Mission of the Pierce Lab

Currently, there are no effective therapies for cocaine addiction, which directly affects over two million people in the United States alone. This reality is the driving force for our research program. The major hurdle for abstaining from abuse of cocaine is intense drug craving, which can be triggered months and even years following the cessation of drug use. The most widely accepted model of craving in animals involves self-administration followed by extinction and the subsequent reinstatement of drug seeking. Using this animal model, our research team pursues a strategy to identify novel neurobiological adaptations produced by cocaine and then uses this information to formulate potential cocaine addiction therapies.

Previous work indicated that two neurotransmitters, dopamine and glutamate, independently contribute to the development of cocaine addiction. Our research suggests that L-type calcium channels provide critical links between dopamine and glutamate that drive the intense craving associated with cocaine addiction. Diltiazem, an L-type calcium channel blocker, disrupts the connection between dopamine and glutamate formed during chronic cocaine use. The fact that diltiazem and similar drugs are already widely used clinically in the treatment of heart disease should facilitate testing compounds of this class as cocaine addiction therapeutics in humans.

Interestingly, calcium-stimulated kinases such as CaM-KII play an important role in learning and memory; in fact, CaM-KII has been labeled the "memory molecule". Our work shows that cocaine increases the levels of CaM-KII specifically in the shell subregion of the nucleus accumbens, a brain area that controls motivation. Thus, cocaine use appears to teach the brain to be addicted, resulting in a dysfunctional form of learning that drives the overwhelming desire to consume more cocaine.

CaM-KII promotes the trafficking of AMPA glutamate receptors to synapses in the nucleus accumbens shell, which precipitates cocaine-seeking behavior. One avenue of our research in the coming years will be to further examine the role of transport of AMPA receptor subunits to and from synapses in the reinstatement of cocaine seeking. We also are interested in taking advantage of recent advances in molecular biology to assess the epigenetic mechanisms underlying changes in gene expression associated with the self-administration of cocaine by rats. For example, our recent work indicates that following cocaine self-administration there are increases in the association of CREB and decreases in the association of MeCP2 with BDNF promoter IV in the medial prefrontal cortex. These mechanisms combine to increase BDNF transcription in this nucleus following chronic cocaine. Somewhat surprisingly, viral-mediated suppression of BDNF transcription in the prefrontal cortex actually increases the reinforcing efficacy of cocaine, suggesting that cocaine-induced enhancement of BDNF transcription in the prefrontal cortex represents a compensatory neuroadaptation. Finally, we also are pursuing surgical interventions as possible treatments for cocaine craving. Thus, we have found that deep brain stimulation of the nucleus accumbens shell attenuates the reinstatement of cocaine seeking. Since deep brain stimulation is increasingly used as a treatment for psychiatric disorders such as depression, it seems reasonable to propose this procedure as a treatment for severe cocaine addiction. By using multi-disciplinary approaches such as these, we hope to identify novel therapeutic targets for cocaine addiction, which thus far remain elusive.

For additional information see: