Divergent Response to Cannabinoid Receptor Stimulation in High and Low Stress-Induced Analgesia Mouse Lines Is Associated with Differential G-Protein Activation

Leśniak, Anna; Chmielewska, Diana; Poznański, Piotr; Bujalska‐Zadrożny, Magdalena; Strzemecka, Joanna; Sacharczuk, Mariusz

doi:10.1016/j.neuroscience.2019.02.015

Cited by 9 publications

(10 citation statements)

References 54 publications

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“…PAC1-hop1 was also shown to regulate Ca 2+ mobilization and neurosecretion [42][43][44][45] . Such differential signal transduction could affect behavioral phenotypes, as previously demonstrated for other GPCRs [46][47][48][49] . Accordingly, we have previously shown in adult mice that acute foot-shock stressor induces a change in the ratio between PAC1-hop and PAC1-short splice isoforms in the hypothalamic paraventricular nucleus 4 .…”

Section: Generation Of Zebrafish Mutant With Germline Deletion Of Thesupporting

confidence: 55%

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Biran

Gliksberg

Shirat

et al. 2020

Sci Rep

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The pituitary adenylate cyclase-activating polypeptide receptor (PAC1, also known as ADCYAP1R1) is associated with post-traumatic stress disorder and modulation of stress response in general. Alternative splicing of PAC1 results in multiple gene products, which differ in their mode of signalling and tissue distribution. However, the roles of distinct splice variants in the regulation of stress behavior is poorly understood. Alternative splicing of a short exon, which is known as the "hop cassette", occurs during brain development and in response to stressful challenges. To examine the function of this variant, we generated a splice-specific zebrafish mutant lacking the hop cassette, which we designated 'hopless'. We show that hopless mutant larvae display increased anxiety-like behavior, including reduced dark exploration and impaired habituation to dark exposure. Conversely, adult hopless mutants displayed superior ability to rebound from an acute stressor, as they exhibited reduced anxiety-like responses to an ensuing novelty stress. We propose that the developmental loss of a specific PAC1 splice variant mimics prolonged mild stress exposure, which in the long term, predisposes the organism's stress response towards a resilient phenotype. Our study presents a unique genetic model demonstrating how early-life state of anxiety paradoxically correlates with reduced stress susceptibility in adulthood. PAC1 (a.k.a. Adcyap1r1) is a G-protein coupled receptor (GPCR) that serves as the high-affinity receptor for the pituitary adenylate cyclase-activating polypeptide (PACAP). PAC1 has pleiotropic functions and was demonstrated to be involved in the regulation of several homeostatic processes including metabolic rate and food consumption 1,2 , circadian rhythm 3 and, in particular, stress response 4,5. Intracerebroventricular injection of PACAP increased phosphorylated cyclic AMP response element binding protein (pCREB) and corticotropin-releasing hormone (CRH) immunoreactivity in the rat paraventricular nucleus 6. PACAP knockout mice display blunted hypothalamic CRH levels in response to restraint challenge 7. PACAP/PAC1 signaling was also associated with hypothalamo-pituitary-adrenal activity and stress-related behaviors in humans and rodents 5,8,9. Furthermore, this pathway was correlated with stress-related risky behaviors in human and rodents 10,11. Overall, these findings support positive stress regulation by PAC1; yet, some reports suggest that it may also act to suppress stress phenotypes 4,12. It has been suggested that genetic vulnerability to post-traumatic stress disorder (PTSD) may depend on PAC1 expression and single-nucleotide polymorphism (SNP) in the PAC1 gene. Ressler et al. demonstrated that a specific PAC1 genotype is strongly correlated with susceptibility to PTSD in women, probably due to perturbed expression of PAC1 resulting in impaired stress responses 13. The same PAC1 SNP was associated with PTSD in African-American females, emotional numbing in traumatized earthquake Chinese survivors, dark-e...

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Section: Generation Of Zebrafish Mutant With Germline Deletion Of Thesupporting

confidence: 55%

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Biran

Gliksberg

Shirat

et al. 2020

Sci Rep

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“…However, little is known about other non-CB 1 receptor mechanisms in cannabinoid action. We and others have recently reported that functional CB 2 receptors are also expressed in the brain (see a comprehensive review by Jordan & Xi, 2019) and are involved in multiple behavioural effects of Δ 9 -THC or other cannabinoids in experimental animals (DeLong, Wolf, Poklis, & Lichtman, 2010;Lesniak et al, 2019;Liu et al, 2017). Although, little is known if brain CB 2 receptors are also involved in cannabinoidinduced tetrad effects.…”

Section: Introductionmentioning

confidence: 99%

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB₁/CB₂ versus GPR55 receptors

Xiaofei

Galaj

et al. 2020

British J Pharmacology

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Background and Purpose Cannabis or cannabinoids produce characteristic tetrad effects—analgesia, hypothermia, catalepsy and suppressed locomotion, which are believed to be mediated by the activation of cannabinoid CB1 receptors. Given recent findings of CB2 and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action. Experimental Approach We compared Δ9‐tetrahydrocannabinol (Δ9‐THC)‐, WIN55212‐2‐, or XLR11‐induced tetrad effects between wild‐type (WT) and each genotype of CB1‐, CB2‐ or GPR55‐knockout (KO) mice and then observed the effects of antagonists of these receptors on these tetrad effects in WT mice. Key Results Systemic administration of Δ9‐THC, WIN55212‐2 or XLR11 produced dose‐dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB1 receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB2 receptor abolished analgesia and catalepsy produced by Δ9‐THC or WIN55212‐2, but not by XLR11. Microinjections of Δ9‐THC into the lateral ventricles also produced tetrad effects in WT, but not in CB1‐KO mice. CB2‐KO mice displayed a reduction in intraventricular Δ9‐THC‐induced analgesia and catalepsy. In contrast to CB1 and CB2 receptors, genetic deletion of GPR55 receptors caused enhanced responses to Δ9‐THC or WIN55212‐2. Antagonisim of CB1, CB2 or GPR55 receptors produced alterations similar to those observed in each genotype mouse line. Conclusions and Implications These findings suggest that in addition to CB1, both CB2 and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB1/CB2, in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.

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“…In the presented study, we used a complex approach for investigating the undertaken problem, which also resulted in the main limitation of our study, i.e., a relatively low sample size per group ( n = 4–6). However, our previous study showed that this number is minimal sample size for obtaining reliable results from behavioral experiments [ 57 ]. A low number of individuals per group also results in a specific statistical approach, which considers parental variant as one, without dividing it into three separate factors–one per parent.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System

et al. 2021

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The development of alcohol dependence and depression is determined by various genetic and environmental factors. In the presented study, we used high analgesia (HA) and low analgesia (LA) mouse lines, characterized by different endogenous opioid system activity and divergent blood–brain barrier permeability, to determine the influence of cross-fostering of these lines raised by surrogate mothers on ethanol consumption and development of depressive-like behaviors. We also investigated ethanol drinking by biological parents or surrogate mothers. Furthermore, we investigated whether these parental changes would alter the effect of naloxone on ethanol intake and depressive-like behaviors in offspring. Our results reveal that cross-fostering of HA and LA raised by surrogate mothers has a greater impact on depressive-like behaviors than ethanol consumption. Ethanol intake by biological parents substantially affected depressive-like behaviors and ethanol consumption in offspring. Moreover, ethanol intake by biological parents or an adoptive mother modified the effect of naloxone on ethanol consumption and preference and depressive-like behaviors in the HA offspring only. Together, these results indicate that cross-fostering differentially affects the effect of naloxone on alcohol consumption and the development of depression.

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Divergent Response to Cannabinoid Receptor Stimulation in High and Low Stress-Induced Analgesia Mouse Lines Is Associated with Differential G-Protein Activation

Cited by 9 publications

References 54 publications

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB₁/CB₂ versus GPR55 receptors

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System

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Divergent Response to Cannabinoid Receptor Stimulation in High and Low Stress-Induced Analgesia Mouse Lines Is Associated with Differential G-Protein Activation

Cited by 9 publications

References 54 publications

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB1/CB2 versus GPR55 receptors

The Influence of Cross-Fostering on Alcohol Consumption and Depressive-Like Behaviors in HA and LA Mice: The Role of the Endogenous Opioid System

Contact Info

Product

Resources

About

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB₁/CB₂ versus GPR55 receptors