Cocaine is a reinforcing drug with high abuse liability, morbidity and mortality. Cocaine is the second most commonly used illicit drug (following marijuana) in the United States. According to the 2003 National Survey on Drug Use and Health, more than 34 million Americans (14.7%) age 12 or older had used cocaine at least once in their lifetime. Effective medication for the treatment of cocaine overdose and addiction is a major unmet need of worldwide importance. Our laboratory has studied the relationship between the long-term effects of chronic cocaine abuse and the regional neuroadaptive changes that occur in human brain. Through our collaboration with the Miami-Dade County Medical Examiner Department, we have developed a bank of postmortem brain specimens from cocaine abusers and age, gender and ethnicity matched control subjects. We also have developed a collection of postmortem brain specimens from victims of cocaine-related excited delirium. Medical examiners nationwide are increasingly citing this condition when suspects die in police custody. We have demonstrated that alpha synuclein, a protein implicated in neurodegenerative disorders, such as Parkinson's disease, may play a role in the development and maintenance of cocaine addiction. Alpha synuclein is an important regulator of the DA system. The protein interacts with the DA transporter, and regulates DA content, neurotransmission and synaptic strength of DA neurons. We propose here integrated molecular approaches to continue our studies to characterize counteradaptations in alpha synuclein, dopamine presynaptic markers and catecholamine metabolism (DA, DOPAC, HVA) in postmortem human brain from chronic cocaine abusers. Together, these studies will provide a molecular and circuit-based accounting of coordinated dysregulation of alpha synuclein and presynaptic markers of the DA system in cocaine dependence. Alpha synuclein dysregulation in DA neurons may be one of the neurobiological factors that produce vulnerability to addiction and relapse in individuals with a history of cocaine dependence. Agents that modulate SNCA expression are under development for the treatment of Parkinson's disease and may be an alternative therapeutic option for normalizing DA homeostasis in cocaine dependence.
Study of the postmortem human brain helps to advance the ultimate validation of addiction as a brain disease. A better understanding of how cocaine abuse affects the CNS will facilitate the development of more successful prevention and treatment strategies.
|Mesner, Larry D; Ray, Brianne; Hsu, Yi-Hsiang et al. (2014) Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density. J Clin Invest 124:2736-49|
|GTEx Consortium (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580-5|
|Sullivan, D; Pinsonneault, J K; Papp, A C et al. (2013) Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction. Transl Psychiatry 3:e222|
|Enoch, Mary-Anne; Zhou, Zhifeng; Kimura, Mitsuru et al. (2012) GABAergic gene expression in postmortem hippocampus from alcoholics and cocaine addicts; corresponding findings in alcohol-naïve P and NP rats. PLoS One 7:e29369|
|Gutierrez, Jose; Glenn, Melanie; Isaacson, Richard S et al. (2012) Thinning of the arterial media layer as a possible preclinical stage in HIV vasculopathy: a pilot study. Stroke 43:1156-8|
|Zhou, Zhifeng; Yuan, Qiaoping; Mash, Deborah C et al. (2011) Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol. Proc Natl Acad Sci U S A 108:6626-31|
|Mash, Deborah C; Duque, Linda; Pablo, John et al. (2009) Brain biomarkers for identifying excited delirium as a cause of sudden death. Forensic Sci Int 190:e13-9|
|Jiang, Xueying; Zhou, Jian; Mash, Deborah C et al. (2009) Human BDNF isoforms are differentially expressed in cocaine addicts and are sorted to the regulated secretory pathway independent of the Met66 substitution. Neuromolecular Med 11:1-12|
|Mash, Deborah C; Adi, Nikhil; Duque, Linda et al. (2008) Alpha synuclein protein levels are increased in serum from recently abstinent cocaine abusers. Drug Alcohol Depend 94:246-50|
|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|
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