Objective: Alcohol use disorder (AUD) remains a leading cause of worldwide mortality and morbidity. The development of neuroanatomical biomarkers offers the potential of novel clinical indicators to guide prevention, early diagnosis, and treatment. Methods: In 76 participants with DSM-5 diagnosed AUD (Mage = 35.75; 51.3% female) and 79 controls (Mage = 34.71; 59.5% female), we utilized magnetic resonance imaging (MRI) to investigate four novel measures: hippocampal and amygdalar subregion volumes, sulcal morphology (SM), and fractal dimensionality (FD). MRI processing, segmentation, and SM and FD quantification were completed using FreeSurfer v6.0 and v7.0, and MATLAB toolboxes, respectively. A significance value of p < .05 was employed for analysis and sex, age, and intracranial volume were included as covariates. Results: Volumes of the right presubiculum, subiculum, and molecular layer head; left lateral and accessory basal nuclei; and corticoamygdaloid transition area were significantly lower in AUD participants relative to healthy controls. Widths of the left occipito-temporal, right middle occipital and lunate, and right marginal part of the cingulate sulci and depth of the post-central sulci were significantly increased in AUD participants relative to controls. Finally, decreased left caudate, left thalamus, right putamen and right pallidum FD and greater inferior lateral and third ventricle FD were observed in AUD participants relative to controls. Each novel measure’s reliability was assessed using test-retest data from the Human Connectome Project and indicated high reliability with median intraclass correlations of .93, .91, .88, and .93 for the hippocampal subfields, amygdalar nuclei, SM, and FD, respectively. Conclusion: These results indicate selectively decreased hippocampal and amygdala subregion volume, increased sulcal depth and width, and differences in FD as promising neuroanatomical biomarkers for AUD. / Thesis / Master of Health Sciences (MSc)

The upcoming Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) will change how Alcohol Use Disorder (AUD) is characterized by going from a twoactor hierarchical model to a unidimensional disorder. In addition, the number of criteria needed are being reduced—which may increase AUD prevalence rates. The present study examines how these changes will impact college students as compared to their non-college attending peers. Participants were asked to complete questionnaires about their alcohol use and what criteria they meet, a daily functioning questionnaire, and a measure to determine their willingness to engage in risky behaviors. Results indicate that college students will show a disproportionate increase in diagnoses, even though college students who meet criteria show no significant differences in functional impairment compared to students who do not meet criteria. These results suggest that the new criteria may not be a good indicator of AUD presence for college students.

Indiana University-Purdue University Indianapolis (IUPUI) / Continued consumption of alcohol despite the knowledge of negative consequences is a hallmark of alcohol use disorder (AUD), yet much remains unknown about what motivates these behaviors. Compulsive drinking may require motivational resources that are not necessary when drinking in unchallenged conditions in order to counteract the addition of these negative consequences. Increased sensitivity to drug-paired stimuli via associative learning processes may provide this additional motivation. To evaluate if alcohol-paired stimuli enhance alcohol seeking, selectively bred crossed High Alcohol Preferring mice experienced Pavlovian conditioning procedures with an alcohol unconditioned stimulus. We hypothesized that after repeated pairings, alcohol cues would elicit seeking conditioned responses. Then, to determine if the motivation provided by these cues influenced responding, mice were trained to respond for alcohol and tested in the presence of alcohol cues. Finally, to test if alcohol-paired cues influence compulsive drinking, this same test was repeated with the addition of response-contingent footshock. We hypothesized the cue paired with alcohol would increase responding for alcohol in unchallenged conditions, but especially in challenged conditions, contributing to compulsivity. An auditory stimulus paired with alcohol did elicit enhanced seeking responses, but contrary to hypothesis, we observed no effect of these same cues on instrumental responding. To validate these findings, training and testing procedures must be optimized to ensure conditioning has properly occurred and compulsivity is being appropriately measured.

Background: Women experience greater health consequences of alcohol compared to their male counterparts. In recent years, rates of drinking and heavy alcohol use have increased in women while remaining relatively steady in men. Thus, our aim was to newly examine associations between sex, AUD, and the presence of medical conditions in a large nationally representative, cross-sectional dataset. Methods: Using data from the U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III; n = 36,309), we evaluated relationships among sex and DSM-5 AUD, and their association with past year clinician-confirmed medical conditions. Results: Women were 1.5 to 2 times more likely to be diagnosed with a past year cancer, pain, respiratory, or other significant medical condition compared to men (odds ratio [OR] = 1.331–2.027). Individuals with an ongoing DSM-5 AUD were nearly 1.5 to 2 times more likely to report a confirmed past year liver, cardiovascular, cancer, or other significant medical condition compared to those without an AUD (OR = 1.437–2.073). Interactive effects demonstrated that women with an ongoing AUD were 2 to 3 times more likely to report a past year doctor- or health professional-confirmed medical condition compared to men; specifically, respiratory conditions and cancers (OR = 1.767–2.713). Conclusions: Results identify that AUD is a critical factor associated with disease that spans organ systems. Associations between AUD and respiratory conditions or cancers are particularly robust in women. Effective interventions for a broad spectrum of medical conditions should consider the role of problematic alcohol use, especially given that rates of drinking in women are increasing.

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Alcohol use disorder (AUD) is a highly stigmatized condition, often associated with negative stereotypes such as being morally weak, incompetent, unpredictable, and aggressive. People with AUD are at risk of experiencing self-stigma, a social-cognitive experience in which people think others hold negative stereotypes about them, expect to be treated unfairly, and/or believe that negative stereotypes are personally accurate. Women in the criminal justice system with AUD in particular are at risk of experiencing self-stigma due to intersecting sources of disadvantage. Given that self-stigma can lead to treatment avoidance and dropout, it is important to understand risk factors for self-stigma to inform prevention and intervention efforts in the justice system. Incarcerated women with AUD (=185) completed measures of alcohol self-stigma as well as a variety of theoretically relevant risk factors including sociodemographics, baseline levels of stress and depression, and alcohol-related factors (i.e., length of drinking history, frequency/amount of use, consequences of use, physician advice to stop, belief that legal involvement is related to alcohol use, alcohol-related charges, self-efficacy to quit, readiness for treatment, pressures to enter treatment, factors that influence treatment) and other stigmatized conditions (drug use, exchanging sex, and homelessness). Results showed that experiencing more consequences of alcohol use, pressures to enter treatment, and perceived stress were associated with internalized stigma and anticipated/enacted stigma. This study begins to identify which incarcerated women with AUD are most at risk of experiencing self-stigma that may interfere with alcohol treatment.

Alcohol use disorder (AUD) is a chronic, relapsing condition with a complex etiology and heritable susceptibility factors interact with environmental factors to produce and maintain the disease. One goal of current neuroscience research is to identify the neuroadaptations mediating the propensity to consume high amounts of alcohol, of either innate or environmental origin. Dysfunctional neuronal communication between prefrontal cortical regions and the nucleus accumbens (NAcc) have been implicated in excessive alcohol drinking and proposed to play a critical role in AUD. However, the exact mechanism by which altered prefrontostriatal transmission may perpetuate excessive drinking is poorly understood. In addition, the exact role of dopamine receptor 1 (D1R) or dopamine receptor 2 (D2R)-expressing medium spiny neurons in the NAcc is unclear and adds another layer of complexity to this framework. This thesis concerns pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved 38 amino acid neuropeptide, and its receptor PAC1R. Studies in rodents and humans have implicated PACAP and PAC1R in the actions of drugs of abuse, including more recently, alcohol. Notably, the PACAP/PAC1R system has also been shown to increase glutamatergic neurotransmission in several circuits. The overall hypothesis of this project was that the PACAP/PAC1 system in the prefrontal cortex-NAcc pathway regulates excessive drinking and the long-lasting neuroplastic changes observed in alcohol addiction, via the modulation of the glutamatergic system. Using alcohol-preferring rats, a hereditary model of AUD, we found that intracerebroventricular administration of a PAC1R antagonist blocked excessive alcohol drinking, motivation to drink, and alcohol seeking behavior selectively in this line and not in outbred rats. Alcohol-preferring rats displayed a higher number of PAC1R positive cells in the NAcc Core. Blockade of PAC1R in the NAcc Core, via pharmacology or gene knockdown, resulted in reduced alcohol drinking. Conversely, we found that knockdown of the PAC1R in the NAcc Shell led to increased alcohol drinking and motivation to drink in alcohol-preferring rats, suggesting that the PACAP/PAC1R system may play an opposite role in these two NAcc subregions. Using a mouse exposure model of excessive drinking, a glutamatergic projection from PACAP-expressing cells in the prelimbic portion of the prefrontal cortex (PrL) to the NAcc Core circuit was found to be recruited by alcohol exposure. Inhibition of these neurons, as well as PACAP neuron ablation or PACAP deletion, led to decreased alcohol intake that was specific to male mice. Systemic PAC1R antagonism, and specific knockdown of PAC1R in the NAcc Core, also decreased alcohol intake in male mice. Using slice electrophysiology and channelrhodopsin assisted circuit mapping, we found that this pathway is biased to D1R-expressing neurons in the NAcc Core following alcohol exposure in males, and that PACAP application increases post-synaptic measures of glutamatergic transmission in this circuit. Overall, these data describe a key role for the corticostriatal PACAP/PAC1R system in aberrant alcohol drinking in both hereditary- and exposure-based models of AUD and give novel insights into the underlying mechanisms of alcohol addiction. / 2025-01-23T00:00:00Z

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are debilitating conditions that often co-occur, with an estimated 41-79% comorbidity rate. A major concern with the co-occurrence of these disorders is the tendency for one to exacerbate the other. Specifically, symptoms related to PTSD are a significant risk factor for the development of AUD, and alcohol abuse worsens PTSD symptoms. This cycle, along with a lack of effective pharmacological treatment options, leads to significant behavioral and physiological deficits. Additionally, remission for comorbid AUD and PTSD is much more difficult to attain due to exacerbated symptomology and a lack of FDA-approved medications. In recent years, cannabidiol (CBD), a non-psychoactive compound found in cannabis, has been a focus of study due to its therapeutic potential. Researchers have demonstrated the anxiolytic and anti-inflammatory effects of CBD in both humans and animals, showing its promise as a novel therapeutic agent in the treatment of psychiatric disorders. The purpose of this study is to investigate the hypothesis that CBD will reduce fear-related behaviors and neuroinflammation in a rat model of comorbid AUD and PTSD. Our AUD/PTSD model utilized restraint stress and chronic intermittent ethanol exposure procedures. To investigate changes in future stress sensitivity all animals were exposed to a contextual fear conditioning paradigm, which was used to train the animals to associate environmental and auditory cues (environment appearance and tone) with an aversive stimulus (mild foot-shock). 30 minutes prior to each conditioning session, rats received an intraperitoneal injection of CBD (20mg/kg) or 0.9% Saline. Once the animals learned to associate the cues with a shock, they were exposed to an extinction learning procedure that involved presentation of the cue alone (no shock). This procedure parallels exposure therapy in humans, allowing for the assessment adaptations to fear learning. The amount of time the rats remain still (freezing) during the tone represents fear-related behavior. Our current results indicate rats with a history of stress and alcohol exposure displayed significantly higher freezing behaviors and this effect was significantly decreased with CBD treatment. This suggests that when CBD is administered during fear learning, it is able to attenuate heightened stress sensitivity associated with AUD/PTSD. To evaluate how CBD mediates the neuroinflammatory response associated with AUD and PTSD, brains from the rats were extracted and analyzed for the inflammatory cytokine tumor necrosis factor a (TNF-a). Specific regions of interest included the medial prefrontal cortex and hippocampus, areas associated with anxiety, memory, and addiction. Neuroinflammation analyses are still ongoing, however it is predicted that rats who received CBD will show a reduction in inflammation in the medial prefrontal cortex and hippocampus. Taken together, the current results show promise for CBD to reduce enhanced fear-related behavior associated with comorbid AUD and PTSD.

Objectives: We investigated the prevalence of substance use disorders among emerging adults and quantified the extent to which emerging adults, compared to young adults, are at increased odds for substance use disorders. Methods: Data come from the 2012 Canadian Community Health Survey – Mental Health (CCHS-MH). Respondents were 15–39 years of age (n=9228) and were categorized as: early emerging adults (15-22 years); late emerging adults (23-29 years); and, young adults (30-39 years). Substance use disorders (alcohol or drug abuse/dependence) were measured using the Composite International Diagnostic Interview 3.0. The prevalence of substance use disorders was compared across age groups using design-based χ2 analyses. Odds ratios (OR) and 95% confidence intervals (CI) were computed from logistic regression models adjusting for sociodemographic and health covariates. All analyses were weighted to maintain representativeness of the study sample to the Canadian population. Results: The prevalence of alcohol use disorder was 8.0%, 6.6%, and 2.7% for early emerging adults, late emerging adults, and young adults respectively. For drug use disorder, the prevalence was 6.4%, 3.6%, and 1.3%. Compared to young adults, early and late emerging adults were more likely to report substance use disorders (p<0.01). The prevalence of drug use disorder was higher among early versus late emerging adults (χ2=119.8, p=0.01). Among all age groups, males were more likely to report alcohol or drug use disorders (p≤0.01 for all). After covariate adjustment, early and late emerging adults had greater odds of reporting alcohol (OR=3.2, 95% CI=2.2-4.9 and OR=2.4, 95% CI=1.6-3.4, respectively) or drug (OR=4.2, 95% CI=2.5-7.0 and OR=2.5, 95% CI=1.6-4.1, respectively) use disorders compared to young adults. Conclusion: Emerging adulthood represents an important developmental period in which individuals are at increased odds of reporting substance use disorders. This finding has implications for the provision of screening and treatment of substance use disorders as these individuals transition from the pediatric to adult healthcare system. / Thesis / Master of Health Sciences (MSc)