Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses

Steiner, Michel; Marsicano, Giovanni; Wotjak, Carsten T.; Lutz, Beat

doi:10.1016/j.psyneuen.2008.06.004

Cited by 71 publications

(44 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, chronic exposure to the CB1 receptor agonist WIN55,212-2 during adolescence attenuated 5-HTergic activity and elicited a depressive-like phenotype in adulthood, further supporting the importance of adolescence as a highly sensitive developmental window within which the disruptive effects of cannabinoid exposure increase the risk for developing psychiatric disorders [145]. Interestingly, inhibition of CB1 receptor signaling induced a depressivelike phenotype in mice, which was mediated by an impairment of 5-HTergic neural activity [152,153,[184][185][186], strenghening the role of the endocannabinoid tone in emotional behaviour through the modulation of the 5-HTergic neurotransmission. As described for conventional antidepressants, which induce a desensitization of the 5-HT 2A/C autoreceptors and/or an enhancement of the tonic activity of 5-HT 1A receptors [187], the antidepressant-like effects elicited by cannabinoids could be due to changes in the expression and function of these receptors [128,188].…”

Section: Effects Of Pharmacological Manipulation Of the Endocannabinomentioning

confidence: 86%

“…1). While CB1 receptor activation inhibits HPA axis activity, as a part of the HPA axis negative feedback inhibition loop, impairment in the CB1 receptor signaling increases HPA axis activity under both basal conditions and following stress exposure [152,[220][221][222]. Collectively the data described above suggests that the antidepressant-like effects of different classes of cannabinoids may in part be due to molecular mechanisms which resemble the ones triggered by antidepressants.…”

Section: Effects Of Pharmacological Manipulation Of the Endocannabinomentioning

confidence: 92%

“…Although the CB1 receptor antagonist rimonabant, which was introduced into clinical practice as antiobesity agent, was withdrawn from the market due to the higher incidence of psychiatric side effects [147], preclinical studies have reported an antidepressant-like activity of rimonabant in rodents [129,130,[148][149][150][151]. Using a genetic approach controversial results regarding the effects of CB1 receptor signaling inhibition on stress coping behaviour have been obtained indicating that they could depend on specific deletion of CB1 receptors in some neuronal subpopulations [129,152,153]. However, compensatory mechanisms which develop in mutant mice could underlie the discrepancies between pharmacological and genetic inhibition of CB1 receptor signaling.…”

Section: Effects Of Pharmacological Manipulation Of the Endocannabinomentioning

confidence: 99%

See 2 more Smart Citations

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

Micale

Tabiová

Kučerová

et al. 2015

Cannabinoid Modulation of Emotion, Memory, and Motivation

View full text Add to dashboard Cite

The endogenous cannabinoid system (ECS) works as pro-homeostatic and pleiotropic signaling system activated in a time-and tissue-specific way during physiological conditions, which include cognitive, emotional and motivational processes. It is composed of two G protein-coupled receptors (the cannabinoid receptors types 1 and 2 [CB1 and CB2] for marijuana's psychoactive ingredient Δ9-tetrahydrocannabinol [Δ9-THC]), their endogenous small lipid ligands (anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and deactivation. Data from preclinical and clinical studies have reported that a hypofunction of the endocannabinoid signaling could induce a depressive-like phenotype; consequently, enhancement of endocannabinoid signaling could be a novel therapeutic avenue for the treatment of depression. To this aim there have been proposed cannabinoid receptor agonists or synthetic molecules that inhibit endocannabinoid degradation. The latter ones do not induce the psychotropic side effects by direct CB1 receptor activation, but rather elicit antidepressant-like effects by enhancing the monoaminergic neurotransmission, promoting hippocampal neurogenesis and normalizing the hyperactivity of hypothalamic-pituitary-adrenal axis, similarly as the standard antidepressants. The dysfunction of elements belonging to the ECS and the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in depression is discussed in this chapter.

show abstract

Section: Effects Of Pharmacological Manipulation Of the Endocannabinomentioning

confidence: 86%

Section: Effects Of Pharmacological Manipulation Of the Endocannabinomentioning

confidence: 92%

Section: Effects Of Pharmacological Manipulation Of the Endocannabinomentioning

confidence: 99%

See 1 more Smart Citation

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

Micale

Tabiová

Kučerová

et al. 2015

Cannabinoid Modulation of Emotion, Memory, and Motivation

View full text Add to dashboard Cite

show abstract

“…The stress-induced reduction in hippocampal anandamide may be mediated by increased levels of glucocorticoids since recent work has shown that a single acute administration of corticosterone to rats results in reduced tissue levels of anandamide in the hippocampus 18 hours later. Finally, an interesting study by Steiner et al (2008c) demonstrated that conditional mutant mice lacking CB 1 Aberrant regulation of neurochemical and neuroendocrine responses to stress is believed to play a key role in the precipitation, maintenance and/or exacerbation of a number of psychiatric and neurological disorders including anxiety, depression and chronic pain. Preclinical work utilising animal models of behavioural stress coping have illuminated our understanding of the receptor expression in principal forebrain neurons (CaMK-CB1(-/-)) exhibit increased forced swim stress-induced corticosterone secretion compared with wildtype controls.…”

Section: Regulation Of the Hpa Axis By The Endocannabinoid Systemmentioning

confidence: 99%

Endocannabinoid-mediated modulation of stress responses: Physiological and pathophysiological significance

Finn¹

2010

Immunobiology

View full text Add to dashboard Cite

The stress response is associated with a broad spectrum of physiological and behavioural effects including hypothalamo-pituitary-adrenal (HPA) axis activation, altered central nervous system activity, neuroimmune alterations, anxiety-and depressive-like behaviour and analgesia. While the acute stress response has essential survival value, chronic stress and dysfunction of the stress response can be maladaptive, contributing to the development and severity of psychiatric and pain disorders. The endogenous cannabinoid (endocannabinoid) system has emerged as an important lipid signalling system playing a key role in mediating and/or modulating behavioural, neurochemical, neuroendocrine, neuroimmune and molecular responses to stress. The weight of evidence, reviewed here, points largely to a system which serves to constrain HPA axis activity, facilitate adaptation or habituation of HPA axis and behavioural responses to stress, reduce anxiety-and depressive-like behaviour and mediate analgesic responses to unconditioned or conditioned stress. Possible involvement of the immune system and associated signalling molecules (e.g. cytokines) in endocannabinoid-mediated modulation of neuroendocrine and behavioural responses to stress is considered. The goal now should be to exploit our understanding of the role of the endocannabinoid system in fundamental stress physiology and pathophysiological processes to better understand and treat a range of stress-related disorders including anxiety, depression and pain.

show abstract

“…Disruption of endocannabinoid signaling increases the activity of the HPA axis (13,14), which could involve a loss of inhibitory regulation of excitatory neurotransmission within the neural stress circuit (15). A growing body of evidence suggests that endocannabinoid signaling also contributes to the process of stress habituation (8).…”

mentioning

confidence: 99%

Endogenous cannabinoid signaling is essential for stress adaptation

Hill¹,

McLaughlin²,

Bingham

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

301

232

View full text Add to dashboard Cite

Secretion of glucocorticoid hormones during stress produces an array of physiological changes that are adaptive and beneficial in the short term. In the face of repeated stress exposure, however, habituation of the glucocorticoid response is essential as prolonged glucocorticoid secretion can produce deleterious effects on metabolic, immune, cardiovascular, and neurobiological function. Endocannabinoid signaling responds to and regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis that governs the secretion of glucocorticoids; however, the role this system plays in adaptation of the neuroendocrine response to repeated stress is not well characterized. Herein, we demonstrate a divergent regulation of the two endocannabinoid ligands, N-arachidonylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), following repeated stress such that AEA content is persistently decreased throughout the corticolimbic stress circuit, whereas 2-AG is exclusively elevated within the amygdala in a stress-dependent manner. Pharmacological studies demonstrate that this divergent regulation of AEA and 2-AG contribute to distinct forms of HPA axis habituation. Inhibition of AEA hydrolysis prevented the development of basal hypersecretion of corticosterone following repeated stress. In contrast, systemic or intra-amygdalar administration of a CB 1 receptor antagonist before the final stress exposure prevented the repeated stress-induced decline in corticosterone responses. The present findings demonstrate an important role for endocannabinoid signaling in the process of stress HPA habituation, and suggest that AEA and 2-AG modulate different components of the adrenocortical response to repeated stressor exposure.corticosterone | endocannabinoid | habituation | hypothalamic-pituitaryadrenal axis | amygdala

show abstract

Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses

Cited by 71 publications

References 20 publications

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

Endocannabinoid-mediated modulation of stress responses: Physiological and pathophysiological significance

Endogenous cannabinoid signaling is essential for stress adaptation

Contact Info

Product

Resources

About