Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Taco J De Vries
    • "Full pharmacological antagonism of CB1 decreases the influence of conditioned factors on cocaine seeking and on extracellular Glu and DA in the NAc (Caillé and Parsons, 2006; Cheer et al, 2007; Oleson and Cheer, 2012; De Vries et al, 2001; Xi et al, 2006), as well as expression of cocaine-induced behavioral sensitization in a context-specific manner (Gerdeman et al, 2008). Differently, full pharmacological blockade or complete genetic deletion of CB1 does not affect, or only marginally affect (Chaperon et al, 1998; Soria et al, 2005), the primary reinforcing (Cossu et al, 2001; De Vries et al, 2001; Caillé and Parsons, 2006) and rewarding properties of cocaine (Houchi et al, 2005; Martin et al, 2000), as well as the underlying DA and GABA mechanisms (Caillé and Parsons, 2006; Soria et al, 2005; De Vries and Schoffelmeer, 2005). Together these data suggest that the primary role of the endocannabinoid system in cocaine selfadministration is to control conditioning-related processes that largely depend on glutamatergic transmission (De Vries and Schoffelmeer, 2005; Wiskerke et al, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine-seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.
    No preview · Article · Nov 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.
    Full-text · Article · Sep 2015 · Cell Reports
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana’s illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana’s psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction.This article is part of a Special Issue entitled SI:Addiction circuits.This article is part of a Special Issue entitled SI:Addiction circuits.
    Full-text · Article · Nov 2014 · Brain Research
Show more