine-exposed neonates. We propose to study the effects of cocaine, administered at different doses, to pregnant rats (prior to and throughout pregnancy or at different stages of pregnancy) or to breeder male rats in order to assess the neurobehavioral consequences in offspring of such exposure. Rats will be tested in adulthood, after exposure prior to fertilization (gametes) and during in utero development. Treatment of neonates with cocaine and drugs known to attenuate or block opiate withdrawal in rats and/or humans will be used to determine if cocaine-exposed neonates show morbidity or mortality as a result of residual cocaine or if toxicity and/or a withdrawal syndrome is treatable during the neonatal period.
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