In this week’s journal club, we have 3 papers on cannabinoid receptors and one on the gut-brain axis. More specifically, we have selected a paper on the effects of cannabinoid receptor 1 and 2 agonist on emotion; a paper on cannabinoid receptor 2 in the context of encephalopathy; a study on the distribution of cannabinoid receptors 1 in the cortex; and finally a study on how the gut-microbiota-brain axis plays a role in the development of psychosis after cannabis exposure. Have fun!
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.
Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior.
Farinha-Ferreira M, Rei N, Fonseca-Gomes J, Miranda-Lourenço C, Serrão P, Vaz SH, Gomes JI, Martins V, de Alves Pereira B, Sebastião AM.
Neuropharmacology. 2022 Aug 15;214:109155.
Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely Δ9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both. Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics.
doi: 10.1016/j.neuropharm.2022.109155. Epub 2022 Jun 2. PMID: 35660545.
Protective Effects of Cannabinoid Type 2 Receptor Activation Against Microglia Overactivation and Neuronal Pyroptosis in Sepsis-Associated Encephalopathy.
Yang L, Li Z, Xu Z, Zhang B, Liu A, He Q, Zheng F, Zhan J.
Neuroscience. 2022 Jun 15;493:99-108.
Sepsis-associated encephalopathy (SAE) has close association with long-term cognitive deficits, resulting in increased mortality. The mechanism of SAE is complicated, including excessive microglial activation and neuroinflammation. Cannabinoid type 2 receptor (CB2R) has been proved to be effective in neuronal protection and survival promotion. Microglia play a role in CB2R mediated neuronal protection when neurons are exposed to noxious stimuli. Pyroptosis is a type of programmed proinflammatory cell death. However, the underlying mechanisms involved in this process still remain to be explored. Here, the SAE model was derived from cecal ligation and puncture (CLP). Tests used to evaluate behavior phenotypes included the open-field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assays (ELISA), Western blotting, and immunofluorescence staining were performed to detect cell injury, cytokine, CB2R and pyroptosis-associated protein expression. Conclusion from these results, we conclude that CLP could induce microglia hyperactivation and neuronal pyroptosis, aggravating brain tissue destruction and cognitive dysfunction. The CB2R-specific agonist HU308 could have protective effects against SAE by inhibiting microglia activity and neuronal pyroptosis. This study provides a new therapeutic option for the treatment of SAE.
doi: 10.1016/j.neuroscience.2022.04.011. Epub 2022 Apr 20. PMID: 35460837.
Cell type specific cannabinoid CB1 receptor distribution across the human and non-human primate cortex.
Chou S, Ranganath T, Fish KN, Lewis DA, Sweet RA.
Sci Rep. 2022 Jun 10;12(1):9605.
Alterations in cannabinoid CB1 receptor (CB1R) are implicated in various psychiatric disorders. CB1R participates in both depolarization induced suppression of inhibition (DSI) and depolarization induced suppression of excitation (DSE), suggesting its involvement in regulating excitatory and inhibitory (E/I) balance. Prior studies examining neuronal cell type specific CB1R distribution have been conducted near exclusively within rodents. Identification of these distribution patterns within the human and non-human primate cortex is essential to increase our insight into its function. Using co-labeling immunohistochemistry and fluorescent microscopy, we examined CB1R protein levels within excitatory and inhibitory boutons of male human and non-human primate prefrontal cortex and auditory cortices, regions involved in the behavioral effects of exogenous cannabinoid exposures. We found that CB1R was present in both bouton populations within all brain regions examined in both species. Significantly higher CB1R levels were found within inhibitory than within excitatory boutons across all regions in both species, although the cell type by brain region interactions differed between the two species. Our results support the importance of conducting more in-depth CB1R examinations to understand how cell type and brain region dependent differences contribute to regional E/I balance regulation, and how aberrations in CB1R distribution may contribute to pathology.
doi: 10.1038/s41598-022-13724-x. PMID: 35688916.
Gut-microbiota-brain axis in the vulnerability to psychosis in adulthood after repeated cannabis exposure during adolescence.
Wan X, Eguchi A, Qu Y, Yang Y, Chang L, Shan J, Mori C, Hashimoto K.
Eur Arch Psychiatry Clin Neurosci. 2022 Jun 6.
Increasing epidemiological evidence shows that the use of cannabis during adolescence could increase the risk for psychosis in adulthood. However, the precise mechanisms underlying long-lasting cannabis-induced risk for psychosis remain unclear. Accumulating evidence suggests the role of gut microbiota in the pathogenesis of psychiatric disorders. Here, we examined whether gut microbiota plays a role in the risk for psychosis of adult after exposure of cannabinoid (CB) receptor agonist WIN55,212-2 during adolescence. Repeated administration of WIN55,212-2 (2 mg/kg/day) during adolescence (P35-P45) significantly increased the expression of Iba1 (ionized calcium-binding adapter molecule 1) in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of adult mice after administration of lipopolysaccharide (LPS: 0.5 mg/kg). In contrast, there were no changes in blood levels of pro-inflammatory cytokines between the two groups. Although alpha-diversity and beta-diversity of gut microbiota were no differences between the two groups, there were several microbes altered between the two groups. Interestingly, there were significant correlations between the relative abundance of microbiota and Iba1 expression in the mPFC and NAc. Furthermore, there were also significant correlations between the relative abundance of microbiota and several metabolites in the blood. These findings suggest that gut microbiota may play a role in the microglial activation in the mPFC and NAc of adult mice after repeated WIN55,212-2 exposure during adolescence. Therefore, it is likely that gut-microbiota-microglia crosstalk might play a role in increased risk for psychosis in adults with cannabis use during adolescence.
doi: 10.1007/s00406-022-01437-1. Epub ahead of print. PMID: 35666299.