The role of 5-HT_1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae)

Abstract

The potential anxiolytic and antipanic properties of cannabidiol have been shown; however, its mechanism of action seems to recruit other receptors than those involved in the endocannabinoid-mediated system. It was recently shown that the model of panic-like behaviors elicited by the encounters between mice and snakes is a good tool to investigate innate fear-related responses, and cannabidiol causes a panicolytic-like effect in this model. The aim of the present study was to investigate the 5-hydroxytryptamine (5-HT) co-participation in the panicolytic-like effects of cannabidiol on the innate fear-related behaviors evoked by a prey versus predator interaction-based paradigm. Male Swiss mice were treated with intraperitoneal (i.p.) administrations of cannabidiol (3 mg/kg, i.p.) and its vehicle and the effects of the peripheral pre-treatment with increasing doses of the 5-HT1A receptor antagonist WAY-100635 (0.1, 0.3 and 0.9 mg/kg, i.p.) on instinctive fear-induced responses evoked by the presence of a wild snake were evaluated. The present results showed that the panicolytic-like effects of cannabidiol were blocked by the pre-treatment with WAY-100635 at different doses. These findings demonstrate that cannabidiol modulates the defensive behaviors evoked by the presence of threatening stimuli, and the effects of cannabidiol are at least partially dependent on the recruitment of 5-HT1A receptors.

Relevance of dorsomedial hypothalamus, dorsomedial division of the ventromedial hypothalamus and the dorsal periaqueductal gray matter in the organization of freezing or oriented and non-oriented escape emotional behaviors

“…Interestingly, after freezing, the rats frequently re-started oriented escapes to the burrow. Previous findings also showed both oriented and explosive escape elicited by rats in polygonal arena in the presence of wild snakes [42,43].…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…These effects partially depended on 5-HT 1A R activation but were not affected by CB 1 R blockade. CBD was also panicolytic in the predator-prey model, which assesses explosive escape and defensive immobility in response to a boa constrictor snake, also partially via 5-HT 1A R activation; however, more consistent with an anxiogenic effect, CBD was also noted to decrease time spent outside the burrow and increase defensive attention (not shown in Table 1) [75,86] . Finally, CBD, partially via CB 1 Rs, decreased defensive immobility and explosive escape caused by bicuculline-induced neuronal activation in the superior colliculus [89].…”

Looking ahead after 50 years of research on cannabinoids

“…These results suggest that the neuroprotective and other effects of CBD in many cases proceed through the serotonergic 5-HT1A receptor . Some additional recent examples: 5-HT1A receptors play a role in the CBD anti-anxiety effects (Gomes et al, 2011) and even in the anti-aversive effects of CBD on panic attack-like behaviours evoked in the presence of a wild snake (Twardowschy et al, 2013). It is involved in some motor effects of CBD (Espejo-Porras et al, 2013) as well as in the attenuation by CBD of vomiting and nausea-like behaviour (Rock et al, 2012), in the amelioration of cognitive and motor impairments in bile-duct ligated mice by CBD (Magen et al, 2010), in inhibition of the reward-facilitating effect of morphine (Katsidoni et al, 2013); in the CBD-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats (Resstel et al, 2009) and so on.…”