Research

Research

Chronic drug and alcohol abuse produces numerous brain changes, but relatively few have been functionally linked to addiction-related increases in drug craving and escalating drug consumption. My laboratory focused on the interaction between these neurobiological and behavioral changes.

Diagram
Bidirectional modification of reward and relapse pathways in cocaine addiction

Our studies integrate both forward (chronic drug use produces biological changes) and reverse (biological changes alter drug-taking and -seeking behaviors) experimental approaches in rodents.

Our experiments are aimed at:

  • Understanding the neural systems that regulate drug reward and craving
  • Understanding how these systems adapt during the addiction process
  • Determining critical adaptations that contribute to addictive behavior itself.

Much of this work is focused on dopamine receptor signaling pathways that regulate drug intake and craving responses.

Our studies suggest that alterations in cyclic AMP-dependent protein phosphorylation, and downstream regulation of gene expression, contributes to escalating drug intake and a propensity for relapse by differentially altering the sensitivity of D1 and D2 dopamine receptors in direct and indirect pathways of the ventral striatum.

In addition, our studies suggest that drug-induced neuroplasticity at excitatory synapses in the mesolimbic dopamine system can facilitate drug craving through specific interactions with dopamine receptors and their regulation of motivated behavior. Many of these neurobiological changes can be reversed or normalized by “extinction training” – a behavioral learning procedure that may be useful in treating drug addiction seeking behavior and the propensity for relapse. Current studies are using optogenetic laser stimulation approaches to mimic or reverse addiction-related neuroplasticity in anatomically distinct pathways in addicted rodents.

Diagram
Drug-induced neuroplasticity of reward and relapse pathways in cocaine addiction

We are also using microarray profiling and deep sequencing technology to search for novel and enduring changes in gene expression that persist or arise during withdrawal from chronic drug use. It is important to identify these changes because the propensity for relapse remains high even after months of abstinence. We have found that long-term drug withdrawal is associated with an up-regulation in endogenous opiate systems that enhance the propensity for relapse.

Colored squares
Gene expression profiling of cocaine withdrawal. Left: early cocaine withdrawal. Right: late cocaine withdrawal

Overall, we research the basic neurobiology of motivated behavior and its disruption during the addiction process, and discover potential treatments based in pharmacology, neurostimulation and behavior.