title: Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption.
abstract: Δ(9)-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.
authors: Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil.
authors: Cristina A J
authors: CA
authors: Stern
authors: Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil.
authors: Lucas
authors: L
authors: Gazarini
authors: Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil.
authors: Ana C
authors: AC
authors: Vanvossen
authors: Department of Neurology, Psychiatry and Medical Psychology, University of São Paulo, Ribeirao Preto, SP, Brazil.
authors: Antonio W
authors: AW
authors: Zuardi
authors: Department of Biochemistry and Molecular Biology I, Complutense University, Madrid, Spain; Centro de Investigación Biomedica en red en Enfermedades Neurodegenerativas, Madrid, Spain.
authors: Ismael
authors: I
authors: Galve-Roperh
authors: Department of Pharmacology, University of São Paulo, Ribeirao Preto, SP, Brazil.
authors: Francisco S
authors: FS
authors: Guimaraes
authors: Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil.
authors: Reinaldo N
authors: RN
authors: Takahashi
authors: Department of Pharmacology, Federal University of Santa Catarina, Florianopolis, SC, Brazil. Electronic address: leandro.bertoglio@ufsc.br.
authors: Leandro J
authors: LJ
authors: Bertoglio
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002185:Cannabidiol / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000009:adverse effects / Q000494:pharmacology*; D004338:Drug Combinations; D005239:Fear / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D004338:Drug Combinations; D002185:Cannabidiol; D013759:Dronabinol
keywords: CB1 receptor; Cannabidiol; Fear memory; Medial prefrontal cortex; Reconsolidation; Δ(9)-Tetrahydrocannabinol