ThePineapple - Journal Club #51: Endothelial dysfunction | CB1 | thyroid | goal-directed behavior

Journal Club #52: Endothelial dysfunction, CB1, thyroid, goal-directed behavior

Week of 07-31-22

This week we have a number of interesting new cannabis science papers to share with you. First on the list is a paper on the effects of marijuana on endothelial dysfunction. This higher impact paper is of particular interest, as it relates both to the findings on the cardiovascular effects of cannabis consumption that were published in CELL a couple of weeks ago, as well as findings on CBD in the context of COVID. 
The next paper on the list is another high impact paper. This one expands the knowledge on the mechanisms of cannabinoid receptor CB1. Followed by a paper suggesting CBD may have beneficial effects on hypothyroidism. And last but not least we have a behavioral study providing evidence that CBD decreases goal-directed behavior. Well, that last one sort of feeds straight into your average pothead cliches. So, ultimately it might not be hugely surprising that cannabinoid treatment produces somewhat chilled-out mice as well. Hope you’ll enjoy this journal club selection. See you next time.

Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid system.

Marijuana and endothelial dysfunction: new mechanism and therapy. 

Feng X, Xu S, Weng J. 

Trends Mol Med. 2022 Aug;28(8):613-615. 

Marijuana (cannabis) can cause cardiovascular side effects, yet the mechanisms and treatments remain poorly understood. In a recent study published in Cell, Wei et al. discovered that soy isoflavone genistein attenuates Δ9-tetrahydrocannabinol (Δ9-THC, a main constituent from marijuana)-induced endothelial dysfunction and atherosclerosis by directly antagonizing peripheral cannabinoid receptor 1, demonstrating a therapeutic potential for ameliorating the cardiovascular side effects of cannabis.

doi: 10.1016/j.molmed.2022.05.009. Epub 2022 Jun 11. PMID: 35701315.

Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.

Yang X, Wang X, Xu Z, Wu C, Zhou Y, Wang Y, Lin G, Li K, Wu M, Xia A, Liu J, Cheng L, Zou J, Yan W, Shao Z, Yang S. 

Nat Chem Biol. 2022 Aug;18(8):831-840. 

Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators.

doi: 10.1038/s41589-022-01038-y. Epub 2022 May 30. PMID: 35637350.

Cannabidiol improves thyroid function via modulating vitamin D3 receptor in vitamin D3 deficiency diet-induced rat model

Trivedi MK, Mondal S, Jana S.

J Food Sci Technol. 2022 Aug;59(8):3237-3244. 

The study was evaluated the impact of cannabidiol (CBD) on thyroid hormones by modulation cannabinoid receptor-2 (CB2) and vitamin D receptor (VDR) in rats fed with vitamin D3 deficiency diet (VDD). CB2-receptors were analyzed by RT-PCR method and others biomarkers by ELISA. The relative expression of CB2 (thyroid ~ 4 folds), VDR protein (liver, 151.72%), and (kidney, 66%) was significantly increased in CBD-60 compared to VDD. Vitamin D3 metabolites were significantly increased serum (189.42%), kidney (73.84%), and liver (58.11%) in CBD-60 than VDD. Increased thyroxine (59.9%) and calcitonin (213.59%); while decreased thyroid-stimulating hormone (36.15%) and parathyroid hormone (38.64%) was observed CBD treatment in VDD rats. In conclusion, CBD treatment improves CB2 and VDR expression and the level of vitamin D3 metabolites, along with improved thyroid hormones, including calcitonin. This is the first report with an improved CB2 and VDR expression after CBD treatment in VDD induced animals. Thus, CBD can be considered to use in hypothyroidism conditions and to maintain bone health.

doi: 10.1007/s13197-022-05492-3. Epub 2022 Jun 23. PMID: 35872737; PMCID: PMC9304503.

Cannabidiol (CBD) drives sex-dependent impairments in omission, but has no effect on reinforcer devaluation.

Morehouse C, Maddox CJ, van der Merwe RK, McLaughlin R, Scott JR, Ghanem M, Ramsson E, Howard CD.

Behav Brain Res. 2022 Jul 25:114023.

Habits are inflexible behaviors that persist despite changes in outcome value. While habits allow for efficient responding, neuropsychiatric diseases such as drug addiction and obsessive-compulsive disorder are characterized by overreliance on habits. Recently, the commercially popular drug cannabidiol (CBD) has emerged as a potential treatment for addictive behaviors, though it is not entirely clear how it exerts this therapeutic effect. As brain endocannabinoids play a key role in habit formation, we sought to determine how CBD modifies goal-directed behaviors and habit formation. To explore this, mice were administered CBD (20mg/kg i.p.) or vehicle as a control and trained on random interval (RI30/60) or random ratio (RR10/20) schedules designed to elicit habitual or goal-directed lever pressing, respectively. Mice were tested for habitual responding using probe trials following reinforcer-specific devaluation as well as omission trials, where mice had to withhold responding to earn rewards. We found that while CBD had little effect on operant behaviors or reward devaluation, CBD inhibited goal-directed behavior in a sex-specific and contextdependent manner during the omission task. Beyond drug treatment, we found an effect of sex throughout training, reward devaluation, and omission. This work provides evidence that CBD has no effect on habit formation in a reward devaluation paradigm. However, the omission results suggest that CBD may slow learning of novel actionoutcome contingencies or decrease goal-directed behavior. This work calls for further examination of sex-dependent outcomes of CBD treatment and highlights the importance of investigating sex effects in habit-related experiments.

doi: 10.1016/j.bbr.2022.114023. Epub ahead of print. PMID: 35901956.