The development of drug addiction in humans involves a switch from experimentation and recreational drug use to compulsive drug taking and habit formation. Following this switch, the habit is rarely `kicked', since periods of voluntary abstinence from drug taking are thwarted by intense drug craving that drives relapse. Even after extended periods of abstinence and conscious recognition of the long-term aversive consequences, the probability of relapse is high. This uncontrolled (compulsive) behavior is the hallmark of addiction. Release of dopamine into the extracellular space has been highly implicated in motivated behavior and is thought to have a central role in drug abuse. However, until recently it was not possible to measure it on a behaviorally-relevant timescale (seconds) in awake animals. With the development of fast-scan cyclic voltammetry, we have now successfully monitored and characterized dopamine release with subsecond resolution during cocaine self-administration in rats that had modest behavioral training, analogous to recreational drug use in humans. We now propose to extend this work to address one of the most pertinent questions in the study of addiction: what are the neurochemical correlates of the switch from recreational to compulsive drug use? The proposed work will study subsecond dopamine release in the nucleus accumbens and dorsolateral striatum in an animal model of addiction that incorporates habitual and compulsive drug taking. Insight into the neural substrates that promote these behaviors will be essential in fully understanding the neurobiology of addictions, and isolating therapeutic targets for the prevention and treatment of these devastating disorders.
| Willuhn, Ingo; Burgeno, Lauren M; Groblewski, Peter A et al. (2014) Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat Neurosci 17:704-9 |
| Willuhn, Ingo; Burgeno, Lauren M; Everitt, Barry J et al. (2012) Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use. Proc Natl Acad Sci U S A 109:20703-8 |
| Ferguson, Susan M; Eskenazi, Daniel; Ishikawa, Masago et al. (2011) Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci 14:22-4 |
| Clark, Jeremy J; Sandberg, Stefan G; Wanat, Matthew J et al. (2010) Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals. Nat Methods 7:126-9 |
| Willuhn, Ingo; Wanat, Matthew J; Clark, Jeremy J et al. (2010) Dopamine signaling in the nucleus accumbens of animals self-administering drugs of abuse. Curr Top Behav Neurosci 3:29-71 |
| Wanat, Matthew J; Willuhn, Ingo; Clark, Jeremy J et al. (2009) Phasic dopamine release in appetitive behaviors and drug addiction. Curr Drug Abuse Rev 2:195-213 |
