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.

Keywords: cocaine; craving; reinstatement; relapse; seeking; stress.

Figure 1:. Neurocircuitry and mechanisms that contribute to stress-triggered cocaine seeking.

1) Ascending noradrenergic projections from neurons that comprise the A1 and A2 cell groups in the lateral tegmentum release norepinephrine (NE) into regions within the extended amygdala, including the bed nucleus of the stria terminalis (BNST). In the BNST, NE activates beta-2 adrenergic receptors (β2AR) which, via a CRF-dependent mechanism (not depicted), promote stimulation of a pathway that co-releases CRF into the ventral tegmental area (VTA). 2) In the VTA, CRF binds to CRF-R1 receptors to promote the activation of dopaminergic neurons that project to the prelimbic region of the prefrontal cortex (PFC). 3) Dopamine released into the prelimbic PFC activates D1 dopamine receptors (D1R) to increase the excitability of pyramidal neuron outputs. 4) Activation of pyramidal neurons that innervate the nucleus accumbens (NAc) core releases glutamate (Glu) to stimulate medium spiny neuron projections to the ventral pallidum that mediate drug seeking.

Figure 2:. Mechanisms implicated in corticosterone-mediated stress-potentiated reinstatement of cocaine seeking.

Stress can “set the stage” for cocaine seeking via at least two rapid signaling mechanisms that are independent of the canonical glucocorticoid receptor. A) In the prelimbic region of the prefrontal cortex, corticosterone engages an undefined membrane-associated target (mGR?) to mobilize the endocannabinoid, 2-arachidonoylglyerol (2-AG), likely via G_q G-protein-dependent production of diacylglycerol (DAG) and conversion to 2-AG via DAG lipase (DAGL). 2-AG is released retrogradely from pyramidal neurons (PNs) and engages CB1 receptors on GABAergic interneurons to attenuate Ca²⁺ influx and Ca²⁺-dependent GABA release, thereby removing PN inhibition and promoting excitability of output pathways the mediate cocaine seeking. B) In the nucleus accumbens (NAc), corticosterone directly binds to and inhibits the organic cation transporter (OCT3) on both neurons and astrocytes to attenuate dopamine transporter- (DAT) independent dopamine (DA) clearance, thus amplifying dopaminergic signaling and regulation of medium spiny neuron outputs that mediate cocaine seeking.