This research is designed to analyze vulnerabilities of the developing brain, and recovery potential, following exposure to the major, illicit drugs of abuse. Five years of funding is requested to permit investigations of the underlying mechanisms of abnormality, as well as of associated epiphenomena. As a problem of epidemic proportions in the U.S.A., the health risks of drug abuse are further compounded by especially high rates of abuse during the years of greatest fertility (late teens and 20's). Fetal exposure is via the mother's blood, and infant exposure includes the suckling of milk, which may convey active substances at the concentration in blood, or even higher. The brain develops as a series of stages, starting in utero and followed by the postnatal brain growth spurt. Each new stage may be thought of as a critical period, although different parts of the brain may express different stages at different times. Myelination in humans spans a time from the 3rd trimester through childhood. The rat brain, which develops similarly to the human brain, presents a well documented, model system for evaluating toxicity. The cellular and biochemical aspects of myelin development have been shown to be an especially vulnerable, critical stage in development. This extensive record provides a solid foundation for similar evaluations of drug toxicity, including problematic epiphenomena, such as nutrition, withdrawal, duration and intervals of exposure, etc. Multifaceted studies of myelin synthesis and accumulation will be correlated with ultrastructural studies of the numbers of myelin-forming cells, the numbers of myelinated axons, numbers of non-myelinated axons, myelin/axon relationships, and neurons, etc. From these coordinated studies, it will be possible to characterize a wide range of primary and secondary manifestations of abnormality. Benzodiazepines, cocaine, marijuana, amphetamines, phenycyclidines, LSD, and heroine/methadone are targeted for an initial 5-year study. Dosages will span a meaningful range of at least two orders, which will be selected to mimick exposure ranging from high to low in humans. Anticipating the extent of normal variance common to both the progressive events in brain development (cell multiplication, myelination, etc.), and the regressive events (cell death, synapse elimination, etc.), the experimental design proposed for characterizing influences of drug exposure will avoid the often conflicting results found in limited surveys with small numbers of rats.
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