Persistent effect of withdrawal from intravenous methamphetamine self-administration on brain activation and behavioral economic indices involving an effort cost

Exposure to drugs of abuse produces maladaptive changes in cost-benefit decision-making, including the evaluation of time and risk. Studies probing the effects of drug exposure on such evaluations have primarily used experimenter-administered drug regimens. Similarly, while much is known about the neural bases of effort, there have been relatively fewer investigations of the effects of drug experience on effort-based choices. We recently reported that experimenter-administered methamphetamine (meth) resulted in steeper discounting of effort for food rewards in rats, when assessed in protracted withdrawal. Here, we studied rats that underwent withdrawal from weeks of meth intravenous self-administration that later could freely select between a high effort, preferred option (progressive ratio lever pressing for sucrose pellets) versus a low effort, less preferred option (freely-available lab chow). We found decreased effort for the preferred reward and changes in a behavioral economic index demonstrating an increased sensitivity to effort in meth-experienced rats. Critically, the decreased effort for the preferred option was only present in the context of a competing option, not when it was the only option. We also confirmed rats preferred sucrose pellets over chow when both were freely available. These long-lasting changes were accompanied by decreased c-Fos activation in ventral striatum and basolateral amygdala, regions known to be important in effort-based choices. Taken together with our previous observations, these results suggest a robust and enduring effect of meth on value-based decision-making, and point to the underlying neural mechanisms that support the evaluation of an effort cost.