Cocaine abuse alters gene expression in brain

Dr. Bannon says elucidating the regulation of the dopamine transporter may also shed light on conditions such as Parkinson’s disease, Alzheimer’s, and schizophrenia.

Brains of cocaine abusers may have cellular glitches which actually feed their drug addiction. According to Michael Bannon, PhD, the brains of cocaine users exhibit  a striking decrease in the expression of the dopamine transporter (DAT), a plasma membrane protein or “pump” which regulates the abundance of the neurotransmitter dopamine. The acute effects of cocaine are due largely to blockade of the DAT. Prolonged decreases in DAT expression would lead to  disregulation of dopamine, making drug users susceptible to depression, agitation and drug craving.

With more than $1.3 million from the National Institutes of Health, Dr. Bannon is investigating the cellular and molecular biology of the cocaine binding DAT. He and his research team have already isolated, cloned and sequenced the gene for DAT. In doing so, they have observed numerous sites which may change DAT gene expression by binding transcription factors. Initial efforts have focused on the transcription factor NOT, which strongly regulates DAT expression in cell culture. Initial experiments using the brains of cocaine abusers indicate that the loss of DAT expression correlates strongly with decreases in brain NOT. Understanding the molecular basis of DAT regulation may provide important insights into the biology of craving and addiction.

 “The normal aging brain experiences gradual dopamine changes, but major damage can occur with insults like drug abuse on top of that,” said Dr. Bannon. “An understanding of DAT regulation and cocaine-induced changes in human DAT gene expression may shed light on the molecular basis of cocaine addiction, an affliction affecting greater than one percent of the U.S. population,” said Dr. Bannon.

 These studies may shed light on other pathophysiological states as well, since DAT expression is altered in different ways in other conditions such as Parkinson’s disease, Alzheimer’s disease, normal aging, Tourette’s syndrome and Lesch-Nyhan disease. This line of research has produced productive collaborations with James Granneman, PhD, professor of psychiatry and behavioral neurosciences, who is investigating novel therapeutic agents to prevent DAT loss and provide relief to people who suffer from a variety of these dopamine-related conditions.