Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking

Abstract

In individuals with substance use disorders, stress is a critical determinant of relapse susceptibility. In some cases, stressors directly trigger cocaine use. In others, stressors interact with other stimuli to promote drug seeking, thereby setting the stage for relapse. Here, we review the mechanisms and neurocircuitry that mediate stress-triggered and stress-potentiated cocaine seeking. Stressors trigger cocaine seeking by activating noradrenergic projections originating in the lateral tegmentum that innervate the bed nucleus of the stria terminalis to produce beta adrenergic receptor-dependent regulation of neurons that release corticotropin releasing factor (CRF) into the ventral tegmental area (VTA). CRF promotes the activation of VTA dopamine neurons that innervate the prelimbic prefrontal cortex resulting in D1 receptor-dependent excitation of a pathway to the nucleus accumbens core that mediates cocaine seeking. The stage-setting effects of stress require glucocorticoids, which exert rapid non-canonical effects at several sites within the mesocorticolimbic system. In the nucleus accumbens, corticosterone attenuates dopamine clearance via the organic cation transporter 3 to promote dopamine signaling. In the prelimbic cortex, corticosterone mobilizes the endocannabinoid, 2-arachidonoylglycerol (2-AG), which produces CB1 receptor-dependent reductions in inhibitory transmission, thereby increasing excitability of neurons which comprise output pathways responsible for cocaine seeking. Factors that influence the role of stress in cocaine seeking, including prior history of drug use, biological sex, chronic stress/co-morbid stress-related disorders, adolescence, social variables, and genetics are discussed.Better understanding when and how stress contributes to drug seeking should guide the development of more effective interventions, particularly for those whose drug use is stress related.

Networks of habenula-projecting cortical neurons regulate cocaine seeking

“…Stress modifies information processing in the mPFC, which triggers behavioral adaptations including alterations in reward seeking (4)(5)(6)(7). Cocaine and other drugs of abuse can profoundly affect mPFC structure and function (8,9), including how mPFC neurons respond to stressful stimuli (10)(11)(12)(13). This action is thought to contribute to vulnerability to cocaine relapse provoked by stressful events during periods of abstinence (12,13).…”

BDNF and Cortisol in the Diagnosis of Cocaine-Induced Depression

“…As previously reported, the monoamine theory of depression cannot completely explain the pathogenesis of induced depressions ( 32 ), and other physiological systems should be studied. Stress is related to both MDD ( 41 , 42 ) and SUD ( 43 , 44 ), and in turn, cortisol is associated with stress. In our study, patients diagnosed with CUD-induced-MDD showed higher levels of cortisol after an acute stress challenge compared with CUD-primary-MDD ones.…”

Repeated cocaine or methamphetamine treatment alters astrocytic CRF2 and GLAST expression in the ventral midbrain

“…While the role of CRF in the VTA has been explored relative to depressants such as morphine and ethanol, 23–25 it has also been studied for its role in stress‐induced cocaine seeking 26 . The most important source of CRF in the VTA for cocaine reinstatement is likely from neurons in the bed nucleus of the stria terminalis, 27 although other inputs such as the lateral hypothalamic area and paraventricular hypothalamic nucleus could also play a role 28,29 . In the VTA, anatomical evidence suggests that CRF peptide is most prominently expressed by glutamate terminals, but it is also seen in GABA terminals 28,30 .…”

“…While the role of CRF in the VTA has been explored relative to depressants such as morphine and ethanol, [23][24][25] it has also been studied for its role in stress-induced cocaine seeking. 26 The most important source of CRF in the VTA for cocaine reinstatement is likely from neurons in the bed nucleus of the stria terminalis, 27 although other inputs such as the lateral hypothalamic area and paraventricular hypothalamic nucleus could also play a F I G U R E 4 Repeated cocaine and methamphetamine injections increase CRF2 signal and decrease astrocyte number in the VTA and SN. Immunofluorescence for CRF2 in the VTA (A) and SN (B) is significantly increased from saline following repeated cocaine or methamphetamine (METH) injections.…”