Smoking-Related Increases in Alcohol Outcomes and Preliminary Evidence for the Protective Effect of a Functional Nicotine Receptor Gene (CHRNA5) Variant on Alcohol Consumption in Individuals Without Alcohol Use Disorder.

BACKGROUND: Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and misuse of these drugs. A missense polymorphism rs16969968 (G>A) in the CHRNA5 gene has shown a strong association with nicotine-related phenotypes. However, less is known about the impact of this variant on alcohol-related phenotypes. METHODS: We assessed the main and interactive effect of smoking and rs16969968 polymorphism on alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT), Timeline Follow Back (TLFB), and Lifetime Drinking History (LDH) in 980 healthy adults without alcohol use disorder. We further examined the effect of the rs16969968 polymorphism on acute alcohol consumption using a free-access i.v. alcohol self-administration (IV-ASA) human laboratory paradigm in a subset of 153 nonsmoking participants. Subjective alcohol responses, alcohol sensitivity, and expectancy measures were compared between genotype groups (GG; AA/AG). RESULTS: We observed a significant association of smoking with AUDIT, TLFB, and LDH measures across genotype groups, with smokers showing higher scores compared with nonsmokers. Additionally, we found an association between genotype and TLFB-total drinks in the IV-ASA subset, with the GG group showing higher scores than AA/AG group. Relatedly, the alcohol negative expectancy score was significantly lower in the GG group than the AA/AG group. CONCLUSIONS: Our findings underscore the association of smoking with alcohol measures. We found preliminary evidence for the protective effect of the functional CHRNA5 polymorphism on alcohol consumption and its association with increased negative alcohol expectancies, which highlights the substantial heterogeneity in alcohol responses.

Behavioral characterization of withdrawal following chronic voluntary ethanol consumption via intermittent two-bottle choice points to different susceptibility categories.

BACKGROUND: Alcohol is among the most commonly abused drugs worldwide. Cessation of chronic alcohol consumption can result in the appearance of withdrawal symptoms that commonly promote relapse in individuals with alcohol use disorder (AUD). Thus, preclinical models of voluntary alcohol consumption, in which animals manifest spontaneous signs of withdrawal after alcohol cessation, can be useful for studying AUD and its treatment. The intermittent two-bottle choice paradigm (I2BC) has been used extensively to examine alcohol intake in rodents. However, previous studies have reported conflicting observations regarding its potential to result in the spontaneous manifestation of withdrawal upon alcohol cessation. METHODS: We employed a battery of behavioral tests to examine the emergence of affective and physical signs of withdrawal in female and male mice exposed to alcohol in the I2BC for 10 weeks. Specifically, mice of both sexes undergoing 24-h withdrawal from the I2BC were tested for physical signs of withdrawal, anxiety-like behavior in the open field arena (OFA) and elevated plus maze (EPM), and anxiety/compulsive-like behavior in the marble burying test (MBT). The main outcomes from these tests were combined into a behavioral severity score to describe the overall behavioral phenotype. RESULTS: Both female and male mice undergoing withdrawal from the I2BC displayed elevated physical signs of withdrawal and anxiety-associated behavior in the EPM and MBT. Analysis of the overall behavioral severity score revealed more severe phenotypes in female and male mice undergoing withdrawal from the I2BC than controls. Additionally, stratification of the mice based on severity scores demonstrated a differential distribution of severities between the exposure groups. CONCLUSIONS: We confirmed that a significant fraction of mice chronically exposed to alcohol in the I2BC display spontaneous withdrawal. In addition, we showed that computing a severity score from a combination of behavioral metrics can be useful in preclinical research to model evaluation tools used in patients with AUD.

Teclistamab: Mechanism of action, clinical, and translational science.

Multiple myeloma (MM) remains incurable despite improvements in treatment options. B-cell maturation antigen (BCMA) is predominantly expressed in B-lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLITM ) is the first T-cell redirecting bispecific antibody approved for patients with MM. Targeting both CD3 receptor complex on T cells and BCMA on myeloma cells, teclistamab leads to T-cell activation and subsequent lysis of BCMA+ cells. The recommended dose of teclistamab is 1.5 mg/kg subcutaneous weekly after two step-up doses of 0.06 and 0.3 mg/kg, which was selected after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Exposure-response analyses of efficacy and safety data were also used to confirm the teclistamab dose. Teclistamab resulted in a high rate of deep and durable responses (63% overall response, 45.5% complete response or better, with 22 months median duration of response) in patients with triple-exposed relapsed/refractory MM. Common adverse reactions included cytokine release syndrome, hematologic abnormalities, and infections. Teclistamab is currently being investigated as monotherapy as well as combination therapy across different MM indications.

Mutation of the α5 nicotinic acetylcholine receptor subunit increases ethanol and nicotine consumption in adolescence and impacts adult drug consumption.

Alcohol and nicotine are commonly used during adolescence, establishing long-lasting neuroplastic alterations that influence subsequent drug use and abuse. Drinking- and smoking-related traits have been extensively associated with variation in CHRNA5 - the gene that encodes the α5 subunit of neuronal nicotinic acetylcholine receptors (nAChRs). The single nucleotide polymorphism (SNP) rs16969968 in CHRNA5 encodes an amino acid substitution (D398N) that alters the function and pharmacokinetics of α5-containing nAChR. When expressed in rodents, this variant results in increased ethanol and nicotine operant self-administration. How disruption of α5-containing nAChRs influences adolescent ethanol and nicotine intake, and how it modulates interactions between these drugs has not been previously explored. In the present study, we examined volitional ethanol and nicotine consumption in adolescent mice (post-natal day 30-43) of both sexes with mutated (SNP) or lacking (KO) the α5 nAChR subunit. The effect of adolescent alcohol or nicotine exposure on home cage consumption of the opposite drug in adulthood and its modulation by Chrna5 mutation and sex were examined. During adolescence, we found that α5 nAChR disruption increases nicotine intake in mice of both sexes, but the effect on alcohol intake was only observed in females. The sex-specific increase in alcohol consumption in α5 SNP and KO was replicated in adulthood. The effect of adolescent alcohol or nicotine exposure on subsequent intake of the opposite drug in adulthood is modulated by sex and Chrna5 mutation. These observations suggest sex differences in the genetic architecture of alcohol dependence, and modulators of alcohol and nicotine interactions.

Antagonism of GluK1-containing kainate receptors reduces ethanol consumption by modulating ethanol reward and withdrawal.

Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide. Topiramate (TPM) is an antiepileptic drug that has been shown to reduce ethanol drinking in humans. However, TPM is associated with a variety of adverse effects due to its interaction with many receptor systems and intracellular pathways. GluK1-containing kainate receptors (GluK1*KARs) are non-selectively inhibited by TPM, and genetic association studies suggest that this receptor system could be targeted to reduce drinking in AUD patients. We examined the efficacy of LY466195, a selective inhibitor of GluK1*KAR, in reducing ethanol consumption in the intermittent two-bottle choice paradigm in mice. The effect of LY466195 on various ethanol-related phenotypes was investigated by quantification of alcohol intake, physical signs of withdrawal, conditioned place preference (CPP) and in vivo microdialysis in the nucleus accumbens. Selective GluK1*KAR inhibition reduced ethanol intake and preference in a dose-dependent manner. LY466195 treatment attenuated the physical manifestations of ethanol withdrawal and influenced the rewarding properties of ethanol. Interestingly, LY466195 injection also normalized changes in dopamine levels in response to acute ethanol in ethanol-dependent mice, but had no effect in ethanol-naïve mice, suggesting ethanol state-dependent effects. The data point to GluK1*KARs as an attractive pharmacological target for the treatment of AUD.