Discriminability of personality profiles in isolated and Co-morbid marijuana and nicotine users

AbstractSpecific personality traits have been linked with substance use disorders (SUDs), genetic mechanisms, and brain systems. Thus, determining the specificity of personality traits to types of SUD can advance the field towards defining SUD endophenotypes as well as understanding the brain systems involved for the development of novel treatments. Disentangling these factors is particularly important in highly co morbid SUDs, such as marijuana and nicotine use, so treatment can occur effectively for both. This study evaluated personality traits that distinguish isolated and co-morbid use of marijuana and nicotine. To that end, we collected the NEO Five Factor Inventory in participants who used marijuana-only (n=59), nicotine-only (n=27), both marijuana and nicotine (n=28), and in non-using controls (n=28). We used factor analyses to identify personality profiles, which are linear combinations of the five NEO Factors. We then conducted Receiver Operating Characteristics (ROC) curve analysis to test accuracy of the personality factors in discriminating isolated and co-morbid marijuana and nicotine users from each other. ROC curve analysis distinguished the four groups based on their NEO personality patterns. Results showed that NEO Factor 2 (openness, extraversion, agreeableness) discriminated marijuana and marijuana+nicotine users from controls and nicotine-only users with high predictability. Additional ANOVA results showed that the openness dimension discriminated marijuana users from nicotine users. These findings suggest that personality dimensions distinguish marijuana users from nicotine users and should be considered in prevention strategies

Baclofen-Induced Changes in the Resting Brain Modulate Smoking Cue Reactivity: A Double-blind Placebo-controlled Functional Magnetic Resonance Imaging Study in Cigarette Smokers

Objective: Smoking cue-(SC) elicited craving can lead to relapse in SC-vulnerable individuals. Thus, identifying treatments that target SC-elicited craving is a top research priority. Reduced drug cue neural activity is associated with recovery and is marked by a profile of greater tonic (resting) activation in executive control regions, and increased connectivity between executive and salience regions. Evidence suggests the GABA-B agonist baclofen can reduce drug cue-elicited neural activity, potentially through its actions on the resting brain. Based on the literature, we hypothesize that baclofen’s effects in the resting brain can predict its effects during SC exposure. Methods: In this longitudinal, double blind, placebo-controlled neuropharmacological study 43 non-abstinent, sated treatment-seeking cigarette smokers (63% male) participated in an fMRI resting-state scan and a SC-reactivity task prior to (T1) and 3 weeks following randomization (T2; baclofen: 80 mg/day; n = 21). Subjective craving reports were acquired before and after SC exposure to explicitly examine SC-induced craving. Results: Whole-brain full-factorial analysis revealed a group-by-time interaction with greater resting brain activation of the right dorsolateral prefrontal cortex (dlPFC) at T2 in the baclofen group (BAC) (pFWEcorr = 0.02), which was associated with reduced neural responses to SCs in key cue-reactive brain regions; the anterior ventral insula and ventromedial prefrontal cortex (pFWEcorr ＜ 0.01). BAC, but not the placebo group reported decreased SC-elicited craving (p = 0.02). Conclusion: Results suggest that baclofen mitigates the reward response to SCs through an increase in tonic activation of the dlPFC, an executive control region. Through these mechanisms, baclofen may offer SC-vulnerable smokers protection from SC-induced relapse

Identification of Trypanosoma brucei AdoMetDC Inhibitors Using a High-Throughput Mass Spectrometry-Based Assay

Human African trypanosomiasis (HAT) is a fatal infectious disease caused by the eukaryotic pathogen Trypanosoma brucei (<i>Tb</i>). Available treatments are difficult to administer and have significant safety issues. <i>S</i>-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the parasite polyamine biosynthetic pathway. Previous attempts to develop <i>Tb</i>AdoMetDC inhibitors into anti-HAT therapies failed due to poor brain exposure. Here, we describe a large screening campaign of two small-molecule libraries (∼400,000 compounds) employing a new high-throughput (∼7 s per sample) mass spectrometry-based assay for AdoMetDC activity. As a result of primary screening, followed by hit confirmation and validation, we identified 13 new classes of reversible <i>Tb</i>AdoMetDC inhibitors with low-micromolar potency (IC₅₀) against both <i>Tb</i>AdoMetDC and <i>T. brucei</i> parasite cells. The majority of these compounds were >10-fold selective against the human enzyme. Importantly, compounds from four classes demonstrated high propensity to cross the blood–brain barrier in a cell monolayer assay. Biochemical analysis demonstrated that compounds from eight classes inhibited intracellular <i>Tb</i>AdoMetDC in the parasite, although evidence for a secondary off-target component was also present. The discovery of several new <i>Tb</i>AdoMetDC inhibitor chemotypes provides new hits for lead optimization programs aimed to deliver a novel treatment for HAT