Cannabinoid facilitation of fear extinction memory recall in humans

Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA. Electronic address: .
Neuropharmacology (Impact Factor: 5.11). 07/2012; 64(1):396-402. DOI: 10.1016/j.neuropharm.2012.06.063
Source: PubMed


A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 h prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 h after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 h after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

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Available from: Christine A Rabinak, Jan 21, 2016
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    • "Longer-lasting effects on extinction recall (day 3) were also observed after a single oral dose of the synthetic form of ∆-9-THC, dronabinol (vs. placebo) administered prior to (not after) the extinction acquisition (day 2;Rabinak et al., 2013). In a similar study, another synthetic THC, marinol, now did not affect SCR during extinction recall (day 3) but led to an increase of vmPFC and hippocampus activation to a previously extinguished CS+ in a differential conditioning paradigm (Rabinak et al., 2014). "
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    ABSTRACT: Fear acquisition and extinction are valid models for the etiology and treatment of anxiety, trauma- and stressor-related disorders. These disorders are assumed to involve aversive learning under acute and/or chronic stress. Importantly, fear conditioning and stress share common neuronal circuits. The stress response involves multiple changes interacting in a time-dependent manner: (a) the fast first-wave stress response (with central actions of noradrenaline, dopamine, serotonin, corticotropin-releasing hormone, plus increased sympathetic tone and peripheral catecholamine release) and (b) the second-wave stress response (with peripheral release of glucocorticoids after activation of the hypothalamus-pituitary-adrenocortical axis). Control of fear during extinction is also sensitive to these stress-response mediators. In the present review, we will thus examine current animal and human data, addressing the role of stress and single stress-response mediators for successful acquisition, consolidation and recall of fear extinction. We report studies using pharmacological manipulations targeting a number of stress-related neurotransmitters and neuromodulators (monoamines, opioids, endocannabinoids, neuropeptide Y, oxytocin, glucocorticoids) and behavioral stress induction. As anxiety, trauma- and stressor-related disorders are more common in women, recent research focuses on female sex hormones and identifies a potential role for estradiol in fear extinction. We will thus summarize animal and human data on the role of estradiol and explore possible interactions with stress or stress-response mediators in extinction. This also aims at identifying time-windows of enhanced (or reduced) sensitivity for fear extinction, and thus also for successful exposure therapy.
    Full-text · Article · Jan 2016 · Frontiers in Behavioral Neuroscience
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    • "Broadly, these results suggest that THC modulates amygdala, but not PFC, activation and amygdala–dlPFC functional connectivity during cognitive reappraisal and negative emotion processing in general. In the current study THC increased amygdala activation during cognitive reappraisal, whereas others have shown that THC decreases amygdala activation during fear inhibition (Rabinak et al, 2013), and can increase or decrease amygdala activation during threat perception (Bhattacharyya et al, 2010;Phan et al, 2008). This suggests that the effects of THC on amygdala activation may differ depending on whether the emotional process is volitional or automatic (cognitive reappraisal vs fear inhibition). "
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    ABSTRACT: Behavioral and brain research indicates that administration of Δ(9)-tetrahydrocannabinol (THC) alters threat perception and enhances the suppression of conditioned fear responses via modulation of the frontolimbic circuit. No prior studies, however, have examined whether THC also affects volitional forms of emotion processing such as cognitive reappraisal. The aim of the current study was therefore to examine the effects of THC on frontolimbic activation and functional connectivity during cognitive reappraisal in a sample of healthy adults. The study was a randomized, double-blind, placebo-controlled, between-subjects design and all participants ingested either an oral dose of synthetic THC (n=41) or placebo (n=37) prior to completion of an emotion regulation task during functional magnetic resonance imaging (fMRI). Functional connectivity was assessed using generalized psychophysiological interaction (gPPI) analyses. Results indicated that while there were no group differences in self-reported attenuation of negative affect during cognitive reappraisal, relative to placebo, THC increased amygdala activation and reduced amygdala and dorsolateral prefrontal cortex (dlPFC) functional coupling during cognitive reappraisal of emotionally negative pictures. This suggests that in addition to automatic emotional processes, THC impacts frontolimbic functioning during cognitive reappraisal.Neuropsychopharmacology accepted article preview online, 09 December 2015. doi:10.1038/npp.2015.359.
    Full-text · Article · Dec 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Indeed, presentation of negative stimuli (pictures of fearful faces) reduces activity in neural structures such as the amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, PFC and regions in the occipital cortex following acute THC exposure, whereas presentation of positive stimuli (pictures of happy faces) increases activity within that network (Bossong et al. 2013). Furthermore, THC facilitates extinction of learned fear in humans and increases activation in the ventromedial PFC and hippocampus upon presentation of the CS relative to subjects that received a placebo (Rabinak et al. 2013, 2014). Cannabidiol, a non-psychoactive cannabinoid found in cannabis, has also been found to enhance consolidation of fear extinction (Das et al. 2013). "
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    ABSTRACT: The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic endocannabinoid signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that endocannabinoid signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic endocannabinoid signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the endocannabinoid system and discuss clinical and rodent models demonstrating endocannabinoid regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the endocannabinoid system in the central nervous system, and models of pharmacological augmentation of endocannabinoid signaling during development in the context of fear learning and anxiety.
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