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.

Rationale-Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g. URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic.Objectives-We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies.Results-We found that URB597 (0.1-0.3mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2010 July 1. Conclusions-Our findings show that FAAH inhibition does not affect anxiety under mildlystressful circumstances but protects against the anxiogenic effects of aversive stimuli.

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Beta-endorphin (betaE) is an important reliever of pain. Various stressors and certain modalities of physiotherapy are potent inducers of the release of endogenous betaE to the blood stream. Most forms of exercise also increase blood betaE level, especially when exercise intensity involves reaching the anaerobic threshold and is associated with the elevation of serum lactate level. Age, gender, and mental activity during exercise also may influence betaE levels. Publications on the potential stimulating effect of manual therapy and massage on betaE release are controversial. Sauna, mud bath, and thermal water increase betaE levels through conveying heat to the tissues. The majority of the techniques for electrical stimulation have a similar effect, which is exerted both centrally and--to a lesser extent--peripherally. However, the parameters of electrotherapy have not yet been standardised. The efficacy of analgesia and the improvement of general well-being do not necessarily correlate with betaE level. Although in addition to blood, increased brain and cerebrospinal fluid betaE levels are also associated with pain, the majority of studies have concerned blood betaE levels. In general, various modalities of physical therapy might influence endorphin levels in the serum or in the cerebrospinal fluid--this is usually manifested by elevation with potential mitigation of pain. However, a causal relationship between the elevation of blood, cerebrospinal fluid or brain betaE levels and the onset of the analgesic action cannot be demonstrated with certainty.

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In adulthood the hypothalamo-pituitary-adrenal axis is controlled by both CRH and arginine vasopressin (AVP). However, in neonates CRH secretion is very low, whereas AVP secretion is fully functional. This suggests that the role of AVP is more pronounced in young than in adult rats. We investigated the role of AVP by studying stress responses in 5, 10, and 20-d-old AVP-deficient Brattleboro rats. Two different stressors were applied: 24-h maternal separation and Hypnorm Grove Oxford UK injections. In heterozygous controls (that do express AVP), both stressors increased plasma ACTH and corticosterone. The ACTH stress response disappeared in AVP-deficient rats, demonstrating that during the perinatal period, the secretion of this hormone is controlled by AVP. Surprisingly, corticosterone responses remained intact in AVP-deficient rats. Similar findings were obtained after 1-, 4-, 12-, and 24-h long maternal separations. Thus, preserved corticosterone stress responses were not explained by changes in the timing of ACTH secretion. In vitro experiments suggested that the dissociation of ACTH and corticosterone stress responses can only be partly explained by higher ACTH responsiveness of the adrenal cortex in AVP-deficient rats. Together, our results show that in neonatal periods, AVP is crucial for the expression of ACTH stress responses, but neither AVP nor ACTH is necessary for the induction of corticosterone stress responses. Discrepant ACTH and corticosterone stress responses may reflect compensatory mechanisms activated by AVP deficiency, but disparate findings suggest that they rather depict a neonate-specific mechanism of hypothalamo-pituitary-adrenal-axis control.

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