Miswiring the brain: Δ9‐tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin‐2 degradation pathway

Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ⁹‐tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor‐driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB₁ cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC‐sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin‐2, a microtubule‐binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis‐exposed fetuses, defining SCG10 as the first cannabis‐driven molecular effector in the developing cerebrum. CB₁ cannabinoid receptor activation recruits c‐Jun N‐terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.     

Moving around the molecule: Relationship between chemical structure and in vivo activity of synthetic cannabinoids

Originally synthesized for research purposes, indole- and pyrrole-derived synthetic cannabinoids are the most common psychoactive compounds contained in abused products marketed as “spice” or “herbal incense.” While CB₁ and CB₂ receptor affinities are available for most of these research chemicals, in vivo pharmacological data are sparse. In mice, cannabinoids produce a characteristic profile of dose-dependent effects: antinociception, hypothermia, catalepsy and suppression of locomotion. In combination with receptor binding data, this tetrad battery has been useful in evaluation of the relationship between the structural features of synthetic cannabinoids and their in vivo cannabimimetic activity. Here, published tetrad studies are reviewed and additional in vivo data on synthetic cannabinoids are presented. Overall, the best predictor of likely cannabimimetic effects in the tetrad tests was good CB₁ receptor affinity. Further, retention of good CB₁ affinity and in vivo activity was observed across a wide array of structural manipulations of substituents of the prototypic aminoalkylindole molecule WIN55,212-2, including substitution of an alkyl for the morpholino group, replacement of an indole core with a pyrrole or phenylpyrrole, substitution of a phenylacetyl or tetramethylcyclopropyl group for JWH-018's naphthoyl, and halogenation of the naphthoyl group. This flexibility of cannabinoid ligand–receptor interactions has been a particular challenge for forensic scientists who have struggled to identify and regulate each new compound as it has appeared on the drug market. One of the most pressing future research needs is determination of the extent to which the pharmacology of these synthetic cannabinoids may differ from those of classical cannabinoids.     

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation

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Perceived morningness–eveningness predicts academic adjustment and substance use across university,but social jetlag is not to blame

Past research has consistently found that evening-types typically report poorer academic adjustment and higher levels of substance use compared to morning-types. An important development within the morningness–eveningness and psychosocial adjustment literature has been the hypothesis that social jetlag (i.e. the asynchrony between an individual’s “biological” and “social” clocks) is one factor that may explain why evening-types are at a greater risk for negative psychosocial adjustment. Yet, only a handful of studies have assessed social jetlag. Furthermore, the few studies that have assessed social jetlag have done so only with concurrent data, and thus have not been able to determine the direction of effects among morningness–eveningness, social jetlag and psychosocial adjustment. To address this important gap in the literature, the present 3-year longitudinal study employed the use of a cross-lagged auto-regressive model to specifically examine the predictive role of perceived morningness–eveningness and social jetlag on two important indices of psychosocial adjustment among university students: academic adjustment and substance use. We also assessed whether there would be an indirect effect between perceived morningness–eveningness and psychosocial adjustment through social jetlag. Participants were 942 (71.5% female; M?=?19 years, SD?=?0.90) undergraduates at a mid-sized university in Southern Ontario, Canada, who completed a survey at three assessments, each one year apart, beginning in first-year university. Measures were demographics (age, gender and parental education), sleep problems, perceived morningness–eveningness, social jetlag, academic adjustment and substance use. As hypothesized, results of path analyses indicated that a greater perceived eveningness preference significantly predicted higher social jetlag, poorer academic adjustment and higher substance use over time. In contrast, we found no support for social jetlag as a predictor of academic adjustment and substance use, indicating that social jetlag did not explain the link between perceived morningness–eveningness and negative psychosocial adjustment. An important finding was the significant predictive effect of higher substance use on social jetlag over time. Results of the present study highlight the importance of employing a longitudinal framework within which to specifically determine the direction of effects among the study variables in order to validate proposed theoretical models that aim to guide our understanding of how perceived morningness–eveningness, social jetlag, academic adjustment and substance use relate to each other.     

The draft genome and transcriptome of <Emphasis Type="Italic">Cannabis sativa</Emphasis>

Background  

Cannabis sativa has been cultivated throughout human history as a source of fiber, oil and food, and for its medicinal and intoxicating properties. Selective breeding has produced cannabis plants for specific uses, including high-potency marijuana strains and hemp cultivars for fiber and seed production. The molecular biology underlying cannabinoid biosynthesis and other traits of interest is largely unexplored.     

Water-soluble glycoproteins from Cannabis sativa (South Africa)

The water-soluble glycoproteins obtained from Cannabis leaves of plants grown from South African seeds have been further studied. Treatment of the glycoprotein fractions with NaOH in the presence of NaBH₄, resulted in a significant decrease in the serine content and a corresponding increase in alanine. The carbohydrate side chains released contained the sugar alcohol, galactitol. By treatment of the glycoprotein fractions with NaOH in the presence of Na₂SO₃, and subsequent acid hydrolysis, cysteic acid was formed. These data indicate that carbohydrate and protein are connected via serine-O-galactoside linkages. Further investigation of the structure of the carbohydrate part of the glycoproteins was carried out by methylation analysis, Smith-degradation and enzyme incubation. The present glycoprotein material of plants grown from South African seeds is similar to the material previously investigated, but in contrast to the latter, it is devoid of hexosamine.     

Tetrahydrocannabinol levels in hemp (cannabis sativa) germplasm resources

In most of the western world where industrial hemp, Cannabis sativa, is licensed for cultivation, the plants must not exceed a level of 0.3% tetrahydrocannabinol (THC), the principal intoxicating constituent of the species. Because there are no publicly available germplasm hemp collections in North America and only a very few, recent North American cultivars have been bred, the future breeding of cultivars suitable for North America is heavily dependent on European cultivars and European germplasm collections. Based mostly on material from Europe, this study surveyed THC levels of 167 accessions grown in southern Ontario, making this the largest survey to date of germplasm intended for breeding in North America. Forty-three percent of these had THC levels ≥0.3% and, therefore, are unsuitable for hemp development in North America. Discrepancies were found between THC levels reported for some germplasm holdings in Europe when they were grown in Canada and, accordingly, verification of THC levels developed in North America is necessary.