Human infants develop opiate dependence and undergo withdrawal if they are exposed in utero to illicit drugs such as heroin, or to prescribed opiates such as methadone, or ex utero when treated with opiates for pain. To devise rationale treatments for this abstinence syndrome, and to understand the long term consequences of opiate dependence in the neonate, it is necessary to understand more fully how these drugs act on the neurobehavioral systems of the neonate. Until recently the only detailed description of an opiate abstinence syndrome in neonates was for humans. The complexity of the human setting made it impossible to tease apart those factors that are due to opiate use and those that are due to the abuse of other drugs, poor prenatal care, undernutrition, or any of the other complications experienced by the mothers of these children. The first and necessary step in this process, to describe the phenomenology of precipitated withdrawal in infants, has been accomplished. Two groups, including ours, have detailed an opiate withdrawal syndrome, in the infant rat, that includes behaviors such as head swaying, stretching, rolling, and the inability to stay quiet. Aspects of this syndrome are seen even in the fetus, and the withdrawal syndrome slowly changes over development to reach, around puberty, the classic constellation of withdrawal behaviors so often described for the adult animal. Furthermore, the dysphoria associated with abstinence appears in the infant rat, but develops later, around 14 days of age, dissociating the unconditioned """"""""physical"""""""" withdrawal signs from the affective component of abstinence. Because the withdrawal syndrome in the infant is now described in great detail, we are poised to ask a number of questions that could not have been addressed even two years ago. The experiments in this proposal examine where and how this syndrome is organized in the brain, and what are the developmental continuities and discontinuities in the neural substrates of opiate withdrawal, describes changes in state regulation that may occur during normal development and under conditions of stress, and begins to study pharmacologic treatments, both clinically approved and experimental, of the opiate abstinence syndrome in the neonate. The data from these experiments shall provide a detailed knowledge of the neural and physiological underpinnings of the neonatal abstinence syndrome, in all its complexity, and represents the first efforts to investigate pharmacologic therapies that might be used to ameliorate the expression of opiate withdrawal in the infant.
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