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: 3.36). 08/2011; 204:117-24. DOI: 10.1016/j.neuroscience.2011.08.021
Source: PubMed


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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Available from: Oliver Vranjkovic,
    • "CPP has been used to demonstrate ongoing pain in multiple models, to test the efficacy of potential therapeutics, and to determine neural mechanisms of chronic pain and pain relief (reviewed by Navratilova et al., 2013). Additionally, CPP has been used in addiction research to demonstrate spontaneous drug-seeking behaviors, and different stress paradigms (i.e., acute/repeated, mild/intense) modifies both the development of the addiction and the reinstatement of behaviors following drug withdrawal (Smith et al., 2012; Vaughn et al., 2012; Mei and Li, 2013). Although the interaction between stress and pain has not been extensively studied with CPP, use of both acute, evoked responses and chronic, spontaneous behavior provides additional validation of analgesic efficacy when developing novel therapeutics. "
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    ABSTRACT: While current therapeutics provide relief from acute pain, drugs used for treatments of chronic pain are typically less efficacious and limited by adverse side effects including tolerance, addiction and gastrointestinal upset. Thus, there is a significant need for novel therapies for the treatment of chronic pain. In concert with chronic pain, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic pain disorders. Stress-exacerbation of chronic pain suggests that centrally acting drugs targeting the pain and stress responsive brain regions represent a valid target for the development of novel therapeutics. This review will provide an overview of how stress modulates spinal and central pain pathways, identify key neurotransmitters and receptors within these pathways, and highlight their potential as novel therapeutics to treat chronic pain.
    Journal of Pharmacology and Experimental Therapeutics 09/2014; 351(2). DOI:10.1124/jpet.114.218065 · 3.97 Impact Factor
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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). "

    • "Stress-induced reinstatement of CPP depended on b2AR activity but was preserved after a1AR blockade (Mantsch et al., 2010). Stress-induced reinstatement could also be blocked by a cannabinoid receptor (CB1) antagonist , and a subthreshold dose of the a2AR antagonist BRL-44408 reinstated cocaine CPP when combined with a CB1 agonist (Vaughn et al., 2012), indicating an interaction of the NE and cannabinoid systems in this paradigm. Moreover, b2AR agonists and a2AR antagonists produced reinstatement on their own (Mantsch et al., 2010; Vranjkovic et al., 2012). "
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    ABSTRACT: Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). While stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, non-human primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to 5 stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms, but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.
    Molecular pharmacology 02/2014; 85(4). DOI:10.1124/mol.113.090118 · 4.13 Impact Factor
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