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. We are currently funded by NIDA to pursue three research programs, which are summarized below.

We recently established a rat model to examine the influence of paternal cocaine self-administration on the behavior of progeny. In our paradigm, male rats self-administered cocaine for 60 days; controls were administered saline. The day after the last self-administration session, they were paired with naïve females. The offspring of these matings were tested for acquisition of cocaine self-administration. Our results indicated that the male offspring, but not the female offspring of cocaine-experienced sires acquired cocaine self-administration more slowly and had decreased levels of cocaine intake relative to controls. Moreover, control animals were willing to work significantly harder for single cocaine infusions than the cocaine-sired rats, suggesting that the rewarding effect of cocaine was decreased. The cocaine-sired rats did not have generalized learning deficits, as there was no difference in acquisition of food self-administration. We next looked at protein expression in the prefrontal cortex of naïve littermates. The male offspring had increased BDNF levels in the prefrontal cortex, which is known to blunt the behavioral effects of cocaine.

In our experiments, the mothers interacted with the fathers only long enough to become impregnated; the fathers played no role in rearing their offspring. This raises the question of how paternal cocaine exposure influenced the behavior of the male offspring. Intriguingly, our results indicated that there were changes in regulators of DNA structure associated with the BDNF gene in the sperm of cocaine-experienced fathers, which might increase BDNF protein expression in the brains of the offspring. This finding indicated that cocaine causes epigenetic changes in sperm, which may alter the physiology and behavior of offspring in the absence of changes in DNA sequence. Taken together, these results indicate that paternal exposure to cocaine can have profound effects on gene expression and behavior of the offspring.

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Supported by R01 DA33641.

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.

For additional information see:

Supported by R01 DA22339.

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 (DBS) 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. Experiments are currently underway to examine other brain regions and also define the mechanism(s) whereby DBS influences the reinstatement of cocaine seeking.

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Supported by R01 DA15214.

By using multi-disciplinary approaches such as these, we hope to identify novel therapeutic targets for cocaine addiction, which thus far remain elusive.

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