Papagianni, Eleni
(2023)
Cannabidiol regulation of extinction and relapse of learned fear.
PhD thesis, University of Nottingham.
Abstract
Anxiety- and trauma-related disorders are chronic debilitating mental conditions, characterized by dysregulation of aversive memory processing and its impaired suppression. Current pharmacological and exposure-based psychotherapeutic approaches often produce inadequate responses, resulting in elevated rates of relapse. Cannabidiol (CBD), the non-psychotropic constituent of Cannabis Sativa, demonstrates a promising therapeutic potential for these disorders due to its modulating effects on the expression and extinction of learned fear.
In this thesis, the potential effects of systemic CBD on extinction and learned fear relapse over time were initially investigated, after developing a working protocol for spontaneous fear recovery. Rats underwent auditory fear conditioning (day 1), extinction training with CBD administered before or after the session (day 2), and drug-free tests of extinction recall (day 4) and spontaneous recovery (day 24). CBD administration before extinction training was found to acutely reduce the expression of contextual fear, without affecting auditory fear expression or extinction training. Although CBD did not affect extinction recall, it suppressed later spontaneous recovery of auditory fear.
Next, the pharmacological mechanisms underlying these CBD effects were investigated by examining the potential involvement of cannabinoid 1 receptor (CB1R) or 5-hydroxytryptamine 1A receptor (5-HT1AR) signaling, molecular targets through which CBD was found to elicit fear-alleviating and anxiolytic-like effects. After performing dose-response studies with the CB1R inverse agonist AM251 and the 5-HT1AR antagonist WAY100,635, these compounds were administered in combination with CBD. However, when CBD was given alone in either study it failed to reproduce the previously observed effects, rendering it impossible to exclude the potential involvement of either transmission mechanism in mediating the effects of CBD on learned fear expression and spontaneous fear recovery.
Lastly, the effects of CBD on stress-induced impairments in extinction learning triggered by recent fear conditioning were examined by using an immediate extinction deficit (IED) protocol. Rats were administered with CBD before immediate or no extinction session, and the next day subjected to a drug-free extinction recall test. CBD enhanced recall of extinction to prevent the IED phenomenon, without interfering with the consolidation of learned fear memory.
Taken together, CBD induced long-term protection against fear relapse after successful extinction and alleviated stress-induced impairments in extinction learning. Because of the inability to reproduce the effects of CBD on fear relapse while investigating the involvement of CB1R or 5-HT1AR mediated signaling, this necessitates further studies to elucidate the exact pharmacological mechanisms underlying the CBD effects observed in this project. However, these findings add valuable insight into CBD’s potential as a candidate therapeutic for the management of anxiety- and trauma-related disorders.
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