The major focus of my research has been the study of adaptations induced by chronic opiate and cocaine treatments in post-receptor, intracellular messenger pathways in specific target brain regions. One area of study has been the locus coeruleus (LC), shown to play an important role in physical opiate dependence and withdrawal. We have found that chronic opiate administration up-regulates the cyclic AMP pathway in the LC and have provided direct evidence that this up-regulation contributes to opiate tolerance, dependence, and withdrawal exhibited by LC neurons. One major objective of the proposed studies is to extend these studies by further characterizing opiate regulation of the cyclic AMP and other intracellular messenger pathways, and by studying similar biochemical adaptations in certain other regions of the CNS, where we have also found chronic opiate-induced up-regulation of the cyclic AMP pathway. Since up-regulation of the cyclic AMP pathway in the LC involves alterations in the levels of specific proteins and in their mRNA's, it is possible that changes in gene expression may be involved. Therefore, one major developmental aspect of this RSDA is to enable me and my laboratory to gain expertise in additional types of molecular biological procedures with which we can investigate the mechanisms, at the molecular level, by which opiates up-regulate the cyclic AMP pathway in the LC and related regions. The other area of study has been the mesolimbic dopamine system, implicated in the rewarding properties of opiates, cocaine, nd other drugs of abuse. We have found common chronic actions of opiates and cocaine on intracellular messenger pathways in this neural system. Moreover, we have demonstrated inherent differences in some of the same messengers, specifically in the mesolimbic dopamine system, between inbred rat strains and among individuals of a single strain that show different preferences for drugs of abuse. In the proposed research, we plan to further investigate the biochemical and molecular adaptations that opiates and cocaine induce in these brain regions. However, to understand the functional significance of these various adaptations, it is necessary to directly study their possible involvement in drug reward mechanisms. Therefore, a second developmental aspect of this RSDA is to gain proficiency with specific behavioral paradigms, in particular, measures of drug self-administration and locomotor activity, which will enable us to directly link our biochemical/molecular observations to drug reward. The proposed studies will contribute to a more complete understanding of the mechanisms underlying opiate and cocaine addiction.
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| Nestler, E J (1994) Molecular neurobiology of drug addiction. Neuropsychopharmacology 11:77-87 |
| Terwilliger, R Z; Ortiz, J; Guitart, X et al. (1994) Chronic morphine administration increases beta-adrenergic receptor kinase (beta ARK) levels in the rat locus coeruleus. J Neurochem 63:1983-6 |
| Widnell, K L; Russell, D S; Nestler, E J (1994) Regulation of expression of cAMP response element-binding protein in the locus coeruleus in vivo and in a locus coeruleus-like cell line in vitro. Proc Natl Acad Sci U S A 91:10947-51 |
