Mechanisms underlying the influence of stress on drug-seeking behavior

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PROJECT SUMMARY/ABSTRACT The effective management of substance use disorders (SUDs) requires interventions that minimize relapse risk. Stress is a troublesome contributor to relapse, as it is pervasive and unavoidable in the lives of those with SUDs. However, the contribution of stress to relapse is complex. While in extreme cases stressors serve as direct triggers for relapse, more commonly they interact with other stimuli to set the stage for drug seeking. This proposal examines the mechanisms and pathways that mediate the stage-setting effects of stress in SUDs and investigates the use-dependent neuroadaptations that emerge with cocaine use that establish stressful stimuli as “triggers”, rather than a “stage setters”, for relapse – a key transition point in the progression to addiction. We have established a rat model for investigating the stage-setting effects of stress on cocaine seeking. Following self-administration under conditions of limited daily access (14 x 2 hrs/day), stress does not reinstate extinguished cocaine seeking but rather potentiates reinstatement to an otherwise subthreshold cocaine priming dose, an effect that is observed in males and females and requires elevated corticosterone and endocannabinoid signaling via the CB1 receptor in the prelimbic prefrontal cortex (PL-PFC). We hypothesize that stressor-induced increases in brain corticosterone levels promote Gq G-protein signaling in PL-PFC pyramidal neurons via a rapid, glucocorticoid receptor-independent, membrane-associated mechanism, thus mobilizing the endocannabinoid, 2-arachodonoylgycerol, and producing CB1R-dependent attenuation of GABA release from PL-PFC interneurons. Further, we hypothesize that the loss of inhibitory control of PL-PFC projection pathways that contribute to drug seeking primes them for activation by excitatory inputs, thus potentiating cocaine seeking. This proposal further characterizes this mechanism (Aim 1) and seeks to identify the PL-PFC output pathways that mediate stress-potentiated drug seeking (Aim 2). The contribution of stress to cocaine seeking changes with the pattern of cocaine use. In contrast to what is observed following limited drug access, more prolonged daily cocaine self-administration (14 x 6 hrs/day) establishes stressors as direct triggers for reinstatement. This transition involves the recruitment of CRF regulation of ventral tegmental area neurons that project to the PL- PFC, in part through increased VTA CRF-R1 expression. We hypothesize that adaptations in stress-related signaling pathways in PL-projecting VTA neurons establish stressor control over drug seeking, representing a key step in the progression of SUDs. This hypothesis is tested in Aim 3. The proposed work has great potential to guide novel pharmacotherapeutic approaches and understanding how the influence of stress on cocaine use varies among subpopulations of users and with addiction severity has important clinical implications. Finally, we identify a novel mechanism through which stress can alter PFC function – a finding that has significance for understanding the influence of stress on a range of healthy/adaptive and pathological/maladaptive behaviors.