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Cannabinoid receptor involvement in stress-induced cocaine reinstatement: Potential interaction with noradrenergic pathways

Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53233, USA.
Neuroscience (Impact Factor: 3.33). 08/2011; 204:117-24. DOI: 10.1016/j.neuroscience.2011.08.021
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ABSTRACT This study examined the role of endocannabinoid signaling in stress-induced reinstatement of cocaine seeking and explored the interaction between noradrenergic and endocannabinergic systems in the process. A well-validated preclinical model for human relapse, the rodent conditioned place preference assay, was used. Cocaine-induced place preference was established in C57BL/6 mice using injections of 15 mg/kg cocaine. Following extinction of preference for the cocaine-paired environment, reinstatement of place preference was determined following 6 min of swim stress or cocaine injection (15 mg/kg, i.p.). The role of endocannabinoid signaling was studied using the cannabinoid antagonist AM-251 (3 mg/kg, i.p.). Another cohort of mice was tested for reinstatement following administration of the cannabinoid agonist CP 55,940 (10, 20, or 40 μg/kg, i.p.). The alpha-2 adrenergic antagonist BRL-44408 (5 mg/kg, i.p.) with or without CP 55,940 (20 μg/kg) was administered to a third group of mice. We found that: (1) AM-251 blocked forced swim-induced, but not cocaine-induced, reinstatement of cocaine-seeking behavior; (2) the cannabinoid agonist CP 55,940 did not reinstate cocaine-seeking behavior when administered alone but did synergize with a non-reinstating dose of the alpha-2 adrenergic antagonist BRL-44408 to cause reinstatement. These results are consistent with the hypothesis that stress exposure triggers the endogenous activation of CB1 receptors and that activation of the endocannabinoid system is required for the stress-induced relapse of the mice to cocaine seeking. Further, the data suggest that the endocannabinoid system interacts with noradrenergic mechanisms to influence stress-induced reinstatement of cocaine-seeking behavior.

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    • "For example, although antagonism of CB 1 receptor precipitates withdrawal from opiates and cannabinoids (Navarro et al, 2001; Rodriguez de Fonseca et al, 1997; Valverde et al, 2000), it has also been shown, at low doses, to reduce anxiety-like responses induced by chronic cocaine and CRF injections (Kupferschmidt et al, 2012b). Furthermore, although CB 1 receptor antagonism blocked forced swim-induced reinstatement of cocaine-seeking behavior (Vaughn et al, 2012), it did not affect reinstatement of cocaine seeking by footshock stress, an effect known to be mediated by CRF (De Vries et al, 2001; Kupferschmidt et al, 2012a). "
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    • "For example, although antagonism of CB 1 receptor precipitates withdrawal from opiates and cannabinoids (Navarro et al, 2001; Rodriguez de Fonseca et al, 1997; Valverde et al, 2000), it has also been shown, at low doses, to reduce anxiety-like responses induced by chronic cocaine and CRF injections (Kupferschmidt et al, 2012b). Furthermore, although CB 1 receptor antagonism blocked forced swim-induced reinstatement of cocaine-seeking behavior (Vaughn et al, 2012), it did not affect reinstatement of cocaine seeking by footshock stress, an effect known to be mediated by CRF (De Vries et al, 2001; Kupferschmidt et al, 2012a). "
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    ABSTRACT: The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB(1)) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB(1) receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB(1) receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB(1) receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB(1) receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.
    Neuropsychopharmacology 11/2013; DOI:10.1038/npp.2013.
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    • "For example, although antagonism of CB 1 receptor precipitates withdrawal from opiates and cannabinoids (Navarro et al, 2001; Rodriguez de Fonseca et al, 1997; Valverde et al, 2000), it has also been shown, at low doses, to reduce anxiety-like responses induced by chronic cocaine and CRF injections (Kupferschmidt et al, 2012b). Furthermore, although CB 1 receptor antagonism blocked forced swim-induced reinstatement of cocaine-seeking behavior (Vaughn et al, 2012), it did not affect reinstatement of cocaine seeking by footshock stress, an effect known to be mediated by CRF (De Vries et al, 2001; Kupferschmidt et al, 2012a). "
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