Common substrates of dysphoria in stimulant drug abuse and primary depression: Therapeutic targets

Examinations of the neural substrates of major depressive disorder (MDD) and of dysphoria in stimulant drug (e.g. cocaine, amphetamine, methamphetamine, nicotine, caffeine) abusers provide increasing evidence that symptom overlap in these conditions reflects common neurobiological mechanisms. These include a dysregulation of corticolimbic systems and activation of the hypothalamic-pituitary-adrenal (HPA) axis. Substantial co-morbidity between MDD and stimulant drug abuse suggests common vulnerability factors. Psychological theories offer explanations for some of the observed phenomena, while neuroimaging studies suggest common anatomical substrates of mood disorder. Dysphoria, and its attendant biological deficits in abstinent drug abusers, may reflect opponent processes. With respect to both MDD and substance abuse disorder, evidence from neuroimaging studies indicates abnormal function of dorsolateral as well as ventral and medial cortical regions, which may contribute to pathological activation of the amygdala, through loss of cortical inhibitory control. In addition, structural deficits, such as those observed in the hippocampi of individuals with MDD and methamphetamine dependence, characterize both conditions. Chronic drug abuse and/or preexisting vulnerability may act as causal factors, aberrant neuroadaptations, and/or compensations for frontal-limbic dysfunction. Chronic stress and its modulation of brain function through the action of corticotropin-releasing factor, a hypothalamic mediator with central effects, may play a key role. Regardless of the direction of causality involving this dysfunction, however, elucidation of the neural substrates of dysphoria in addiction and depression, may lead to better treatments for both, and enhance our understanding of emotional processes in both healthy and diseased individuals.