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Background and Purpose: Activation of CB1 by exogenous agonists causes adverse effects in vivo. Positive allosteric modulation may offer improved therapeutic potential and a reduced on‐target adverse effect profile compared with orthosteric agonists, due to reduced desensitisation/tolerance, but this has not been directly tested. This study investigated the ability of PAMs/ago‐PAMs to induce receptor regulation pathways, including desensitisation and receptor internalisation. Experimental Approach: Bioluminescence resonance energy transfer (BRET) assays in HEK293 cells were performed to investigate G protein dissociation, ERK1/2 phosphorylation and β‐arrestin 2 translocation, while immunocytochemistry was performed to measure internalisation of CB1 in response to the PAMs ZCZ011, GAT229 and ABD1236 alone and in combination with the orthosteric agonists AEA, 2‐AG, and AMB‐FUBINACA. Key Results: ZCZ011, GAT229 and ABD1236 were allosteric agonists in all pathways tested. The ago‐PAM ZCZ011 induced a biphasic ERK1/2 phosphorylation time course compared to transient activation by orthosteric agonists. In combination with 2‐AG but not AEA or AMB‐FUBINACA, ZCZ011 and ABD1236 caused the transient peak of ERK1/2 phosphorylation to become sustained. All PAMs increased the potency and efficacy of AEA‐induced signalling in all pathways tested; however, no notable potentiation of 2‐AG or AMB‐FUBINACA was observed. Conclusion and Implications: Ago‐PAMs can potentiate endocannabinoid CB1 agonism by AEA to a larger extent compared with 2‐AG. However, all compounds were found to be allosteric agonists and induce activation of CB1 in the absence of endocannabinoid, including β‐arrestin 2 recruitment and internalisation. Thus, the spatiotemporal signalling of endogenous cannabinoids will not be retained in vivo. [ABSTRACT FROM AUTHOR]

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

While the opioid crisis has justifiably occupied news headlines, emergency rooms are seeing many thousands of visits for another cause: cannabinoid toxicity. This is partly due to the spread of cheap and extremely potent synthetic cannabinoids that can cause serious neurological and cardiovascular complications—and deaths—every year. While an opioid overdose can be reversed by naloxone, there is no analogous treatment for cannabis toxicity. Without an antidote, doctors rely on sedatives, with their own risks, or 'waiting it out' to treat these patients. We have shown that the canonical synthetic 'designer' cannabinoids are highly potent CB1 receptor agonists and, as a result, competitive antagonists may struggle to rapidly reverse an overdose due to synthetic cannabinoids. Negative allosteric modulators (NAMs) have the potential to attenuate the effects of synthetic cannabinoids without having to directly compete for binding. We tested a group of CB1 NAMs for their ability to reverse the effects of the canonical synthetic designer cannabinoid JWH018 in vitro in a neuronal model of endogenous cannabinoid signaling and also in vivo. We tested ABD1085, RTICBM189, and PSNCBAM1 in autaptic hippocampal neurons that endogenously express a retrograde CB1-dependent circuit that inhibits neurotransmission. We found that all of these compounds blocked/reversed JWH018, though some proved more potent than others. We then tested whether these compounds could block the effects of JWH018 in vivo, using a test of nociception in mice. We found that only two of these compounds—RTICBM189 and PSNCBAM1—blocked JWH018 when applied in advance. The in vitro potency of a compound did not predict its in vivo potency. PSNCBAM1 proved to be the more potent of the compounds and also reversed the effects of JWH018 when applied afterward, a condition that more closely mimics an overdose situation. Lastly, we found that PSNCBAM1 did not elicit withdrawal after chronic JWH018 treatment. In summary, CB1 NAMs can, in principle, reverse the effects of the canonical synthetic designer cannabinoid JWH018 both in vitro and in vivo, without inducing withdrawal. These findings suggest a novel pharmacological approach to at last provide a tool to counter cannabinoid toxicity. [ABSTRACT FROM AUTHOR]

Accident, infection, surgery, or stroke resulting in brain trauma can leave individuals with significant and pervasive cognitive disabilities. The need to increase fiinctional recovery for these individuals challenges the combined knowledge, skills, and vision across disciplines including neuropsychology, rehabilitation psychology, occupational therapy, speech pathology, and computer science. This paper reports such interdisciplinary research to develop an approach to computer-assisted retraining that can support and encourage patients' own efforts to take charge of their lives again and rebuild their cognitive skills and thereby enhance their vocational and social opportunities. The Adaptable Learning Environment for Rehabilitation Training (ALERT) will track user performance levels, interest, preferences, and progress within an environment that uses Virtual Reality for life-skill simulations and activities to functionally model cognitive task domains. A single standardized assessment method is being designed to collect information about cognitive variables in the context of mediating and support variables. The functional developmental model of recovery upon which ALERT is based will use the ongoing assessment as it updates the patient user model within the intelligent tutoring system to guide the suggestions for treatment at each successive stage.

Background: The endocannabinoid system has demonstrated roles in Alzheimer's Disease (AD), such as modulation of inflammation. Fatty Acid Amide Hydrolase (FAAH) is the enzyme responsible for the rapid inactivation of the endocannabinoid anandamide into arachidonic acid and ethanolamine. In doing so, FAAH modulates the concentration of anandamide and influences neurobehavioral functions and physiological conditions such as nociception and inflammatory responses. A missense single nucleotide polymorphism in the FAAH gene rs324420‐A>C (Minor allele frequency = 26.4%) is associated with higher levels of anandamide, reduced susceptibility to PTSD and increased risk of substance use disorders. However, the relationship between rs324420 and AD progression has not been explored. In AD, FAAH methylation is lower resulting in increased activity, and FAAH inhibition is suggested to drive microglial polarisation towards anti‐inflammatory phenotypes. rs324420 increases proteolytic degradation, thus reducing functionality of FAAH. Due to lowered FAAH activity, we hypothesise that rs324420 minor allele carriers will have slower neurodegeneration and slower cognitive decline in AD. Methods: This retrospective, longitudinal, observational study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Patients diagnosed with mild cognitive impairment or mild AD (MCI or AD) from ADNI2/GO/3 were selected. Linear regression models evaluated baseline differences between rs324420 minor allele carriers (AC/CC) and major allele homozygotes (AA) controlling for sex, age, baseline cognitive status, APOE‐e4 status and baseline intracranial volume. Longitudinal associations were assessed as interactions between SNP and visit number (baseline to 48 months) in mixed models. Results: In Aβ‐positive patients with AD or MCI, carrying the rs324420 minor allele was associated with smaller nucleus accumbens volume (F(1,311) = 15.7, p = 0.018) at baseline. Longitudinally, several brain regions showed less volumetric decline in minor allele carriers over 48 months: caudal anterior cortex (F(1,163) = 5.18, p = 0.024), fusiform gyrus (F(1,85.6) = 5.28, p = 0.024), rostral anterior cortex (F(1,59.9) = 6.41, p = 0.014) and nucleus accumbens (F(1,84.7) = 4.75, p = 0.032). Carriers of the minor allele also showed less decline MMSE score over 48 months (F(1,544.15) = 5.13, p = 0.024). Conclusions: Slower rates of cognitive and neuroanatomical decline in amyloid positive patients with MCI or mild dementia due to AD suggest a potential protective role of the rs324420 minor allele in the FAAH gene. Further investigation is warranted, including cognitive, anatomical, fluid biomarker and neuropsychiatric symptom profiles. [ABSTRACT FROM AUTHOR]