A Striatal Mechanism and Evolutionary Origin of Impulsive Reward Choice in Protracted Withdrawal

Substance use disorder is a chronic, relapsing condition characterized by preoccupation with acquiring or taking a drug, to the detriment of other healthy behaviors. Even after long periods of abstinence from the drug, there is a high chance of relapse in the presence of stress or cues of drug availability, rendering short-term treatment strategies inadequate. A major barrier to the success of treatments for substance use disorder is that drug users tend to be more impulsive than the general population: they are less able to appropriately inhibit reward-seeking behaviors, and tend to overvalue short-term reward acquisition over long-term benefits. This impulsivity can predispose certain individuals toward developing substance use disorder, but there is also compelling evidence that a history exposure to drugs of abuse can induce impulsivity in animals with no preexisting differences in behavior. While this is well established in tasks of risky decision making and intertemporal choice, it has not been investigated in tests of effort allocation. Evidence is presented herein that rats assessed in protracted withdrawal from methamphetamine (mAMPH) show a unique behavioral pattern when given the opportunity to work for rewards: effort expenditure is enhanced when animals are given a choice between rewarded action and unrewarded inaction, and reward value is steeply discounted by increasing effort demands when in the presence of an acceptable alternative reward source. The neural mechanisms underlying impulsive choice in mAMPH withdrawal are unclear. It has been hypothesized that mAMPH disrupts top-down executive control over reward seeking by interfering with neurotransmission in the frontal cortex. It has also been proposed that drug-induced neural changes in the basal ganglia, especially reduction in expression of the dopamine D2 receptor, may underlie impulsive behavior. The present work expands on these hypotheses by showing that mAMPH withdrawal, but not mAMPH exposure, is related to decreased striatal D2 expression. Additionally, steep effortful discounting in mAMPH withdrawal was mimicked by pharmacologic activation of D2-expressing medium spiny neurons in the striatum. Finally, the above findings are considered in the framework of evolutionary theory to answer the question of why natural selection has favored traits which left the body vulnerable to this kind of manipulation. It is proposed that natural selection on foraging behavior favored the development of decision rules which adapt reward seeking behavior to suit the relative reward density and distribution in the environment. Exposure to and withdrawal from mAMPH provides misleading information to this system, leading to impulsive behavior which persists long after the cessation of drug use. Implications of this hypothesis for treatment of substance use disorders are discussed