Large numbers of human infants are exposed in utero to illicit opiate drugs such as heroin and to prescribed opiates such as methadone. It is therefore important to understand the effect of acute and chronic exposure to drugs such as these on the immature organisms. A necessary step in understanding the long term effects of early drug exposure is to describe fully how the drug acts on neurobehavioral systems in the neonate. Because infants typically experience withdrawal from opiates, either in utero or shortly after parturition, a fuller understanding of the consequences of opiate withdrawal in the immature animal is important but is a largely unexplored area of research. Although there has been some question as to whether infants undergo withdrawal, from our previous experiments we have reason to believe that rat neonate experiences clear behavioral changes during opiate abstinence, including the induction of """"""""dysphoric"""""""" states on cessation of drug exposure. It is hypothesized that the infant undergoes withdrawal, but that the signs and symptoms experienced differ from those suffered by the adult. In the proposed research we will describe the effects that repeated exposure to and withdrawal from the prototypic opiate, morphine, has on the immature organism. The rat is the model of choice because it is an altricial species and thus quite immature at birth and because there is a large existent database that describes the neurobiology and behavior of this species. Using classic paradigms from the adult literature, and developmentally appropriate measures, we will examine in depth the behavioral and physiological changes that occur during precipitated and spontaneous opiate abstinence. We begin by using observational methods to describe behavioral changes during precipitated withdrawal in the fetus, young infant and older animal, comparing these changes to those describe for the adult. We relate these behaviors to measured levels of morphine in brain and plasma both prior and subsequent to the development of the blood brain barrier. Secondly we explore alterations in physiological systems including cardiovascular, thermoregulatory and sleep/wake states. During withdrawal from morphine, pups increase ultrasonic vocalizations, fail to quiet in the company of a companion, and can learn to avoid stimuli previously associated with precipitated withdrawal. These may be developmental parallels to negative affective states experienced by adults in withdrawal. These behavioral changes will be explored in detail. We will also initiate studies on the neural bases of the development of opiate abstinence syndromes, specifically focussing on two brain areas, the nucleus accumbens and the locus coeruleus, demonstrated in the adult to be involved in separable components of that syndrome. The last series of experiments explores the consequences of spontaneous opiate withdrawal or later mother-infant interactions. The results from these experiments should provide important data on the effects of drugs exposure and withdrawal during development.
Showing the most recent 10 out of 23 publications
