Bimodal Control of Fear-Coping Strategies by CB₁Cannabinoid Receptors

Abstract

To maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB 1 ) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB 1 receptors in CB 1 Ϫ/Ϫ mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB 1 receptors from cortical glutamatergic neurons. CB 1 receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized by the predominance of active coping. The CB 1 receptor agonist ⌬ 9 -tetrahydrocannabinol exerted a biphasic control of fear coping strategies, with lower and higher doses favoring active and passive responses, respectively. Finally, viral re-expression of CB 1 receptors in the amygdala of CB 1 Ϫ/Ϫ mice restored the normal switch between the two coping strategies. These data strongly suggest that CB 1 receptor signaling bimodally controls the spontaneous adoption of active or passive coping strategies in individuals. This primary function of the endocannabinoid system in shaping individual behavioral traits should be considered when studying the mechanisms of physiological and pathological fear.

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

“…Indeed, previous observations revealed increased interest of these conditional mutant mice in novel food or object exploration (Lafenêtre et al, 2009), but also in favoring active coping strategies, such as escape, in fear cued conditioning (Metna-Laurent et al, 2012). In the present study, when we paired cocaine selfadministration with foot shocks, GABA-CB1-KO expressed increased unconditioned and conditioned foot-shockinduced suppression of cocaine seeking.…”

“…When targeted genetic deletion of CB1 is applied in feeding-, novelty-, and fear-related behaviors (Bellocchio et al, 2010;Dubreucq et al, 2012;Metna-Laurent et al, 2012), deletion localized to cortical glutamatergic neurons (Glu-CB1-KO mice) produces similar effects to full CB1 blockade, apparently confirming that CB1 exclusively controls glutamatergic-dependent processes (Bellocchio et al, 2010;Dubreucq et al, 2012;Metna-Laurent et al, 2012). However, deletion of CB1 in forebrain GABAergic neurons (GABA-CB1-KO mice) is not without effect.…”

“…However, deletion of CB1 in forebrain GABAergic neurons (GABA-CB1-KO mice) is not without effect. Interestingly, it can produce opposing or qualitatively different results as compared with deletion in cortical glutamatergic neurons (Bellocchio et al, 2010;Dubreucq et al, 2012;Metna-Laurent et al, 2012).…”

The effects anandamide signaling in the prelimbic cortex and basolateral amygdala on coping with environmental stimuli in rats

“…enhances active responses on the expense of passive responses. Metna-Laurent et al (2012) showed that conditional CB1-KO mice show a decrease in active coping in the conditioned fear test as indicated by a delayed return to normal activity after exposure to fear-associated cues. We have shown that rats treated with URB597 disregard environmental information (e.g.…”

“…It was recently suggested that endocannabinoid signaling -in addition to, or instead of regulating particular behaviors -controls coping with environmental challenges (Haller et al 2014;Haller et al 2013;McLaughlin et al 2012;Metna-Laurent et al 2012). In our studies, coping was conceptualized according to Koolhaas et al (1999) who defined active and passive coping styles as distinct behavioral phenotypes, which differ in patterns of responding upon challenge.…”