Aggression and defeat: Persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits

The question of how ostensibly aversive social stress experiences in an aggressive confrontation can persistently increase intense drug taking such as cocaine 'bingeing' needs to be resolved. The biology of social conflict highlights distinctive behavioral, cardiovascular and endocrine profiles of dominant and subordinate animals, as seen also in rodents and primates under laboratory conditions. In contrast to continuous subordination stress that produces chronic pathophysiological consequences and often is fatal, animals adapt to brief episodes of social defeat stress, but show enduring functional activation in mesocorticolimbic microcircuits. Uncontrollable episodes of social defeat stress produce long-lasting tolerance to opiate analgesia and, concurrently, behavioral sensitization to challenges with either amphetamine or cocaine. One week after a single social defeat stress, cross-sensitization to cocaine is evident in terms of enhanced motor activity as well as in terms of increased Fos labeling in the periaqueductal grey area, the locus coeruleus, and the dorsal raphe nuclei. When challenged with a low amphetamine dose, the behavioral and neural effects of repeated brief episodes of social defeat stress persist for months. Previous exposure to social defeat stress can (1) significantly shorten the latency to acquire cocaine self-administration, (2) maintain this behavior at low cocaine unit doses, (3) significantly increase the levels of cocaine taking during a 24 h binge of continuous drug availability, (4) dysregulate the timing of consecutive infusions, and (5) abolish the circadian pattern of self-administration. Amygdaloid modulation, especially originating from central and basolateral nuclei, of dopaminergic pathways via peptidergic and glutamatergic neurons appears to be a key mechanism by which social defeat stress affects cocaine self-administration. Social stress alters the feedback from prefrontal cortex and thereby may contribute to the dysregulation of dopaminergic activity that is necessary for cocaine self-administration.