The Role of Prefrontal Cortex CB1 Receptors in the Modulation of Fear Memory

Lin, Hui Ching; Mao, Sheng Chun; Su, Chun Li; Gean, Po Wu

doi:10.1093/cercor/bhn075

Cited by 111 publications

(101 citation statements)

References 46 publications

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“…On the other hand, CB1 agonists mimicked extinction training, facilitating and causing a reduction of startle potentiation in a dose-dependent manner. The effect of CB1 agonists was mimicked by the endocannabinoid uptake inhibitor AM404 and the fatty acid amidehydrolase inhibitor URB597, and could be blocked by a specific CB1 receptor antagonist (Lin et al 2008). In the present study, we show that WIN-pretreated rats exhibited much less extinction to cue-alone presentations.…”

Section: Discussionsupporting

confidence: 55%

Chronic cannabinoid administration in vivo compromises extinction of fear memory

Lin¹,

Mao²,

Chen³

et al. 2008

Learn. Mem.

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Endocannabinoids are critically involved in the extinction of fear memory. Here we examined the effects of repeated cannabinoid administration on the extinction of fear memory in rats and on inhibitory synaptic transmission in medial prefrontal cortex (mPFC) slices. Rats were treated with the CB1 receptor agonist WIN55212-2 (WIN 10 mg/kg, i.p.) once per day for 7 d. On day 8, the rats were submitted to a standard fear conditioning procedure, and retention of memory was measured with potentiated startle paradigm. We found that (1) WIN-pretreated rats exhibited much less extinction to cue alone presentations; (2) the reduction of fear-potentiated startle normally seen when the CB1 receptor agonists were infused into the mPFC was absent in the WIN-pretreated rats; (3) WIN-induced inhibition of GABAergic transmission was significantly less in slices from the WIN-pretreated rats than that from the vehicle-pretreated control; (4) WIN failed to induce extracellular signal-regulated kinases (ERKs) phosphorylation in the WIN-pretreated rats; and (5) the level of CB1 receptor in the WIN-pretreated rats was lower than that of vehicle-pretreated rats. These results suggest that endocannabinoids within the mPFC play an important role in the extinction of conditioned fear. However, long-term marijuana use may limit its clinical efficacy for the treatment of anxiety disorders.

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Section: Discussionsupporting

confidence: 55%

Chronic cannabinoid administration in vivo compromises extinction of fear memory

Lin¹,

Mao²,

Chen³

et al. 2008

Learn. Mem.

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show abstract

“…Previous studies reported an increase in Fos-ir in the central amygdala of naive mice following pharmacological blockade of CB1 (Patel et al, 2005a). In addition, CB1 plays a complex role in the regulation of fear and anxiety within the medial prefrontal cortex (Lin et al, 2009), and neuronal activity within the prelimbic cortex seems to directly Figure 6. Neuroanatomical signature of extinction training.…”

Section: Discussionmentioning

confidence: 98%

Dissociation of within- and between-Session Extinction of Conditioned Fear

Plendl¹,

2010

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Recent findings obtained in patients with phobias or trauma-related anxiety disorders raise doubts concerning the interrelation between acute fear relief during an exposure-based therapeutic session and beneficial treatment progress. In a mouse model explicit for exposure therapy, we challenge the view that within-session fear reduction is the turning point for relearning of a stimulus-threat association. Even though within-session extinction of auditory-cued fear memory was identical for prolonged and spaced tone presentations, only the latter caused between-session extinction. Furthermore, spaced tone presentations led to between-session extinction even in the complete absence of within-session extinction, as observed for remote fear memories and in case of abolished cannabinoid receptor type 1 signaling. Induction of between-session extinction was accompanied by an increase in the number of c-Fos-positive neurons within the basolateral amygdala, the cingulate cortex, and the dentate gyrus, independent of the level of within-session extinction. Together, our findings demonstrate that within-session extinction is neither sufficient nor essential for between-session extinction, thus calling for a reconsideration of current concepts underlying exposure-based therapies.

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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

Neuropsychopharmacol

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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.

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The Role of Prefrontal Cortex CB1 Receptors in the Modulation of Fear Memory

Cited by 111 publications

References 46 publications

Chronic cannabinoid administration in vivo compromises extinction of fear memory

Chronic cannabinoid administration in vivo compromises extinction of fear memory

Dissociation of within- and between-Session Extinction of Conditioned Fear

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

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