Human drug addiction is associated with staggering personal and societal costs. It's thought that the persistence of drug craving and the risk of relapse involve long-lasting changes in neural gene expression arising through a number of transcriptional and epi- genetic mechanisms. It's also known that midbrain dopamine (DA)-synthesizing neu- rons play an important role in both the positive and negative reinforcing features of drug abuse, providing a compelling rationale for identifying drug-induced molecular changes arising within these cells. Yet, remarkably, in contrast to the intensive study of targets of DA signaling, we have but a fragmentary understanding of the molecular consequences of chronic drug exposure on DA neurons themselves. The study of postmortem brains from human drug abusers should provide an valuable window through which we can examine the pathophysiology of addiction and evaluate the molecular concordance be- tween human drug abuse and animal models- a salient point given some important dif- ferences in the manner in which people abuse drugs and the anatomical substrates up- on which those drugs act. Unfortunately, postmortem human studies have lagged be- hind other areas of drug abuse research. This proposal will tap into the promise of postmortem studies to address critical gaps in our knowledge regarding human addic- tion, DA neurons, and epigenetics. Microarray analysis will identify changes in midbrain gene expression associated with chronic cocaine abuse, determining the biological pro- cesses most impacted and the statistical performance of robustly changed transcripts as biomarkers diagnostic for this disorder. Subsequent experiments will determine the extent to which these key changes generalize to other drug abusing cohorts (to address potential commonalities of addiction mechanisms), as well as how cocaine abuse modi- fies the known age-vulnerability of DA neurons- questions warranting serious considera- tion given the increasing prevalence of opioid abuse and poly-drug abuse, including drug abuse among older adults. Final experiments will investigate the role of specific epigenetic mechanisms (e.g. DNA methylation and long noncoding RNAs) in mediating the chronic effects of cocaine abuse. These studies will provide important new insights into the molecular pathophysiology of human drug addiction and should facilitate the development of new therapeutic strategies.
Drug addiction is associated with staggering costs to both affected individuals and society as a whole. It's thought that persistent drug craving and relapses into drug abuse are related to long-lasting changes in the activity of certain genes within a few critical areas of the brain. This project will uncover, for the first time, a complete picture of gene activity in one such area by studying the brains of individuals who have died of chronic cocaine abuse, with the ultimate goal of identifying new molecular targets for treating drug addiction.
|Miller, M L; Ren, Y; Szutorisz, H et al. (2018) Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23:1328-1335|
|Hernandez-Chan, Nancy G; Bannon, Michael J; Orozco-Barrios, Carlos E et al. (2015) Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson's disease. J Biomed Sci 22:59|
|Bannon, Michael J; Savonen, Candace L; Hartley, Zachary J et al. (2015) Investigating the potential influence of cause of death and cocaine levels on the differential expression of genes associated with cocaine abuse. PLoS One 10:e0117580|
|Bannon, Michael J; Savonen, Candace L; Jia, Hui et al. (2015) Identification of long noncoding RNAs dysregulated in the midbrain of human cocaine abusers. J Neurochem 135:50-9|
|Razgado-Hernandez, Luis F; Espadas-Alvarez, Armando J; Reyna-Velazquez, Patricia et al. (2015) The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease. PLoS One 10:e0117391|
|Bannon, Michael J; Johnson, Magen M; Michelhaugh, Sharon K et al. (2014) A molecular profile of cocaine abuse includes the differential expression of genes that regulate transcription, chromatin, and dopamine cell phenotype. Neuropsychopharmacology 39:2191-9|
|Zhou, Yanhong; Michelhaugh, Sharon K; Schmidt, Carl J et al. (2014) Ventral midbrain correlation between genetic variation and expression of the dopamine transporter gene in cocaine-abusing versus non-abusing subjects. Addict Biol 19:122-31|
|Jacobs, M M; Ökvist, A; Horvath, M et al. (2013) Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels. Mol Psychiatry 18:1205-10|
|Johnson, Magen M; David, James A; Michelhaugh, Sharon K et al. (2013) Authors' response. J Forensic Sci 58:562|
|Anderson, Sarah Ann R; Michaelides, Michael; Zarnegar, Parisa et al. (2013) Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression. J Clin Invest 123:5334-41|
Showing the most recent 10 out of 46 publications