The dopamine transporter (DAT) is a plasma membrane protein that limits dopamine (DA) neurotransmission in the brain and, in doing so, modifies human behavior. It is an important site of action for cocaine and other abused psychostimulants. Altered expression of the DAT may contribute to some polygenic neuropsychiatric disorders. For other disorders, altered DAT expression represents a response to pathological processes. Despite its obvious clinical importance, surprisingly few studies have functionally characterized putative regulatory sequences within the DAT gene. This is the gap in scientific knowledge that our lab seeks to fill. The long-term goal of this project is to develop a much better understanding of the molecular mechanisms regulating DAT gene expression, which may lead to novel therapeutic strategies for the treatment of drug abuse and other brain disorders involving alterations DA neurotransmission.
Specific Aim 1 will determine the site and mechanism of action by which the transcription factors nurr1 and pitx3 increase DAT gene transcription, as well as their roles in maintaining DA phenotype in vivo, using a series of newly developed reagents (e.g. ChIP, siRNA, AAV vectors). Nurr1 and pitx3 binding to the DAT gene in postmortem brains from cocaine abusers will also be determined.
Specific Aim 2 will investigate the molecular effects of the therapeutic drug valproate on DAT gene transcription, DAT expression in vivo, and cocaine-induced changes in DAT expression. Given the cocaine-induced decreases in DAT gene expression seen in both animal models and human cocaine abusers, it is possible that some of valproate's suggested therapeutic effects in addiction may involve activation of DAT gene expression.
Specific Aim 3 will develop a comprehensive profile of human midbrain gene expression and genes co-regulated with the DAT in cocaine abusers, providing molecular insights into the addicted brain that complement our current cellular and animal models of addiction. Genes that may regulate the DAT, as well as additional nurr1/pitx3 target genes, will be identified.
These Aims are conceptually linked, building from mechanistic studies of the regulation of DAT transcription (Specific Aim 1), to investigating a regulatory mechanism that may prove therapeutically important (Specific Aim 2), to examining genes co-regulated with DAT, leading to a more comprehensive understanding of cocaine's effects on DA systems.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Wu, Da-Yu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wayne State University
Schools of Medicine
United States
Zip Code
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; ├ľkvist, 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