Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption

• Published in: European neuropsychopharmacology Vol. 25; no. 6; pp. 958 - 965
• Main Authors: Stern, Cristina A.J., Gazarini, Lucas, Vanvossen, Ana C., Zuardi, Antonio W., Galve-Roperh, Ismael, Guimaraes, Francisco S., Takahashi, Reinaldo N., Bertoglio, Leandro J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2015
• Subjects: Analysis of Variance; Animals; Cannabidiol; Cannabidiol - adverse effects; Cannabidiol - pharmacology; CB1 receptor; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol - adverse effects; Dronabinol - pharmacology; Drug Combinations; Fear - drug effects; Fear memory; Male; Maze Learning - drug effects; Medial prefrontal cortex; Memory - drug effects; Memory Disorders - chemically induced; Rats; Rats, Wistar; Reconsolidation; Time Factors; Δ9-Tetrahydrocannabinol; Fear memory; Reconsolidation; Medial prefrontal cortex; Cannabidiol; Δ9-Tetrahydrocannabinol; CB1 receptor; Δ-Tetrahydrocannabinol
• DOI: 10.1016/j.euroneuro.2015.02.001
• ISSN: 0924-977X

Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3–10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.