Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance.

Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health–related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

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Abstract

Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.

Journal of Neuroscience, 34 (19) 6647-6658; DOI: https://doi.org/10.1523/JNEUROSCI.5390-13.2014

Cheng Wang1 *, John R. Hipp2,3, Carter T. Butts3,4, Cynthia M. Lakon5 1 Department of Sociology, University of Notre Dame, Notre Dame, IN, United States of America, 2 Department of Criminology, Law and Society, University of California, Irvine, Irvine, CA, United States of America, 3 Department of Sociology, University of California, Irvine, Irvine, CA, United States of America, 4 Department of Statistics, University of California, Irvine, Irvine, CA, United States of America, 5 Program in Public Health, University of California, Irvine, Irvine, CA, United States of America

Abstract: The concurrent or sequential usage of multiple substances during adolescence is a serious public health problem. Given the importance of understanding interdependence in substance use during adolescence, the purpose of this study is to examine the co-evolution of cigarette smoking, alcohol, and marijuana use within the ever-changing landscape of adolescent friendship networks, which are a primary socialization context for adolescent substance use. Utilizing Stochastic Actor-Based models, we examine how multiple simultaneous social processes co-evolve with adolescent smoking, drinking, and marijuana use within adolescent friendship networks using two school samples from early waves of the National Longitudinal Study of Adolescent to Adult Health (Add Health). We also estimate two separate models examining the effects from using one substance to the initiation and cessation of other substances for each sample. 

Based on the initial model results, we simulate the model forward in time by turning off one key effect in the estimated model at a time, and observe how the distribution of use of each substance changes. We find evidence of a unilateral causal relationship from marijuana use to subsequent smoking and drinking behaviors, resulting in the initiation of drinking behavior. 

Marijuana use is also associated with smoking initiation in a school with a low substance use level, and smoking cessation in a school with a high substance use level. In addition, in a simulation model excluding the effect from marijuana use to smoking and drinking behavior, the number of smokers and drinkers decreases precipitously. Overall, our findings indicate some evidence of sequential drug use, as marijuana use increased subsequent smoking and drinking behavior and indicate that an adolescent’s level of marijuana use affects the initiation and continuation of smoking and drinking

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Translational Psychiatry volume 8, Article number: 89 (2018) 

Abstract 

There is a strong association between cannabis use and schizophrenia but the underlying cellular links are poorly understood. Neurons derived from human-induced pluripotent stem cells (hiPSCs) offer a platform for investigating both baseline and dynamic changes in human neural cells. Here, we exposed neurons derived from hiPSCs to Δ9-tetrahydrocannabinol (THC), and identified diagnosis-specific differences not detectable in vehicle-controls. RNA transcriptomic analyses revealed that THC administration, either by acute or chronic exposure, dampened the neuronal transcriptional response following potassium chloride (KCl)-induced neuronal depolarization. THC-treated neurons displayed significant synaptic, mitochondrial, and glutamate signaling alterations that may underlie their failure to activate appropriately; this blunted response resembles effects previously observed in schizophrenia hiPSC- derived neurons. Furthermore, we show a significant alteration in THC-related genes associated with autism and intellectual disability, suggesting shared molecular pathways perturbed in neuropsychiatric disorders that are exacerbated by THC. 

In summary, we found significant associations of THC- related pathways to autism and intellectual disability. Furthermore, we have used a dynamic, human-relevant system to demonstrate a phenotypic link between THC treatment and schizophrenia. We hypothesize that THC exposure, by impacting many of the same synaptic and epigenetic pathways already associated with psychiatric disorders, may serve as an additive risk to existing genetic/ epigenetic risk factors.  

For complete paper

There is a strong association between cannabis use and schizophrenia but the underlying cellular links are poorly understood. Neurons derived from human-induced pluripotent stem cells (hiPSCs) offer a platform for investigating both baseline and dynamic changes in human neural cells. Here, we exposed neurons derived from hiPSCs to Δ9-tetrahydrocannabinol (THC), and identified diagnosis-specific differences not detectable in vehicle-controls. RNA transcriptomic analyses revealed that THC administration, either by acute or chronic exposure, dampened the neuronal transcriptional response following potassium chloride (KCl)-induced neuronal depolarization. THC-treated neurons displayed significant synaptic, mitochondrial, and glutamate signaling alterations that may underlie their failure to activate appropriately; this blunted response resembles effects previously observed in schizophrenia hiPSC- derived neurons. Furthermore, we show a significant alteration in THC-related genes associated with autism and intellectual disability, suggesting shared molecular pathways perturbed in neuropsychiatric disorders that are exacerbated by THC.

Full Article  (cited 26/6/18)

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