Behavioral compensation in goal-directed action: Long term effects of voluntary methamphetamine taking versus passive exposure

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PROJECT SUMMARY Goals can change over time, and it is important to adapt our actions according to our current goals. There is extensive evidence that long-term drug use can lead to dysfunction of neural circuits involved in goal-directed decision-making. However, decision-making impairments are not always apparent in drug users, possibly because drug-induced malfunction in certain brain areas involved in decision-making causes compensation in which the brain reorganizes and/or different strategies are used to maintain adequate decision-making. This proposal will examine changes in behavioral strategy and alterations in neuronal processing that maintain adequate decision-making when the brain areas that normally support decision-making malfunction due to prior voluntary methamphetamine intake or targeted disruption. The proposed studies will assess rats in a devaluation task in which specific responses and cues predict rewards, and then the value of one of the rewards is decreased. Flexible decision-making that is goal-directed would lead to a decrease in responses for the reward with decreased value. Importantly, in our task, the action that leads to the devalued reward is signaled by a response on a lever in a particular spatial location and with a particular light cue above the lever, although normal rats guide their behavior based on the lever-location. However, decreasing the function of prelimbic cortex (usually required to associate a response in a particular location with a specific reward) does not impair the ability to decrease responses on the lever-light compound associated with that reward. Prior research from our lab suggests that animals compensate for the loss of ability to associate the lever-location with the reward (due to prelimbic cortex lesions) by instead associating the cuelight above the lever with the reward, a type of learning that is supported by orbitofrontal cortex. These prelimbic cortex lesions are associated with an increase in neuronal activity in orbitofrontal cortex and in neuronal activity in mediodorsal thalamus neurons projecting to orbitofrontal cortex during learning. As prior research suggests that psychostimulant exposure can lead to alterations in the function of prelimbic cortex and/or lateral orbitofrontal cortex, I will determine long-term effects of prior methamphetamine self-administration on the neural circuits underlying devaluation and whether compensation between brain areas can preserve intact devaluation behavior. In addition, as prior research suggests that voluntary drug-taking causes different neurobiological and behavioral changes than being passively exposed to drugs, I will compare effects of passive methamphetamine exposure to those of voluntary drug-taking. The proposed research is relevant to one component of NIDA’s mission, to “develop new and improved treatments to help people with substance use disorders achieve and maintain a meaningful and sustained recovery”. Our findings may help to understand how drug users may maintain adequate decision-making after drug-induced brain dysfunction, and may identify alternative behavioral strategies that could improve this decision-making after past drug use.