The Hippocampus as a Neural Link between Negative Affect and Vulnerability for Psychostimulant Relapse

Psychostimulant dependence (including cocaine, amphetamine, and methamphetamine) is a chronic relapsing disorder with significant personal, health, and financial burdens. Attempts at abstinence produce a severe and protracted withdrawal syndrome characterized by stress hypersensitivity that can facilitate drug craving, anxiety, and dysphoria. These negative withdrawal symptoms can induce relapse, maintaining the addiction cycle. The hippocampus mediates cognitive, emotional, and endocrine responses to stressors. The ventral hippocampus is in a pivotal position to regulate the mesoaccumbal dopamine reward system, and interacts with serotonergic and glucocorticoid systems that mediate anxiety and stress responsiveness. Psychostimulant actions on the hippocampus induce long-term changes to these systems and impact the process of adult neurogenesis in the hippocampus, which may facilitate drug dependence by altering drug-cue learning and emotional regulation. Multiple studies indicate that psychostimulant-induced hippocampal neuroadaptations heighten hippocampal-mesoaccumbal activity to amplify drug- and drug-cue responses while persistent dysregulation of hippocampal emotional systems potentiate negative affect. Understanding how psychostimulants modulate the hippocampus to alter hippocampal-mesoaccumbal activity—and how hippocampal neurogenesis influences drug-related memories and reward—is important for identifying novel treatment strategies that can ameliorate negative affect and relapse vulnerability in psychostimulant addiction.