Department of Psychiatry, UCSD

Environmental conditioning factors have a profound impact on alcohol-seeking behavior and the maintenance of alcohol use in individuals with alcohol dependence. Cues associated with alcohol, depending on the perceived value of the primary reinforcer, gain salience and can trigger relapse. This study investigates the correlation between the reward magnitude of the primary reinforcer and the reinstatement evoked by cues predictive of their availability in male rats. Rat self-administration procedures were used to test reinstatement, with reinforcers consisting of 10% alcohol, 10% sucrose, or 2% sodium chloride (NaCl) experienced under need-state conditions. The effect of MTEP ([(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine), a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, on motivation and reinstatement behaviors was also evaluated. RESULTS: demonstrate that under Fixed Ratio 1 (FR1) schedule, the three reinforcers maintain operant responding with the following order of magnitude 10% sucrose >2% NaCl >10% alcohol > water. Under a progressive ratio (PR) schedule of reinforcement, rats exhibit a significantly higher breakpoint for 2% NaCl (under Na-depletion), followed by 10% sucrose and 10% alcohol. After extinction, a significant reinstatement is observed with the magnitude order of 10% sucrose >10% alcohol >2% NaCl. However, only re-exposure to alcohol-paired cues induced significant reinstatement of alcohol-seeking after 4 and 8 months. Treatment with MTEP significantly reduces reinstatement of responding across all reinforcers, with the strongest effect observed on alcohol-seeking. These findings suggest that mGluR5 plays a general role in controlling cue-reactivity, but the effect is prominent in the case of alcohol compared to natural rewards. In conclusion, the results demonstrate a remarkable dissociation between the rewarding magnitude of the primary reinforcer and its ability to trigger relapse upon presentation of a cue previously associated with it. Importantly, alcohol, despite having lower intrinsic motivational value compared to a natural reward (sucrose) or a consummatory stimulus experienced under need state conditions (NaCl), can elicit more robust and longer-term reinstatement of seeking responses. Finally, our data demonstrate a significant involvement of the mGluR5 system in the regulation of seeking behavior.

Introduction: Elevated levels of behavioral inhibition (BI) may connote risk for both anxiety and substance use disorders. BI has consistently been shown to be associated with increased levels of anxiety, while the association between BI and substance use has been mixed. It is possible that the relationship between BI and substance use varies by individual difference factors. Hispanic/Latinx (H/L) youth in particular may have stronger relationships between BI, anxiety, and substance use. Methods: The present study therefore evaluated (1) the prospective relationships between BI [assessed via self-reported behavioral inhibition system (BIS) scale scores], anxiety, and substance use in youth (n = 11,876) across baseline, 1-, and 2-year follow-ups of the Adolescent Brain Cognitive Development (ABCD) Study (ages 9–12) and (2) whether these relationships differed by H/L ethnicity while covarying for average behavioral approach system scores, race, sex, age, highest parental income, highest parental education, and past-year substance use (for analyses involving substance use outcomes). Results: Baseline levels of BIS scores predicted increased anxiety symptoms at both 1- and 2-year follow-ups and did not differ by H/L ethnicity. Baseline levels of BIS scores also prospectively predicted increased likelihood of substance use at 2-year follow-up, but only for H/L youth and not at 1-year follow-up. Discussion: High scores on the BIS scale contribute risk to anxiety across ethnicities and may uniquely contribute to risk for substance use in H/L youth.

Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.

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Some sources report increases in alcohol use have been observed since the start of the COVID-19 pandemic, particularly among women. Cross-sectional studies suggest that specific COVID-19-related stressful experiences (e.g., social disconnection) may be driving such increases in the general population. Few studies have explored these topics among individuals with a history of Alcohol Use Disorders (AUD), an especially vulnerable population. Drawing on recent data collected by the Collaborative Study on the Genetics of Alcoholism (COGA; COVID-19 study N = 1651, 62% women, age range: 30-91) in conjunction with AUD history data collected on the sample since 1990, we investigated associations of COVID-19 related stressors and coping activities with changes in drunkenness frequency since the start of the pandemic. Analyses were conducted for those without a history of AUD (N: 645) and three groups of participants with a history of AUD prior to the start of the pandemic: (1) those experiencing AUD symptoms (N: 606), (2) those in remission who were drinking (N: 231), and (3) those in remission who were abstinent (had not consumed alcohol for 5+ years; N: 169). Gender-stratified models were also examined. Exploratory analyses examined the moderating effects of 'problematic alcohol use' polygenic risk scores (PRS) and neural connectivity (i.e., posterior interhemispheric alpha EEG coherence) on associations between COVID-19 stressors and coping activities with changes in the frequency of drunkenness. Increases in drunkenness frequency since the start of the pandemic were higher among those with a lifetime AUD diagnosis experiencing symptoms prior to the start of the pandemic (14% reported increased drunkenness) when compared to those without a history of AUD (5% reported increased drunkenness). Among individuals in remission from AUD prior to the start of the pandemic, rates of increased drunkenness were 10% for those who were drinking pre-pandemic and 4% for those who had previously been abstinent. Across all groups, women reported nominally greater increases in drunkenness frequency when compared with men, although only women experiencing pre-pandemic AUD symptoms reported significantly greater rates of increased drunkenness since the start of the pandemic compared to men in this group (17% of women vs. 5% of men). Among those without a prior history of AUD, associations between COVID-19 risk and protective factors with increases in drunkenness frequency were not observed. Among all groups with a history of AUD (including those with AUD symptoms and those remitted from AUD), perceived stress was associated with increases in drunkenness. Among the remitted-abstinent group, essential worker status was associated with increases in drunkenness. Gender differences in these associations were observed: among women in the remitted-abstinent group, essential worker status, perceived stress, media consumption, and decreased social interactions were associated with increases in drunkenness. Among men in the remitted-drinking group, perceived stress was associated with increases in drunkenness, and increased relationship quality was associated with decreases in drunkenness. Exploratory analyses indicated that associations between family illness or death with increases in drunkenness and increased relationship quality with decreases in drunkenness were more pronounced among the remitted-drinking participants with higher PRS. Associations between family illness or death, media consumption, and economic hardships with increases in drunkenness and healthy coping with decreases in drunkenness were more pronounced among the remitted-abstinent group with lower interhemispheric alpha EEG connectivity. Our results demonstrated that only individuals with pre-pandemic AUD symptoms reported greater increases in drunkenness frequency since the start of the COVID-19 pandemic compared to those without a lifetime history of AUD. This increase was more pronounced among women than men in this group. However, COVID-19-related stressors and coping activities were associated with changes in the frequency of drunkenness among all groups of participants with a prior history of AUD, including those experiencing AUD symptoms, as well as abstinent and non-abstinent participants in remission. Perceived stress, essential worker status, media consumption, social connections (especially for women), and relationship quality (especially for men) are specific areas of focus for designing intervention and prevention strategies aimed at reducing pandemic-related alcohol misuse among this particularly vulnerable group. Interestingly, these associations were not observed for individuals without a prior history of AUD, supporting prior literature that demonstrates that widespread stressors (e.g., pandemics, terrorist attacks) disproportionately impact the mental health and alcohol use of those with a prior history of problems.

Alcohol use disorders (AUD) are commonly occurring, heritable and polygenic disorders with etiological origins in the brain and the environment. To outline the causes and consequences of alcohol-related milestones, including AUD, and their related psychiatric comorbidities, the Collaborative Study on the Genetics of Alcoholism (COGA) was launched in 1989 with a gene-brain-behavior framework. COGA is a family based, diverse (~25% self-identified African American, ~52% female) sample, including data on 17,878 individuals, ages 7-97 years, in 2246 families of which a proportion are densely affected for AUD. All participants responded to questionnaires (e.g., personality) and the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) which gathers information on psychiatric diagnoses, conditions and related behaviors (e.g., parental monitoring). In addition, 9871 individuals have brain function data from electroencephalogram (EEG) recordings while 12,009 individuals have been genotyped on genome-wide association study (GWAS) arrays. A series of functional genomics studies examine the specific cellular and molecular mechanisms underlying AUD. This overview provides the framework for the development of COGA as a scientific resource in the past three decades, with individual reviews providing in-depth descriptions of data on and discoveries from behavioral and clinical, brain function, genetic and functional genomics data. The value of COGA also resides in its data sharing policies, its efforts to communicate scientific findings to the broader community via a project website and its potential to nurture early career investigators and to generate independent research that has broadened the impact of gene-brain-behavior research into AUD.

The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal-a GABAA receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats.

Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies.

Background: Substance-related diagnoses (SRDs) are a common healthcare presentation. This study identified sociodemographic and health-related characteristics associated with having an SRD as the primary reason for a clinical encounter compared to those with an SRD who are treated for other reasons. Methods: Electronic health record (EHR) data on patients with an SRD (n=12,358, ages 18-90) were used to assess if an SRD was the primary reason for a clinical encounter from January 1, 2012-January 1, 2018. Patients were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios, and 95% confidence intervals were calculated. Results: In the matched cohort of 8,630, most reported male sex (65.8%), White race (70.0%), and single marital status (62.7%) with a mean age of 47.2 (SD=14.6). Patient reported female sex, Black race, age 70+, married status, and low-income (<$50,000) were associated with a lower likelihood of presenting to care for an SRD as the primary reason for a clinical encounter. A nicotine-, alcohol-, opioid-, or stimulant-related diagnosis was associated with a higher likelihood of presenting to care for an SRD as the primary reason for the clinical visit. Conclusion: This is the first study to investigate whether sociodemographic and health-related characteristics were associated with having an SRD as the primary reason for a clinical encounter. Using rigorous methods, we investigated a unique clinical question adding new knowledge to predictors of patients seeking clinical care. Understanding these predictors can help us better align service provision with population needs and inform new approaches to tailoring care.

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