Context‐dependent effects of CB1 cannabinoid gene disruption on anxiety‐like and social behaviour in mice

Abstract

Contrasting data were reported regarding the effects of cannabinoids on anxiety and social behaviour in both animals and humans. The cognitive effects of cannabinoids and their interactions with the HPA-axis raise the possibility that cannabinoid effects are context but not behaviour specific. To assess this hypothesis, we submitted CB1 receptor knock-out (CB1-KO) and wild-type (WT) mice to tests, which involved similar behaviours, but the behavioural context was different. The elevated plus-maze test was performed under less and more anxiogenic conditions, i.e. under low and high light, respectively. We also compared the social behaviour of the two genotypes in the resident/intruder and social interaction tests. Both tests represent a social challenge and induce similar behaviours, but involve different contexts. The behaviour of CB1-KO and WT mice was similar under low light, but CB1 gene disruption increased anxiety-like behaviour under the high light condition. CB1 gene disruption promoted aggressive behaviour in the home-cage, whereas it inhibited social behaviour in the unfamiliar cage. Thus, the anxiogenic-like effect was restricted to the more stressful unfamiliar environment. These data suggest that the effects of CB1 gene disruption were context and not behaviour specific. Novelty stress resulted in higher ACTH levels in CB1-KOs than in WTs, which suggests that context dependency occurred in conjunction with an altered HPA axis function. The present data at least partly explain contrasting effects of cannabinoids in different contexts as well as in different species and strains that show differential stress responses and coping strategies.

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

“…Specifically, we demonstrate that systemic administration of rimonabant precipitates anxiety-like behavior and more potently induces anorexia and weight loss in rats during early protracted withdrawal from a palatable high-sucrose diet compared with chow-fed controls. In addition, at a time when diet-cycled rats no longer showed the increased spontaneous anxiety-like behavior elicited by acute withdrawal from this diet (Cottone et al, 2009a;Cottone et al, 2009b), they still exhibited increased vulnerability to the anxiogenic-like effects of rimonabant (Haller et al, 2004). These results are consistent with the hypothesis that rats withdrawn from chronic, palatable diet cycling become vulnerable to the pharmacological effects of rimonabant.…”

“…Symbols denote: *significant difference from Chow/Chow group po0.05, **po0.01. Haller et al, 2004). In addition, rimonabant-precipitated anxiety-like behavior in rats withdrawn from chronic, intermittent access to palatable food was independent of the degree of adrenocortical activation.…”

Interactions between endocannabinoids and stress-induced decreased sensitivity to natural reward

“…In support of this hypothesis, it has been demonstrated that endocannabinoids modulate hypothalamus-pituitaryadrenal axis function (Haller et al, 2004;Manzanares et al, 1999;Patel et al, 2004). In particular, earlier studies from our laboratory (Patel et al, 2004) demonstrated that CB 1 receptor blockade potentiates restraint stress-induced hypothalamus-pituitary-adrenal axis activation and neuronal activity in the paraventricular nucleus of the hypothalamus, and CB 1 receptor activation blocks restraint stress-induced hypothalamus-pituitary-adrenal axis activation.…”

“…For example, blockade of endogenous CB 1 receptor activity with rimonabant increases adrenocorticotropin hormone and corticosterone plasma concentrations (Manzanares et al, 1999). Similarly, basal adrenocorticotropin hormone concentrations are increased in CB 1 receptor null mice (Haller et al, 2004). On the other hand, inhibition of fatty acid amide hydrolase (FAAH) activity during stress inhibits activation of the hypothalamic-pituitaryadrenal axis (Patel et al, 2004).…”

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

“…17 These discrepancies might be ascribed to differences in the genetic background of the rodent 8,15,16 or in the test conditions, 18 especially regarding the averseness of the test situation. 19 Given the high comorbidity between anxiety and major depression, 20 recent research has also focused on a potential role of the endocannabinoid system in the pathology of major depression 13,21 particularly of the melancholic subtype. 13 CB1 receptor-deficient mice share several symptoms with patients suffering from melancholic depression such as, for example, altered responsiveness to reward stimuli, 22 altered neurovegetative functions, 23 a predominance and persistence of aversive memories, 8,9 and possibly neurodegeneration.…”