Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System

Norris, Christopher; Loureiro, Michaël; Kramar, Cecilia P.; Zunder, Jordan; Renard, Justine; Rushlow, Walter; Laviolette, Steven R.

doi:10.1038/npp.2016.93

Cited by 59 publications

(65 citation statements)

References 49 publications

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“…We have previously reported that CB1R‐mediated modulation of mesolimbic DA activity states requires local GABA A and GABA B receptor transmission within the VTA (Draycott et al., ). Thus, the ability of both intra‐PFC and intra‐NASh cannabinoid‐mediated modulation of VTA DAergic neurones has been found to require localized VTA GABA A/B receptor transmission as intra‐VTA antagonists of these receptors blocks the effects of PFC or NAc‐mediated cannabinoid modulation of the VTA and fear‐related associative memory formation (Draycott et al., ; Norris et al., ). Accordingly, we hypothesized that intra‐NASh THC administration may modulate fear‐related conditioning salience through a local GABA A/B signalling mechanism in the VTA.…”

Section: Resultsmentioning

confidence: 99%

“…Bilateral microinfusions were performed over 1 min with injectors left in place for an additional minute to allow adequate diffusion from the injector tip. All drug dose ranges were based upon previously published and carefully established dose–response curves for intracranial microinfusions that have demonstrated pharmacological specificity and behavioural efficacy (Laviolette, Nader, & van der Kooy, ; Laviolette & van der Kooy, ; Norris et al., ).…”

Section: Methodsmentioning

confidence: 99%

“…Fear memory formation was examined with an olfactory fear conditioning paradigm as previously described (Laviolette & Grace, ; Norris et al., ). Using sub‐ versus suprathreshold footshock levels (0.4 and 0.8 mA, respectively), we tested whether specific drug treatments could block or potentiate the acquisition of either a normally subthreshold or suprathreshold associative fear memory.…”

Section: Methodsmentioning

confidence: 99%

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Delta‐9‐tetrahydrocannabinol potentiates fear memory salience through functional modulation of mesolimbic dopaminergic activity states

Fitoussi

Zunder

Tan

et al. 2018

Eur J of Neuroscience

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Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and preclinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally subthreshold fear conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurones whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurones. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Delta‐9‐tetrahydrocannabinol potentiates fear memory salience through functional modulation of mesolimbic dopaminergic activity states

Fitoussi

Zunder

Tan

et al. 2018

Eur J of Neuroscience

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“…The regulation of conditioned fear expression by CBD in these brain areas was shown to be dependent on 5‐HT 1A receptors (Gomes et al , ; Fogaça et al , ; Marinho et al , ). The inhibitory effect of CBD on the acquisition of fear conditioning has also been shown to depend on 5‐HT 1A receptor activation in the nucleus accumbens shell (Norris et al , ).…”

Section: Pharmacological Mechanisms and Brain Sites Involved In The Ementioning

confidence: 99%

Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety‐related and substance abuse disorders

Lee

Bertoglio

Guimarães

et al. 2017

British J Pharmacology

122

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Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear-and drug-related stimuli can develop into anxiety-related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5-HT 1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety-related and substance abuse disorders. LINKED ARTICLESThis article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit

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“…One study in humans showed that CBD enhanced the extinction of visual fear memory when given immediately after, but not before, extinction (Das et al, 2013). More recently it was found in rats that CBD infused into the nucleus accumbens shell impaired the encoding of olfactory fear memory, an effect blocked by 5-HT 1A R antagonism (Norris et al, 2016). To investigate this issue further we determined the effect of systemic CBD administration on the expression and extinction of auditory fear memory.…”

Section: Cbd Regulation Of Fear Memory Processing Involving Discrete mentioning

confidence: 99%

Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders

et al. 2016

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Anxiety and trauma-related disorders are psychiatric diseases with a lifetime prevalence of up to 25%. Phobias and post-traumatic stress disorder (PTSD) are characterized by abnormal and persistent memories of fear-related contexts and cues. The effects of psychological treatments such as exposure therapy are often only temporary and medications can be ineffective and have adverse side effects. Growing evidence from human and animal studies indicates that cannabidiol, the main non-psychotomimetic phytocannabinoid present in Cannabis sativa, alleviates anxiety in paradigms assessing innate fear. More recently, the effects of cannabidiol on learned fear have been investigated in preclinical studies with translational relevance for phobias and PTSD. Here we review the findings from these studies, with an emphasis on cannabidiol regulation of contextual fear. The evidence indicates that cannabidiol reduces learned fear in different ways: (1) cannabidiol decreases fear expression acutely, (2) cannabidiol disrupts memory reconsolidation, leading to sustained fear attenuation upon memory retrieval, and (3) cannabidiol enhances extinction, the psychological process by which exposure therapy inhibits learned fear. We also present novel data on cannabidiol regulation of learned fear related to explicit cues, which indicates that auditory fear expression is also reduced acutely by cannabidiol. We conclude by outlining future directions for research to elucidate the neural circuit, psychological, cellular, and molecular mechanisms underlying the regulation of fear memory processing by cannabidiol. This line of investigation may lead to the development of cannabidiol as a novel therapeutic approach for treating anxiety and trauma-related disorders such as phobias and PTSD in the future.

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Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System

Cited by 59 publications

References 49 publications

Delta‐9‐tetrahydrocannabinol potentiates fear memory salience through functional modulation of mesolimbic dopaminergic activity states

Delta‐9‐tetrahydrocannabinol potentiates fear memory salience through functional modulation of mesolimbic dopaminergic activity states

Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety‐related and substance abuse disorders

Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders

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