A cannabinoid mechanism in relapse to cocaine seeking

Research Institute Neurosciences Vrije Universiteit, Department of Medical Pharmacology, VU Medical Center, Amsterdam, The Netherlands.
Nature Medicine (Impact Factor: 27.36). 11/2001; 7(10):1151-4. DOI: 10.1038/nm1001-1151
Source: PubMed


Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction. The active ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system and has rewarding effects in preclinical models of drug abuse. We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.

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    • "We also show that cocaine's ability to increase the frequency of DA transients in the NAc is dependent on 2-AG synthesis and CB1R signaling in the VTA, collectively implicating an eCB-dependent disinhibition of VTA DA neurons. Our results thereby provide a mechanism to explain the disruption of cocaine-motivated behavior that is observed during antagonism of the eCB system in animal models of addiction and relapse to drug seeking (De Vries et al., 2001; Li et al., 2009; Soria et al., 2005; Xi et al., 2006, 2008). Based on these findings, we hypothesize that cocaine-induced 2-AG mobilization in the VTA facilitates DA release in the NAc to support cocaine reinforcement. "
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    Cell Reports 09/2015; 12(12). DOI:10.1016/j.celrep.2015.08.041 · 8.36 Impact Factor
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    • "This is supported by the ability of CB 1 agonists, including Δ 9 -THC, to reinstate extinguished drug-seeking behavior for cannabinoids (Justinova et al., 2008; Spano et al., 2004), opioids (De Vries et al., 2003; Fattore, et al., 2005), ethanol (Lopez- Moreno et al., 2004), nicotine (Biala et al., 2009), and cocaine (De Vries et al., 2001). Additionally, CB 1 receptor antagonists potently attenuate cue-or drug-induced reinstatement of drug seeking for Δ 9 -THC (Justinova et al., 2008), heroin (De Vries et al., 2003; Fattore et al., 2005), ethanol (Cippitelli et al., 2005; Economidou et al., 2006), nicotine (Cohen et al., 2005; De Vries et al., 2005), and cocaine (De Vries et al., 2001; Xi et al., 2006). Thus, CB 1 receptor signaling supports the conditioned reinforcing properties of drug-paired cues, and pharmacologically increasing or decreasing CB 1 receptor activation can increase or decrease drug seeking, respectively. "
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    • "These effects do not seem to be reinforcer specific as endocannabinoid signaling is critical for cue-induced reinstatement of drug-seeking behavior. Systemic rimonabant attenuates cue-induced reinstatement of cocaine (126), heroin (132), methamphetamine (133), alcohol (134), nicotine (127), and THC (135). Further, the effects of CB1 antagonism on cue-induced reinstatement of reward seeking may be dependent on DAergic mechanisms, as DA antagonism also blocks cue-induced reinstatement of reward seeking behavior (136, 137). "
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