Chronic cannabis use affects cerebellum dependent visuomotor adaptation.

BACKGROUND: Cannabis is one of the most commonly used substances in the world. However, its effects on human cognition are not yet fully understood. Although the cerebellum has the highest density of cannabinoid receptor type 1 (CB1R) in the human brain, literature on how cannabis use affects cerebellar-dependent learning is sparse. This study examined the effect of chronic cannabis use on sensorimotor adaptation, a cerebellar-mediated task, which has been suggested to depend on endocannabinoid signaling. METHODS: Chronic cannabis users (n = 27) with no psychiatric comorbidities and healthy, cannabis-naïve controls (n = 25) were evaluated using a visuomotor rotation task. Cannabis users were re-tested after 1 month of abstinence (n = 13) to assess whether initial differences in performance would persist after cessation of use. RESULTS: Cannabis users showed lower adaptation rates compared to controls at the first time point. However, this difference in performance did not persist when participants were retested after one month of abstinence (n = 13). Healthy controls showed attenuated implicit learning in the late phase of the adaptation during re-exposure, which was not present in cannabis users. This explains the lack of between group differences in the second time point and suggests a potential alteration of synaptic plasticity required for cerebellar learning in cannabis users. CONCLUSIONS: Overall, our results suggest that chronic cannabis users show alterations in sensorimotor adaptation, likely due to a saturation of the endocannabinoid system after chronic cannabis use.

Mid and long-term effects of a SBIRT program for at-risk drinkers attending to an emergency department. Follow-up results from a randomized controlled trial.

BACKGROUND AND IMPORTANCE: SBIRT programs (Screening Brief Intervention and Referral to Treatment) for at-risk drinkers in emergency departments (ED) have shown to be effective, particularly at short term. In this article, we report mid and long-term follow-up results of a specialized SBIRT program. A short-term follow-up after 1.5 months showed encouraging results, with more than a 20% greater reduction of at-risk drinking in the intervention group and more than double of successful referrals to specialized treatment. OBJECTIVE: We aimed to evaluate the mid and long-term efficacy of an SBIRT program conducted by psychiatrist specialists in addictive disorders and motivational interviewing in the ED of a tertiary hospital. DESIGN, SETTINGS AND PARTICIPANTS: We conducted a secondary analysis of a previously published randomized controlled trial of an SBIRT program conducted by alcohol specialists for at-risk drinkers presenting to the ED, measured with the AUDIT-C scale. INTERVENTION OR EXPOSURE: Patients were randomized into two groups, with the control group receiving two leaflets: one regarding alcohol use and the other giving information about the study protocol. The intervention group received the same leaflets as well as a brief motivational intervention on alcohol use and, where appropriate, a referral to specialized treatment. OUTCOMES MEASURE AND ANALYSIS: Long-term assessment primary outcome was the proportion of at-risk alcohol use measured by AUDIT-C scale. The main effectiveness analysis at 18 weeks and 12 months' follow-up was conducted with multilevel logistic regression analyses. Missing values were imputed with the last observation carried forward. MAIN RESULTS: Of 200 patients included in the study, 133 (66.5%) and 131 (65.5%) completed 18 weeks and 1-year follow-up respectively. Although the proportion of risky drinkers was substantially lower in the intervention group (38.5 vs. 57.4% at 4.5 months and 58.5 vs 68.2% at 1 year), these results did not reach statistical significance (OR = 2.15; CI, 0.87-5.33). CONCLUSIONS: In this secondary analysis for mid- and long-term effects of a specialized SBIRT program, there was no significant difference in the reduction of risky drinkers at 18 weeks and 1 year. The small size of the studied sample and the low retention rate precluded any significant conclusion, although point estimates suggest a positive effect. Overall, SBIRT programs are an effective tool to reduce alcohol use at short time and to refer patients to specialized treatment; however, its effects seem to decay over time.

Motor Adaptation Impairment in Chronic Cannabis Users Assessed by a Visuomotor Rotation Task.

Background-The cerebellum has been recently suggested as an important player in the addiction brain circuit. Cannabis is one of the most used drugs worldwide, and its long-term effects on the central nervous system are not fully understood. No valid clinical evaluations of cannabis impact on the brain are available today. The cerebellum is expected to be one of the brain structures that are highly affected by prolonged exposure to cannabis, due to its high density in endocannabinoid receptors. We aim to use a motor adaptation paradigm to indirectly assess cerebellar function in chronic cannabis users (CCUs). Methods-We used a visuomotor rotation (VMR) task that probes a putatively-cerebellar implicit motor adaptation process together with the learning and execution of an explicit aiming rule. We conducted a case-control study, recruiting 18 CCUs and 18 age-matched healthy controls. Our main measure was the angular aiming error. Results-Our results show that CCUs have impaired implicit motor adaptation, as they showed a smaller rate of adaptation compared with healthy controls (drift rate: 19.3 +/- 6.8° vs. 27.4 +/- 11.6°; t(26) = -2.1, p = 0.048, Cohen's d = -0.8, 95% CI = (-1.7, -0.15)). Conclusions-We suggest that a visuomotor rotation task might be the first step towards developing a useful tool for the detection of alterations in implicit learning among cannabis users.

Cerebellar alterations in cannabis users: A systematic review.

Cannabis is the most used illicit substance in the world. As many countries are moving towards decriminalization, it is crucial to determine whether and how cannabis use affects human brain and behavior. The role of the cerebellum in cognition, emotion, learning, and addiction is increasingly recognized. Because of its high density in CB1 receptors, it is expected to be highly affected by cannabis use. The aim of this systematic review is to investigate how cannabis use affects cerebellar structure and function, as well as cerebellar-dependent behavioral tasks. Three databases were searched for peer-reviewed literature published until March 2018. We included studies that focused on cannabis effects on cerebellar structure, function, or cerebellar-dependent behavioral tasks. A total of 348 unique records were screened, and 40 studies were included in the qualitative synthesis. The most consistent findings include (1) increases in cerebellar gray matter volume after chronic cannabis use, (2) alteration of cerebellar resting state activity after acute or chronic use, and (3) deficits in memory, decision making, and associative learning. Age of onset and higher exposure to cannabis use were frequently associated with increased cannabis-induced alterations. Chronic cannabis use is associated with alterations in cerebellar structure and function, as well as with deficits in behavioral paradigms that involve the cerebellum (eg, eyeblink conditioning, memory, and decision making). Future studies should consider tobacco as confounding factor and use standardized methods for assessing cannabis use. Paradigms exploring the functional activity of the cerebellum may prove useful as monitoring tools of cannabis-induced impairment.

Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile.

Mitochondria are a major target for aging and are instrumental in the age-dependent deterioration of the human brain, but studying mitochondria in aging human neurons has been challenging. Direct fibroblast-to-induced neuron (iN) conversion yields functional neurons that retain important signs of aging, in contrast to iPSC differentiation. Here, we analyzed mitochondrial features in iNs from individuals of different ages. iNs from old donors display decreased oxidative phosphorylation (OXPHOS)-related gene expression, impaired axonal mitochondrial morphologies, lower mitochondrial membrane potentials, reduced energy production, and increased oxidized proteins levels. In contrast, the fibroblasts from which iNs were generated show only mild age-dependent changes, consistent with a metabolic shift from glycolysis-dependent fibroblasts to OXPHOS-dependent iNs. Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs. Our data indicate that iNs are a valuable tool for studying mitochondrial aging and support a bioenergetic explanation for the high susceptibility of the brain to aging.

Tyrosine phosphorylation of Munc18-1 inhibits synaptic transmission by preventing SNARE assembly.

Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18-1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho-proteomics abolished the stimulatory effect of Munc18-1 on SNARE complex formation ("SNARE-templating") and membrane fusion in vitro Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18-1-null neurons expressing Munc18-1Y473D Synaptic transmission was temporarily restored by high-frequency stimulation, as well as by a Munc18-1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming. On the other hand, expression of non-phosphorylatable Munc18-1 supported normal synaptic transmission. We propose that SFK-dependent Munc18-1 phosphorylation may constitute a potent, previously unknown mechanism to shut down synaptic transmission, via direct occlusion of a Synaptobrevin/VAMP2 binding groove and subsequent hindrance of conformational changes in domain 3a responsible for vesicle priming. This would strongly interfere with the essential post-docking SNARE-templating role of Munc18-1, resulting in a largely abolished pool of releasable synaptic vesicles.