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

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Cannabidiol reduces the expression of auditory and contextual fear memory in rats. (A) Schematic representation of the experimental procedures used; the arrow indicates that drug was injected 30 min before extinction. (B) Freezing during tone-shock pairings did not differ between the groups during auditory fear conditioning. (C) Rats treated with 20 mg/kg of cannabidiol showed significantly decreased freezing during tone presentations at the start of extinction, compared to rats given 5 mg/kg or vehicle (*P <0.05). (D) There were no differences in tone-induced freezing between the groups during extinction recall. (E) Rats treated with 5, 10, or 20 mg/kg of cannabidiol showed significantly decreased freezing in the 2 min period before tone presentations during extinction, compared to vehicle-treated controls (**P <0.01). (F) There were no differences in freezing between the groups in the 2 min period before tone presentations during extinction recall (see Supplementary Material for more details).
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Figure 2: Cannabidiol reduces the expression of auditory and contextual fear memory in rats. (A) Schematic representation of the experimental procedures used; the arrow indicates that drug was injected 30 min before extinction. (B) Freezing during tone-shock pairings did not differ between the groups during auditory fear conditioning. (C) Rats treated with 20 mg/kg of cannabidiol showed significantly decreased freezing during tone presentations at the start of extinction, compared to rats given 5 mg/kg or vehicle (*P <0.05). (D) There were no differences in tone-induced freezing between the groups during extinction recall. (E) Rats treated with 5, 10, or 20 mg/kg of cannabidiol showed significantly decreased freezing in the 2 min period before tone presentations during extinction, compared to vehicle-treated controls (**P <0.01). (F) There were no differences in freezing between the groups in the 2 min period before tone presentations during extinction recall (see Supplementary Material for more details).

Mentions: In contrast to contextual fear memory processing, few studies have examined the effects of CBD on learned fear related to discrete cues. 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-HT1AR 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. Male Lister hooded rats were habituated to two distinct contexts (A and B), subjected to auditory fear conditioning (tone habituation and tone-shock pairings) in context A, treated with CBD (0, 5, 10, or 20 mg/kg, i.p.; n = 10–11/group) 30 min before undergoing extinction training (tone presentations) in context B, and underwent extinction recall testing (tone presentations) in context B (Figure 2A).


Cannabidiol Regulation of Learned Fear: Implications for Treating Anxiety-Related Disorders
Cannabidiol reduces the expression of auditory and contextual fear memory in rats. (A) Schematic representation of the experimental procedures used; the arrow indicates that drug was injected 30 min before extinction. (B) Freezing during tone-shock pairings did not differ between the groups during auditory fear conditioning. (C) Rats treated with 20 mg/kg of cannabidiol showed significantly decreased freezing during tone presentations at the start of extinction, compared to rats given 5 mg/kg or vehicle (*P <0.05). (D) There were no differences in tone-induced freezing between the groups during extinction recall. (E) Rats treated with 5, 10, or 20 mg/kg of cannabidiol showed significantly decreased freezing in the 2 min period before tone presentations during extinction, compared to vehicle-treated controls (**P <0.01). (F) There were no differences in freezing between the groups in the 2 min period before tone presentations during extinction recall (see Supplementary Material for more details).
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Figure 2: Cannabidiol reduces the expression of auditory and contextual fear memory in rats. (A) Schematic representation of the experimental procedures used; the arrow indicates that drug was injected 30 min before extinction. (B) Freezing during tone-shock pairings did not differ between the groups during auditory fear conditioning. (C) Rats treated with 20 mg/kg of cannabidiol showed significantly decreased freezing during tone presentations at the start of extinction, compared to rats given 5 mg/kg or vehicle (*P <0.05). (D) There were no differences in tone-induced freezing between the groups during extinction recall. (E) Rats treated with 5, 10, or 20 mg/kg of cannabidiol showed significantly decreased freezing in the 2 min period before tone presentations during extinction, compared to vehicle-treated controls (**P <0.01). (F) There were no differences in freezing between the groups in the 2 min period before tone presentations during extinction recall (see Supplementary Material for more details).
Mentions: In contrast to contextual fear memory processing, few studies have examined the effects of CBD on learned fear related to discrete cues. 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-HT1AR 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. Male Lister hooded rats were habituated to two distinct contexts (A and B), subjected to auditory fear conditioning (tone habituation and tone-shock pairings) in context A, treated with CBD (0, 5, 10, or 20 mg/kg, i.p.; n = 10–11/group) 30 min before undergoing extinction training (tone presentations) in context B, and underwent extinction recall testing (tone presentations) in context B (Figure 2A).

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.