Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation

Abstract

Background : Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals. The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD. Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD. In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear. Method : Male Sprague-Dawley rats received six 1.0 mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context. Immediately following memory retrieval (recall) rats received oral administration of low dose THC, high dose THC, CBD, CBD + low THC, CBD + high THC [as isolated phytochemicals and, in separate experiments, in combination with plant background material (BM)]. Rodents were tested for freezing response context re-exposure at 24 h and 7 days following training. Results : CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM. Conclusion : CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning.

Effects of ∆9-tetrahydrocannabinol on aversive memories and anxiety: a review from human studies

“…In a dose range from 0.3 to 10 mg/kg, the acute and systemic treatment with THC impaired the reconsolidation of specific and recent contextual fear memories in adult male rats, an effect dependent on prelimbic cortex CB1 receptor activation [124]. The acute treatment with 5.0 (but not 50) mg/kg of THC similarly impaired the reconsolidation of a recent cued fear memory in male rats [125]. Future studies should address whether THC can impair the reconsolidation of more remote and generalized aversive memories in both male and female animals.…”

“…As early mentioned, however, this association could be advantageous. Accordingly, administering both THC and CBD in a subeffective dose impaired either contextual or cued fear memory reconsolidation in adult male rats [124,125]. In both cases, the THC:CBD dose ratio was 1:10, and combining THC with CBD allowed the use of 3-fold lower doses of them in the study by Stern et al [124].…”

Potencial uso terapêutico dos compostos canabinoides – canabidiol e delta-9-tetrahidrocanabinol

“…Em contrapartida, o CBD interage com receptores cerebrais incluindo os receptores canabinoides 1 e 2 (CB1 e CB2), o receptor transitório vaniloide tipo 1 (TRVP1 transient vanilloid receptor subtype-1) e o receptor de serotonina 1A (5-HT1A, um subtipo de receptor 5-HT receptor 5-hidroxitriptamina) que inibe ou afeta de outras formas a função da enzima que degrada endogenamente neurotransmissores canabinoides liberados (amida hidrolase de ácido graxo -FAAHfatty acid amide hydrolase). Pesquisas pré-clínicas indicam que o CBD aumenta a extinção e a reconsolidação do medo, e os antagonistas do CB1 bloqueiam tais efeitos (Murkar et al, 2019). Estudos sugerem o potencial uso do CBD para aumentar especificamente a extinção de medos patológicos, com a vantagem de poder ser administrado ocasionalmente.…”

“…Os efeitos comportamentais do THC são alterados pela coadministração de outros compostos, atenuando seus efeitos psicoativos (sedativo e ansiogênico) e potencializando os efeitos potencialmente terapêuticos, como por exemplo, a diminuição da ativação da amígdala em resposta a imagens de rostos associados a ameaças. Contudo, os estudos indicam que não é preciso o uso a longo prazo para alívio do medo aprendido, e que o CBD ao ser administrado de forma isolada é potencialmente eficaz (Murkar et al, 2019).…”

“…O THC é extraído do composto ácido tetrahidrocanabinólico (THCA) forma inativada, não apresentando efeitos psicoativos, embora tenha propriedades neuroprotetoras. O THC é a forma mais ativa de canabinoide produzindo alterações características de humor e de percepção (Murkar et al, 2019;Villas Bôas & Rezende, 2020).…”