OPIOID SYSTEMS IN VENTRAL STRIATUM AND FOOD REWARD

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Opiates, such as heroin and morphine, constitute one of the major classes of abused drugs in the world. Although the treatment of opiate addiction remains problematic, enormous advances have been made in our general understanding of the systems on which these drugs act in the brain. The endogenous opioids are believed to play a major role in diverse biological processes such as pain modulation, affect and emotion, response to stress, and reinforcement. One major area of research has focused on opioid mediation of feeding and drinking. A hypothesis that has received considerable support states that opioids specifically regulate the rewarding or hedonic aspects of food. Moreover, clinical findings suggest that dysfunction of opioids may in some way be linked to human disorders characterized by excessive cravings, impulsive behavior and loss of control, much as in bulimia and alcoholism. In the past several years, our laboratory has investigated the effects of opioid manipulations of the nucleus accumbens on feeding behavior. This brain structure, part of the ventral striatum, is thought to be a critical substrate for the reinforcing effects of opiate and psychostimulant drugs. Our research to date has shown that microinjection of morphine into the nucleus accumbens results in a striking increase in feeding behavior and excessive food intake. This effect has been shown to be primarily mu-receptor mediated and anatomically localized to ventral, limbic-afferented striatal regions. Moreover, conditioned feeding develops following control or sham injections in animals that have received repeated microinjections of morphine. Injection of an opiate antagonist into this region reduces consumption of a sucrose solution. This project aims to further explore these findings and to test the hypothesis that opioid systems in the ventral striatum may be particularly involved in the hedonic and associative mechanisms underlying ingestive behavior. Our three specific objectives are: (i) To conduct a pharmacological analysis of the role of specific opiate receptor subtypes within the nucleus accumbens and other striatal sites in the rewarding effects of a highly palatable saccharin solution. (ii) To carry out a behavioral analysis of the motivational state induced by opioid manipulation of the nucleus accumbens. Several behavioral paradigms will be utilized including responding for sweet reward on a progressive ratio schedule, conditioned reinforcement, discrete-trial learning in a T-maze, and diet selection in rats previously selected for specific patterns of baseline diet preferences. (iii) To analyze the development and expression of the conditioned feeding response that results from repeated exposure of the nucleus accumbens to opiates. The approach common to all these experiments is the utilization of direct brain microinjection of opioid agonists and antagonists in conjunction with specific behavioral paradigms. The outcome of these experiments may contribute to our understanding of the ventral striatum in brain reinforcement processes.