CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats

Abstract

Rationale Under some conditions stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a sub-threshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well-defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior. Objectives To test the hypothesis that cannabinoid receptor 1 (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats. Methods Following i.v. cocaine self-administration (2 hr access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking, but reinstatement is observed when footshock is followed by an injection of an otherwise subthreshold dose of cocaine (2.5 mg/kg, i.p.). CB1R involvement was tested by systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.) prior to testing for stress-potentiated reinstatement. Results Stress-potentiated reinstatement was blocked by both 1 and 3 mg/kg AM251. By contrast, AM251 only attenuated food-reinforced lever pressing at the higher (i.e., 3 mg/kg) dose and did not affect locomotor activity at either dose tested. Neither high-dose cocaine-primed reinstatement (10 mg/kg, i.p.) nor footshock stress-triggered reinstatement following long-access cocaine self-administration (6 hr access/day) were affected by AM251 pretreatment. Footshock stress increased concentrations of both endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, in regions of the prefrontal cortex. Conclusions These findings demonstrate that footshock stress increases prefrontal cortical endocannabinoids and stress-potentiated reinstatement is CB1R-dependent, suggesting that CB1R is a potential therapeutic target for relapse prevention, particularly in individuals whose cocaine use is stress-related.

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

“…We previously reported that, under conditions in which stressors do not directly evoke cocaine seeking in rats, they can 'set the stage' for relapse, enhancing the reinstatement of cocaine seeking in response to an otherwise subthreshold priming dose of cocaine (Graf et al, 2013;McReynolds et al, 2016). These stage-setting effects of stress are mediated by glucocorticoids (Graf et al, 2013).…”

“…A consequence of such alterations appears to be a heightened susceptibility to drug-seeking behavior. We recently established a rat self-administration/reinstatement model in which acute stress potentiates the reinstatement of cocaine seeking in response to an otherwise subthreshold priming dose of cocaine but does not by itself directly evoke cocaine seeking (Graf et al, 2013;McReynolds et al, 2016). This stage-setting effect of stress appears to be mediated by glucocorticoids, in that the ability of footshock to potentiate reinstatement in response to a subthreshold low dose of cocaine is eliminated by adrenalectomy, and mimicked in the absence of stress by administration of corticosterone at a dose that results in plasma levels comparable to those observed during stress.…”

Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis

“…Interestingly, this effect of CORT was abolished by coadministration of the CRH-R1 antagonist, antalarmin, suggesting a role for elevated CRH in the ability of repeated elevation of CORT to potentiate 2-AG content in the mPFC. Further mechanistic insights come from studies of (102) Patel and colleagues who demonstrated that repeated stress results in increased 2-AG in the amygdala, likely as a result of reduced MAGL-mediated catabolism of 2-AG (139). Interestingly, MAGL activity was not altered, but less protein was present at the plasma membrane where it is more likely to encounter 2-AG that is involved in CB1R activation (139).…”

“…Studies in mice (147) and rats (102) demonstrate the requirement for CB1R in stress-induced reinstatement of cocaine seeking behavior. Low doses of dexamethasone reduce motion sickness in rats, an effect that is partially reversed by the CB1R antagonist, AM251 (158).…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…However, these antagonists reduce reinstatement of cocaine seeking produced by stress, drug-associated stimuli, or priming with the drug itself (De Vries et al, 2001; Ward et al, 2009; Vaughn et al, 2012; Jing et al, 2014; McReynolds et al, 2016), and also reduce cocaine seeking in a progressive ratio task and cocaine enhancement of intracranial self-stimulation (aka rewarding brain stimulation; Xi et al, 2008; Orio et al, 2009). “Impulsive” responding for cocaine in a delay-discounting task is also reduced by a CB1 antagonist (Hernandez et al, 2014).…”