Accumbens-pallidal GABA and morphine reinforcement

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DESCRIPTION (provided by applicant): Opiate abuse continues to be a major public health concern in the United States, especially in light of the dramatic increase in the number of first time users. The development of more effective pharmacotherapies requires a more detailed understanding of the neurochemical, molecular and behavioral variables that mediate opiate reinforcement. To date, a vast majority of animal studies assess the biological underpinnings of opiate reinforcement in the absence physical dependence, even though physical dependence is a characteristic of human opiate abuse. GABAergic medium spiny neurons projecting from the NAc to the ventral pallidum (VP) are likely neuronal loci for the reinforcing effects of opiates and are necessary for the expression of opiate self-administration. The long-term objective of this proposal is to further the understanding of the involvement of the accumbens-pallidal pathway in morphine self-administration in physically dependent rats. The first series of studies will assess the correlation of VP GABA with the effects of morphine administration in dependent rats. More specifically, these experiments will determine extracellular GABA concentrations ([GABA]e) in the ventromedial VP and dorsolateral VP, projection terminal regions of the shell and core accumbal-pallidal MSNs, respectively. These effects will be compared with subjects receiving yoked morphine and saline to assess the contribution of VP GABA in the reinforcing and direct pharmacological effects of morphine respectively. The second series of experiments will determine the role of VP GABA-A and -B receptors in mediating morphine self-administration. The effects of systemic and intra-VP administration of selective antagonists will be compared with food-maintained responding. A second series of experiments. In a third series of experiments, regional and single cell gene expression techniques will be employed to assess morphine-induced regulation of cAMP pathway transcripts in accumbens-pallidal MSN projections from the NAc shell to the ventromedial VP and NAc core to the dorsolateral VP. Changes in the expression levels of multiple genes will be assessed in terms of morphine reinforcement and direct pharmacological effects of the drug.