Extinction learning of rewards in the rat: Is there a role for CB1 receptors?

Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn Street, Baltimore, MD 2120, USA.
Psychopharmacology (Impact Factor: 3.88). 04/2011; 217(2):189-97. DOI: 10.1007/s00213-011-2275-7
Source: PubMed

ABSTRACT Endocannabinoids have been widely studied in the context of addiction and reward due to their role in reinstatement. However, little is known about the role of CB1 receptors during extinction learning of an appetitively motivated task.
The aim of this study was to evaluate the role of endocannabinoids at different stages of extinction learning.
Endocannabinoid signaling was disrupted by injecting the CB1 receptor antagonist rimonabant (0, 200, 300 μg/kg i.v.) during the acquisition or consolidation phases of learning. The rate of extinction and its half-life were analyzed, as well as food-seeking in a reward-induced reinstatement test. We further investigated the interaction between extinction and endocannabinoids in different groups of rats that received drug treatments but did not undergo extinction training (abstinence). In addition, the effects of rimonabant on cue retrieval were investigated in a cue-induced reinstatement test in which rimonabant (0, 300 μg/kg i.v.) was given immediately prior to the reinstatement session.
Blockade of CB1 receptors during acquisition or consolidation of extinction learning had no effect on the rate extinction or its half-life and these pretreatments had no long term consequences on reward-seeking behavior. Furthermore, rats that underwent extinction training responded at lower levels than those that received the drug in the absence of extinction (p = 0.000, η (2) = 0.40). Rimonabant was effective in inhibiting behavior only if it was immediately given before a cue-induced reinstatement session (p = 0.000, η (2) = 0.92).
The present results clarify and isolate the role of endocannabinoids in reinstatement as key mediators of cue retrieval, rather than orchestrators of extinction learning processes.

1 Follower
3 Reads
  • Source
    • "Extinction of conditioned behavior is thought to be a process of new and active learning [4] [6] [10] [25]. CaMKII is well known as an important molecule in the mechanisms of learning and memory [8] [18] [19] [27] and the NAc is found to be involved in the extinction of conditioned behavior [11] [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) may be a core component in the common molecular pathways for drug addiction. Moreover, studies using animal models of drug addiction have demonstrated that changing CaMKII activity or expression influences animals' responses to the drugs of abuse. Here, we explored the roles of CaMKII in the nucleus accumbens (NAc) shell in the extinction and reinstatement of morphine-seeking behavior. Rats were trained to obtain intravenous morphine infusions through poking hole on a fixed-ratio one schedule. Selective CaMKII inhibitor myristoylated autocamtide-2-inhibitory peptide (myr-AIP) was injected into the NAc shell of rats after the acquisition of morphine self-administration (SA) or before the reinstatement test. The results demonstrated that injection of myr-AIP after acquisition of morphine SA did not influence morphine-seeking in the following extinction days and the number of days spent for reaching extinction criterion. However, pretreatment with myr-AIP before the reinstatement test blocked the reinstatement of morphine-seeking behavior induced by morphine-priming. Our results strongly indicate that CaMKII activity in the NAc shell is essential to the relapse to morphine-seeking.
    Neuroscience Letters 05/2012; 518(2):167-71. DOI:10.1016/j.neulet.2012.05.003 · 2.03 Impact Factor
  • Source
    • "Despite the remarkable effect on reinstatement, consensus is emerging in the literature on the lack of effect of (endo)cannabinoids on extinction of learned appetitively motivated tasks (Hernandez and Cheer, 2011). On the other hand, endocannabinoid mechanisms are strongly engaged in extinction of negatively motivated behavior (Marsicano et al., 2002; Lutz, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Endocannabinoids serve as retrograde signaling molecules at many synapses within the CNS, particularly GABAergic and glutamatergic synapses. Synapses onto midbrain dopamine (DA) neurons in the ventral tegmental area (VTA) make no exception to this rule. In fact, the effects of cannabinoids on dopamine transmission as well as DA-related behaviors are generally exerted through the modulation of inhibitory and excitatory afferents impinging onto DA neurons. Endocannabinoids, by regulating different forms of synaptic plasticity in the VTA, provide a critical modulation of the DA neuron output and, ultimately, of the systems driving and regulating motivated behaviors. Because DA cells exhibit diverse states of activity, which crucially depend on their intrinsic properties and afferent drive, the understanding of the role played by endocannabinoids in synaptic modulations is critical for their overall functions. Particularly, endocannabinoids by selectively inhibiting afferent activity may alter the functional states of DA neurons and potentiate the responsiveness of the reward system to phasic DA.
    Frontiers in Pharmacology 02/2012; 3:7. DOI:10.3389/fphar.2012.00007 · 3.80 Impact Factor
  • Source
    • "The endocannabinoid system is another focus of research investigating new potential therapeutic approaches for anxiety disorders. Indeed, cannabinoid (CB) receptors have been linked to extinction learning in animal models, type 1 CB (CB1) receptors have been found in brain areas related to anxiety and emotional learning (such as the amygdala and hippocampus),76 and CB1 antagonists lead to significant deficits in extinction learning,77 suggesting that CB receptor modulators may improve efficacy of exposure-based psychotherapies in phobic syndromes;78 however, data are not available on PD with AG. Cortisol has been also proposed as an augmentation strategy of extinction consolidation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although there are controversial issues (the "American view" and the "European view") regarding the construct and definition of agoraphobia (AG), this syndrome is well recognized and it is a burden in the lives of millions of people worldwide. To better clarify the role of drug therapy in AG, the authors summarized and discussed recent evidence on pharmacological treatments, based on clinical trials available from 2000, with the aim of highlighting pharmacotherapies that may improve this complex syndrome. A systematic review of the literature regarding the pharmacological treatment of AG was carried out using MEDLINE, EBSCO, and Cochrane databases, with keywords individuated by MeSH research. Only randomized, placebo-controlled studies or comparative clinical trials were included. After selection, 25 studies were included. All the selected studies included patients with AG associated with panic disorder. Effective compounds included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, selective noradrenergic reuptake inhibitors, and benzodiazepines. Paroxetine, sertraline, citalopram, escitalopram, and clomipramine showed the most consistent results, while fluvoxamine, fluoxetine, and imipramine showed limited efficacy. Preliminary results suggested the potential efficacy of inositol; D-cycloserine showed mixed results for its ability to improve the outcome of exposure-based cognitive behavioral therapy. More studies with the latter compounds are needed before drawing definitive conclusions. No studies have been specifically oriented toward evaluating the effect of drugs on AG; in the available studies, the improvement of AG might have been the consequence of the reduction of panic attacks. Before developing a "true" psychopharmacology of AG it is crucial to clarify its definition. There may be several potential mechanisms involved, including fear-learning processes, balance system dysfunction, high light sensitivity, and impaired visuospatial abilities, but further studies are warranted.
    Neuropsychiatric Disease and Treatment 10/2011; 7(1):621-37. DOI:10.2147/NDT.S12979 · 1.74 Impact Factor
Show more


3 Reads
Available from