Highlights of Indiana ARC Science

 

Medication-assisted treatment for alcohol use disorder

The Indiana Alcohol Research Center (ARC)’s Information Dissemination Core, led by David Crabb, MD, and Linda Chezem, is assessing the knowledge of primary care providers and judges about alcohol use disorders and the effectiveness of medication-assisted treatment (MAT). Although MAT for alcohol use disorder have existed for quite some time, they remain underutilized, especially in general medical settings. The Information Dissemination Core surveyed primary care and behavioral health specialists working in the Eskenazi Health system (the safety net hospital for Indianapolis, serving large numbers of patients with substance use disorders) in late 2019 and early 2020, as well as judges participating in four different national conferences during 2021.

The respondents indicated that, while MAT was common for substance use disorder (91% used MAT for smoking cessation and 52% for opioid use disorders), only 52% had used MAT for alcohol use disorder. The providers were generally well-informed about naltrexone’s pharmacology, over half felt it was “important” or “very important” to offer MAT and 86% felt it was superior to counseling.

However, perceived barriers to use included lack of comfort in prescribing the drug, lack of other behavioral health services to offer with the MAT, uncertainty about the effectiveness of treatment in adolescents or those over 65 years of age, lack of time during primary care visits to discuss alcohol use disorder and its treatment, and (surprisingly) concern about liability. Eighty percent had been asked about MAT by patients at least once, but infrequently, suggesting lack of public awareness. Critically, interest in MAT seemed to track with readiness to reduce or stop drinking.

Since this survey effort, increased numbers of patients in the Eskenazi system are receiving prescriptions for MAT (see table) over the past 4 years. This includes prescriptions by primary care and behavioral health providers.

Medication	2018	2019	2020	2021
Acamprosate	17	18	22	107
Naltrexone HCl	177	306	437	911
Naltrexone microspheres (Vivitrol)	73	149	173	328

Scroll/swipe this table left and right to see more information.

This effort suggests that raising awareness about treatment options for providers may have a significant impact on prescribing trends, especially among providers who are involved in the use of MAT for nicotine and opioid use disorders.

Intravenously administered alcohol to study alcohol reinforcement in humans

A central concept in alcohol use disorder (and addiction more broadly) is the difference between “liking” and “wanting.” While an individual may like sensations induced by alcohol intoxication, more extreme “wanting” is a potent force in persistent and compulsive alcohol consumption. Although long studied in animal models of alcohol use disorder, studying these behaviors in humans is more complex. IARC researchers Melissa Cyders, PhD, Sean O’Connor, MD, and Martin Plawecki, MD, PhD, recently published data using the IARC-conceived and developed “CAIS” (computer-assisted infusion system) method to intravenously infuse alcohol. This study demonstrates how the CAIS system can be used to reflect both “liking” and behavioral aspects of “wanting,” suggesting a potential platform for testing behavioral and medical treatments for alcohol use disorder.

A key aspect of research in our center is the use of animal models developed by the IARC to study alcohol use disorder’s genetic risks.  Part of this work is understanding the brain mechanisms engaged when animals “decide” to drink alcohol. In this research, Christopher Lapish, PhD, and his laboratory team recorded neural activity in medial prefrontal brain areas while animals were deciding whether to consume alcohol. This neural activity accurately predicted occasions when Wistar rats would drink alcohol.  However, in P rats (a model of a family history of alcohol use disorder) this frontal neural activity was both blunted and unable to predict when animals would drink.  This suggests that one inherited risk for alcohol use disorder is a lack of (frontal brain) supervisory control over decisions to drink.

Working in collaboration at the IARC, the laboratories of Joaquin Goñi, PhD, of Purdue University and the team of David A. Kareken, PhD, and Mario Dzemidzic, PhD, of Indiana University, used a novel measure of network connectivity to determine if family history influences human brain network flexibility. These data showed that when transitioning from exerting behavioral inhibition to quiet rest, subjects without a family history of alcohol use disorder show a transient reconfiguration of network states. Those with a family history of alcohol use disorder, however, showed less of this reconfiguration. This implicates inflexibility in network reconfiguration when switching between mental state transitions as a possible underlying risk factor for alcohol use disorder.

When an individual continues to drink despite aversive consequences, it suggests an advanced stage of an alcohol use disorder where treatment can be especially difficult. Therefore, identifying the parts of the brain that are involved in this transition is critical for developing novel ways to prevent and treat this stage. The laboratories of Marian Logrip, PhD, and Stephen Boehm, PhD, developed an animal model of this stage using animals that continue to drink alcohol after it is made to taste excessively bitter. They identified changes in the activity of neurons on specific parts of the brain that are associated with this transition. This model is now being used to develop ways to offset these changes and inspire new treatments based on these findings.

There are two decision points with regards to drinking alcohol that could contribute to problematic drinking. The first is whether to drink at all on a particular day, which could be related to craving. The second is whether to continue drinking after consuming a few drinks, which could reflect a tendency to binge drink. Cristine Czachowski, PhD’s work has long been focused on understanding the behaviors and brain regions underlying these two decision points. Two different rat models of a “family history of drinking,” the alcohol-preferring (P) rats and the high alcohol drinking (HAD) rats, differ in these behaviors (the P rats will work hard to start drinking and then drink a lot, while the HAD rats will not work hard to start drinking, but once they start, they also consume high amounts of alcohol). More recently, work with the ARC has revealed that P rats also demonstrate behaviors like impulsivity and an inability to adjust their responding when the “rules about reward” change. Importantly, this is before they have ever had access to alcohol, so these decision-making problems may be inherited risk factors that predispose them to craving and binge drinking.

The lab of Woody Hopf, PhD,  is interested in identifying specific brain connections and activity patterns that drive pathological alcohol drinking (including binging and drinking that is consequence-resistance). The lab is also interested in and co-morbid anxiety, especially critical sex differences in the mechanisms promoting such co-morbid conditions. Researchers focus strongly on understanding the human condition, so that they can design rodent work most closely relevant to clinical human clinical conditions, with the goal of conducting parallel human research. They are particularly interested in a brain system that mediates quick responding under high-importance conditions, the salience network, with a specific focus on the insula and insula connections to other brain areas. These circuits are crucial for quick adaptive action and good emotional regulation, but become commandeered by addiction and anxiety memories (and innate tendencies). To best understand the mechanisms by which the brain areas drive maladaptive behavior, researchers employ a range of cutting edge methods:  measure the actual activity within brain areas during addiction and anxiety (in vivo electrophysiology);  inhibit specific brain connections to understand their importance for driving behavior (projection-specific opto- and chemo- genetics);  use cardiovascular and other body-level detectors to understand a rat’s (or human’s) feeling and arousal state;  break behaviors into component parts (the behavior “microstructure”) to best understand which parts are most linked to pathological motivation; and examine how human-approved pharmacological agents regulate addiction and anxiety. Together, Hopf's team seeks to revolutionize our understanding of the interconnected brain activation, feeling states, and uncontrollable drives that underlie addiction, especially how negative emotions automatically promote intoxicant seeking.

The research of Eric A. Engelman, PhD, uses animal models to examine the changes in neurochemistry that underlie compulsive drinking. This allows for more precise measurements of neurochemistry than would be capable in humans. Engelman’s experiments have focused on a part of the brain that are critical for advanced forms of cognition— the prefrontal cortex. The focus on this brain region is motivated, in part, by past data in his lab that finds differences in the neurochemistry in P rats, which are a model of a family history of alcohol use disorder. In agreement with other IARC projects, Engelman finds that P rats progress quickly to a stage of compulsive drinking and he has extended these findings to examine sex-differences in compulsive drinking. He finds that males P rats exhibit stronger compulsive behaviors than females. Future studies will examine changes in neurochemistry that underlie this phenomenon.

Researchers in the laboratory of Stephen Boehm, PhD, are studying binge alcohol drinking. Binge alcohol drinking has been defined as drinking too much too fast, with blood alcohol concentrations reaching or exceeding 0.08 g/dL or higher within 2 hours. This pattern of drinking can pose considerable risk to the individual ranging from risky behavior to blackouts, and even death by overdose. Dr. Boehm’s research explores how repeated bouts of binge alcohol drinking impact brain and behavior in a mouse model. C57BL/6J inbred mice readily engage in daily binge alcohol drinking, repeatedly reaching blood alcohol concentrations exceeding 0.08 g/dL that produce motor tolerance, rapid initial drinking (“frontloading”), and compulsive alcohol drinking. Dr. Boehm’s recent ARC-supported work suggests that AMPA receptors in the dorsal striatum (regions involved in habit-based behavior) are important mediators of binge alcohol drinking.

Nicholas J. Grahame, PhD, has been using ARC-supported, selectively bred crossed High Alcohol Preferring (cHAP) mice that drink to blood ethanol concentrations of over 250 mg/dl during simple two-bottle choice access to 10% alcohol and water. This serves as a model to explore why these animals escalate alcohol intake over time. The cHAP mice also develop compulsive-like drinking, as measured by continued consumption of alcohol tainted with bitter quinine. Recent work shows that this compulsive-like drinking depends upon dopamine D1 receptors in the striatum (a region important for habits), but doesn’t emerge with saccharin drinking. Escalation of voluntary intake also increases subsequent binge-like drinking (using a 2-hour-limited access model of alcohol drinking), suggesting that these animals develop tolerance to the rewarding effects of alcohol.