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.
