Elevation of endocannabinoids in the brain by synthetic cannabinoid JWH-018: mechanism and effect on learning and memory

Li, Renshi; Fukumori, Ryo; Takeda, Tomoki; Song, Yingxia; Morimoto, Satoshi; Kikura‐Hanajiri, Ruri; Yamaguchi, Taku; Watanabe, Kazuhito; Aritake, Kousuke; Tanaka, Yoshitaka; Yamada, Hideyuki; Yamamoto, Tsuneyuki; Ishii, Yuji

doi:10.1038/s41598-019-45969-4

Cited by 10 publications

(12 citation statements)

References 55 publications

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“…Our in vitro electrophysiological analysis in brain slices of mice treated with JWH-018 revealed an impairment in LTP. Previous studies revealed that a single JWH-018 administration induced an impairment in short-(2 h) and longterm (24 h) working memory in mice (Barbieri et al, 2016;Barbieri et al, 2022;Li et al, 2019), in line with preclinical studies demonstrating amnesic properties of either natural or SCBs. These alterations have been associated with CB 1 receptor activation and with the ability of the drug to disrupt hippocampal LTP (Barbieri et al, 2016;Barbieri et al, 2022;Hoffman et al, 2017), although treatment with JWH-018 does not substantially modify the synaptic excitability.…”

Section: Discussionsupporting

confidence: 72%

“…The tail suspension test (TST) is one of the most widely used models for assessing antidepressant‐like behaviours in mice. It was suggested in many studies that the endocannabinoid system, in particular the cannabinoid receptors (CB 1 and CB 2 ) play a significant role in the pathophysiology of depression and stress/anxiety disorders (Li et al, 2019; Maldonado et al, 2020; Poleszak et al, 2020; Smaga et al, 2017). We investigated in a previous study the acute effects of Δ9‐THC and JWH‐018 and its halogenated derivatives on the tail suspension test as a first investigation to reveal their possible actions in affecting stress/anxiety in mice, as suggested by literature (Barbieri et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

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Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH‐018 in male mice

Bilel

Zamberletti

Caffino

et al. 2023

British J Pharmacology

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Background and PurposePsychotic disorders have been reported in long‐term users of synthetic cannabinoids. This study aims at investigating the long‐lasting effects of repeated JWH‐018 exposure.Experimental ApproachMale CD‐1 mice were injected with vehicle, JWH‐018 (6 mg·kg−1), the CB1‐antagonist NESS‐0327 (1 mg·kg−1) or co‐administration of NESS‐0327 and JWH‐018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH‐018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) and their main synthetic and degrading enzymes in the striatum and hippocampus.Key ResultsThe repeated treatment with JWH‐018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH‐018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH‐018, reduced hippocampal CB1 receptor density and induced a long‐term alteration in AEA and 2‐AG levels and their degrading enzymes, FAAH and MAGL, in the striatum.Conclusion and ImplicationsOur findings suggest that repeated administration of a high dose of JWH‐018 leads to the manifestation of psychotic‐like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system.

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Section: Discussionsupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH‐018 in male mice

Bilel

Zamberletti

Caffino

et al. 2023

British J Pharmacology

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“…A decrease in BDNF following JWH-018 treatment was observed in the hippocampus. As previously mentioned, the neurotrophic factor BDNF plays an important role in modulating the learning and memory process, promoting neurogenesis, synaptogenesis [ 109 ], and the alteration of BDNF levels after JWH-018 exposition, which may explain its negative effect on memory performance. Nevertheless, this effect on BDNF release observed with JWH-018 is in contradiction with the effect reported previously with THC administration, where an increased BDNF production was observed.…”

Section: Cannabinoids and Endocannabinoid Systemsmentioning

confidence: 99%

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

Abate

Uberti

Tambaro

2021

Biology

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Alzheimer’s disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy—sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence.

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“…The abuse liabilities of THC and synthetic cannabinoids are usually attributed to their influence on CB 1 receptors expressed in the VTA and NAC, which are major brain regions associated with the development of addiction-related behaviors ( Nestler, 2001 ). Cannabinoids may also affect the expression of CB 2 receptors ( Sun et al, 2017 ), along with enzymes that degrade endocannabinoids ( Li et al, 2019 ). Thus, we measured the mRNA levels of endocannabinoid-related genes in the VTA and NAC of mice repeatedly treated with JWH-018.…”

Section: Resultsmentioning

confidence: 99%

Deletion of Cryab increases the vulnerability of mice to the addiction-like effects of the cannabinoid JWH-018 via upregulation of striatal NF-κB expression

et al. 2023

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Synthetic cannabinoids have exhibited unpredictable abuse liabilities, especially self-administration (SA) responses in normal rodent models, despite seemingly inducing addiction-like effects in humans. Thus, an efficient pre-clinical model must be developed to determine cannabinoid abuse potential in animals and describe the mechanism that may mediate cannabinoid sensitivity. The Cryab knockout (KO) mice were recently discovered to be potentially sensitive to the addictive effects of psychoactive drugs. Herein, we examined the responses of Cryab KO mice to JWH-018 using SA, conditioned place preference, and electroencephalography. Additionally, the effects of repeated JWH-018 exposure on endocannabinoid- and dopamine-related genes in various addiction-associated brain regions were examined, along with protein expressions involving neuroinflammation and synaptic plasticity. Cryab KO mice exhibited greater cannabinoid-induced SA responses and place preference, along with divergent gamma wave alterations, compared to wild-type (WT) mice, implying their higher sensitivity to cannabinoids. Endocannabinoid- or dopamine-related mRNA expressions and accumbal dopamine concentrations after repeated JWH-018 exposure were not significantly different between the WT and Cryab KO mice. Further analyses revealed that repeated JWH-018 administration led to possibly greater neuroinflammation in Cryab KO mice, which may arise from upregulated NF-κB, accompanied by higher expressions of synaptic plasticity markers, which might have contributed to the development of cannabinoid addiction-related behavior in Cryab KO mice. These findings signify that increased neuroinflammation via NF-κB may mediate the enhanced addiction-like responses of Cryab KO mice to cannabinoids. Altogether, Cryab KO mice may be a potential model for cannabinoid abuse susceptibility.

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Elevation of endocannabinoids in the brain by synthetic cannabinoid JWH-018: mechanism and effect on learning and memory

Cited by 10 publications

References 55 publications

Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH‐018 in male mice

Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH‐018 in male mice

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

Deletion of Cryab increases the vulnerability of mice to the addiction-like effects of the cannabinoid JWH-018 via upregulation of striatal NF-κB expression

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