Sex and stressor modality influence acute stress-induced dynamic changes in corticolimbic endocannabinoid levels in adult Sprague Dawley rats

Vecchiarelli, Haley A.; Morena, Maria; Lee, Tiffany TY; Nastase, Andrei S.; Aukema, Robert J.; Leitl, Kira D.; Gray, Jennifer M.; Petrie, Gavin N; J.Tellez-Monnery, Kristin; Hill, Matthew N.

doi:10.1016/j.ynstr.2022.100470

Cited by 14 publications

(9 citation statements)

References 61 publications

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“…Investigating sex differences is an important part of understanding neural physiology, especially in the context of stress. However, previous work has provided evidence for both sexes exhibiting similar eCB responses to stress (Vecchiarelli et al, 2022), and the ability of AM251 to increase CORT levels during the daily trough of the HPA axis (which was when we tested mice in the current study) is seen in both males and females (Atkinson et al, 2010).…”

Section: Discussionmentioning

confidence: 47%

Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response

Petrie

Balsevich

Füzesi

et al. 2023

British J Pharmacology

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Background and PurposeEndocannabinoid (eCB) signalling gates many aspects of the stress response, including the hypothalamic‐pituitary‐adrenal (HPA) axis. The HPA axis is controlled by corticotropin releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood.Experimental ApproachUsing an array of cellular, endocrine and behavioral readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signaling to the generation of a stress response.Key ResultsThe CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243, and NAPE PLD inhibitor LEI401 all uniformly increased Fos in the PVN, unmasked stress‐linked behaviors, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress‐like behavioral changes produced by disruption of eCB signaling.Conclusions and ImplicationsThese data indicate that under resting conditions, constitutive eCB signaling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN.

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Section: Discussionmentioning

confidence: 47%

Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response

Petrie

Balsevich

Füzesi

et al. 2023

British J Pharmacology

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“…For the main outcome variables of eCB/NAE plasma concentrations, we used analyses of covariance (ANCOVAs) with GROUP as the fixed factor to control for the confounding variables sex [64], age [65], and recent cannabis use, i.e., THC and CBD plasma levels as well as current alcohol dependence based on their previously reported influences on 2-AG [53,66].…”

Section: Discussionmentioning

confidence: 99%

Plasma endocannabinoids in cocaine dependence and their interaction with cocaine craving and metabotropic glutamate receptor 5 density in the human brain

Kroll

Hulka

Kexel

et al. 2023

Preprint

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Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N=103; 69 recreational CU and 34 dependent CU) and stimulant-naive healthy controls (N=92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N=33; controls: N=43). In an additional analysis using 11C-ABP688 positron emission tomography (PET) in a male subsample (CU: N=18; controls: N=16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence.

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“…LC/MS was conducted as in [ 32 ]. Briefly, samples were homogenized in 2 ml of acetonitrile with 5 pmol d8-AEA (Cayman Chemical Company, Ann Arbor, Michigan, USA, #390050) in a borosilicate glass tube with a glass rod.…”

Section: Methodsmentioning

confidence: 99%

CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats

Huckleberry

Calitri

et al. 2023

Neuropsychopharmacol.

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Increasing evidence suggests that the neurobiological processes that govern learning and memory can be different in males and females, but many of the specific mechanisms underlying these sex differences have not been fully defined. Here we investigated potential sex differences in endocannabinoid (eCB) modulation of Pavlovian fear conditioning and extinction, examining multiple defensive behaviors, including shock responsivity, conditioned freezing, and conditioned darting. We found that while systemic administration of drugs acting on eCB receptors did not influence the occurrence of darting, females that were classified as Darters responded differently to the drug administration than those classified as Non-darters. Most notably, CB1R antagonist AM251 produced an increase in cue-elicited freezing and context generalization selectively in female Non-darters that persisted across extinction and extinction retrieval tests but was prevented by co-administration of TRPV1R antagonist Capsazepine. To identify a potential synaptic mechanism for these sex differences, we next employed biochemical and neuroanatomical tracing techniques to quantify anandamide (AEA), TRPV1R, and perisomatic CB1R expression, focusing on the ventral hippocampus (vHip) given its known role in mediating contextual fear generalization. These assays identified sex-specific effects of both fear conditioning-elicited AEA release and vHip-BLA circuit structure. Together, our data support a model in which sexual dimorphism in vHip-BLA circuitry promotes a female-specific dependence on CB1Rs for context processing that is sensitive to TRPV1-mediated disruption when CB1Rs are blocked.

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Sex and stressor modality influence acute stress-induced dynamic changes in corticolimbic endocannabinoid levels in adult Sprague Dawley rats

Cited by 14 publications

References 61 publications

Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response

Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response

Plasma endocannabinoids in cocaine dependence and their interaction with cocaine craving and metabotropic glutamate receptor 5 density in the human brain

CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats

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