Cocaine and crack addiction remains a significant medical and social problem. While the dopamine transporter is thought to be the primary site of action for the acute reinforcing effects of cocaine, the post-synaptic consequences of cocaine use and the neurobiological mechanisms that subserve the addictive process remain to be confirmed. The identification of the genetic components underlying cocaine addiction is a critical step in identifying potential targets for therapeutic intervention. The central hypothesis of this application is that chronic drug abuse produces a metastable epigenetic imprint that may contribute to clinical issues such as tolerance, physical dependence, and withdrawal. This application proposes to use multiplex DNA hybridization arrays to examine the interface of functional genomics and behavior. - In Specific Aim # 1, DNA hybridization arrays will be used to profile the CNS epigenetic imprint induced by cocaine self-administration in rats. This will be accomplished using commercially available arrays as well as custom arrays, imprinted at this institution and designed to test specific hypotheses regarding cocaine abuse. These will then be followed by studies in Specific Aim #2 that examine a new binge abstinence model of cocaine administration. This model recapitulates several key features of human cocaine abuse (specifically, the progressive loss of behavioral control). Finally, studies at the end of the funding period (Specific Aim #3) will establish the time course for gene expression changes following cessation of cocaine self-administration. These last experiments will provide very important insights into the stable changes in gene expression that survive long-term cessation of the drug, while simultaneously identifying new genes whose expression is altered during the withdrawal period. In addition to the specific proposed experiments, efforts will be coordinated with Emory University, during the funding period, to establish a central repository for array data for general access by the NIDA research community (www.arraydata.org) as well as a tissue/RNA bank. The results of the studies described within the present application should provide a wealth of information concerning functional genomic contributions to the cocaine addiction process.
| Carkaci-Salli, Nurgul; Salli, Ugur; Kuntz-Melcavage, Kara L et al. (2011) TPH2 in the ventral tegmental area of the male rat brain. Brain Res Bull 84:376-80 |
| Lull, Melinda E; Freeman, Willard M; VanGuilder, Heather D et al. (2010) The use of neuroproteomics in drug abuse research. Drug Alcohol Depend 107:11-22 |
| Freeman, Willard M; Lull, Melinda E; Patel, Kruti M et al. (2010) Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration. BMC Neurosci 11:29 |
| Lull, Melinda E; Erwin, Mandi S; Morgan, Drake et al. (2009) Persistent proteomic alterations in the medial prefrontal cortex with abstinence from cocaine self-administration. Proteomics Clin Appl 3:462-472 |
| Kuntz-Melcavage, Kara L; Brucklacher, Robert M; Grigson, Patricia S et al. (2009) Gene expression changes following extinction testing in a heroin behavioral incubation model. BMC Neurosci 10:95 |
| Freeman, Willard M; Patel, Kruti M; Brucklacher, Robert M et al. (2008) Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Neuropsychopharmacology 33:1807-17 |
| Lull, Melinda E; Freeman, Willard M; Vrana, Kent E et al. (2008) Correlating human and animal studies of cocaine abuse and gene expression. Ann N Y Acad Sci 1141:58-75 |
| Kuntz, Kara L; Patel, Kruti M; Grigson, Patricia S et al. (2008) Heroin self-administration: II. CNS gene expression following withdrawal and cue-induced drug-seeking behavior. Pharmacol Biochem Behav 90:349-56 |
| Kuntz, Kara L; Twining, Robert C; Baldwin, Anne E et al. (2008) Heroin self-administration: I. Incubation of goal-directed behavior in rats. Pharmacol Biochem Behav 90:344-8 |
| VanGuilder, Heather D; Vrana, Kent E; Freeman, Willard M (2008) Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques 44:619-26 |
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