Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit

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Acute stress results in release of glucocorticoids, which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors have a key role in regulating the hypothalamic-pituitaryadrenal (HPA) axis. Growing attention has been focused on nucleus accumbens (NAc) plasticity, which regulates mood and motivation. The NAc integrates affective and context-dependent input from the BLA and ventral subiculum (vSub), respectively. As our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity. Bilateral, ipsilateral, and contralateral BLA administration of RU or WIN reversed the stress-induced impairment in vSub-NAc long-term potentiation (LTP) and the decrease in cAMP response element-binding protein (CREB) activity in the NAc. BLA CB1 receptors were found to mediate the preventing effects of WIN on plasticity, but not the preventing effects of RU, after stress. Inactivating the ipsilateral BLA, but not the contralateral BLA, impaired LTP. The possible mechanisms underlying the effects of BLA on NAc plasticity are discussed; the data suggest that BLA-induced changes in the NAc may be mediated through neural pathways in the brain's stress circuit rather than peripheral pathways. The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may have a central role in the treatment of a variety of stress-related disorders.

Section: Stress Effects On Accumbal Plasticity a Segev And I Akiravsupporting

confidence: 89%

Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal–Accumbens Plasticity After Stress

Segev

Akirav

2015

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“…Recent evidence, however, suggests that activity in the medial prefrontal cortex (mPFC) is critical for cued fear learning, in addition to the amygdala (Quirk et al, 1995(Quirk et al, , 2003. As anatomical evidence demonstrates that CCK, CCKBR and Cnr1 localize to prefrontal cortex (Larsson and Rehfeld, 1979;Zarbin et al, 1983;Herkenham et al, 1990) and behavioral studies implicate prefrontal Cnr1 in fear (Laviolette and Grace, 2006;Lin et al, 2008Lin et al, , 2009Ganon-Elazar and Akirav, 2013;Kuhnert et al, 2013), similar immunofluorescence experiments should be performed in mPFC. In addition, site-specific behavioral experiments should be conducted in follow-up studies to determine whether the observed Cnr1-CCKBR interaction occurs in BLA.…”

Section: Discussionmentioning

confidence: 99%

Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention

Bowers

Ressler

2014

Post-traumatic stress disorder (PTSD) is thought to develop, in part, from improper inhibition of fear. Accordingly, one of the most effective treatment strategies for PTSD is exposure-based psychotherapy. Ideally, neuroscience would inform adjunct therapies that target the neurotransmitter systems involved in extinction processes. Separate studies have implicated the cholecystokinin (CCK) and endocannabinoid systems in fear; however, there is a high degree of anatomical colocalization between the cannabinoid 1 receptor (Cnr1) and CCK in the basolateral amygdala (BLA), a brain region critical for emotion regulation. Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnr1 mediates fear inhibition, we hypothesize that a functional interaction between Cnr1 and CCKB receptor (CCKBR) is critical for fear extinction processes. In this study, systemic pharmacological manipulation of the cannabinoid system modulated cued fear expression in C57BL/6J mice after consolidation of auditory fear conditioning. Knockout of the CCKBR, however, had no effect on fear-or anxiety-like behaviors. Nonetheless, administration of a Cnr1 antagonist increased freezing behavior during a cued fear expression test in wild-type subjects, but had no effect on freezing behavior in CCKBR knockout littermates. In addition, we found that Cnr1-positive fibers form perisomatic clusters around CCKBR-positive cell bodies in the BLA. These CCKBR-positive cells comprise a molecularly heterogenous population of excitatory and inhibitory neurons. These findings provide novel evidence that Cnr1 contributes to cued fear expression via an interaction with the CCK system. Dysfunctional Cnr1-CCKBR interactions might contribute to the etiology of, or result from, fear-related psychiatric disease.

“…The preventing effects of WIN 55,212-2 are mediated by CB1 receptors, and in some of the stress paradigms (see Ganon-Elazar and Akirav, 2013) this effect is mediated by GRs in the amygdala and hippocampus. Here, cannabinoid receptor activation prevented the effects of CMS exposure on emotional learning and LTP in a brain circuit relevant to motivation and emotions.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, stress and glucocorticoids can trigger eCB synthesis and CB1 receptors signaling to constrain HPA axis activity under acute conditions (Hill et al, 2011;Rademacher et al, 2008). We have recently found that WIN55,212-2 can prevent the impairing effects of an acute stressful experience on contextual extinction in a rat model for post-traumatic stress disorder and that these ameliorating effects of WIN55,212-2 on extinction were mediated by glucocorticoid receptors (GRs) in the basolateral amygdala (BLA) and hippocampus (Ganon-Elazar and Akirav, 2013). …”

Section: Introductionmentioning

confidence: 99%

Cannabinoid Receptor Activation Prevents the Effects of Chronic Mild Stress on Emotional Learning and LTP in a Rat Model of Depression

Segev

Rubin

Abush

et al. 2013

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Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1-21. The agonist WIN55,212-2 or vehicle were administered on days 19-21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression.