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Browsing by Author "Hopf, Frederic W."
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Item Animal models of compulsion alcohol drinking: Why we love quinine-resistant intake and what we learned from it(Frontiers Media, 2023-03-24) De Oliveira Sergio, Thatiane; Frasier, Raizel M.; Hopf, Frederic W.; Psychiatry, School of MedicineAlcohol Use Disorder (AUD) ranks among the most prevalent mental disorders, extracting ~$250 billion/year in the US alone and producing myriad medical and social harms. Also, the number of deaths related to problem drinking has been increasing dramatically. Compulsive alcohol drinking, characterized by intake that persists despite negative consequences, can be particularly important and a major obstacle to treatment. With the number of people suffering from AUD increasing during the past years, there is a critical need to understand the neurobiology related to compulsive drives for alcohol, as well as the development of novel AUD pharmacological therapies. Here we discuss rodent compulsion-like alcohol drinking (CLAD) models, focusing on the two most widely used adverse stimuli to model rodent compulsion-like responding, quinine adulteration of alcohol and footshook-resistant alcohol intake. For both cases, the goal is to uncover behavior patterns and brain circuits that underlie drive for alcohol even in the face of negative consequences. We discuss caveats, benefits, and potential brain mechanisms, of models for consequence-resistant responding for alcohol more generally, and especially highlight some advantages of quinine-resistance over footshook-resistance. Further, since this review contributes to a Special issue focused on Molecular Aspects of Compulsive Drug Use, we discuss our new findings showing how the noradrenergic system is related to CLAD responding. In particular, we comment on the importance of α1 and β adrenergic receptors (ARs) as potential targets for treating AUD.Item Behavioral indicators of succeeding and failing under higher-challenge compulsion-like alcohol drinking in rat(Elsevier, 2020-09-01) Darevsky, David; Hopf, Frederic W.; Psychiatry, School of MedicineIntake despite negative consequences (compulsivity) contributes strongly to the harm of alcohol use disorder, making the underlying psychological and circuit mechanisms of great importance. To gain insight into possible underlying action strategies, we compared rat licking microstructure across compulsion-like and non-compulsive conditions. We previously showed that drinking under a moderate-challenge, quinine-alcohol model (Alc-ModQ) shows less variable responding in many measures, suggesting a more automatic strategy to overcome challenge. Here, we reanalyzed our original data, newly focusing on the behavioral profile of higher-challenge intake (100 mg/L quinine in alcohol, Alc-HighQ). Alc-HighQ greatly dropped consumption, yet retained aspects of greater automaticity and drive seen with Alc-ModQ, including earlier bout initiation and measures suggesting more stereotyped tongue control. In contrast, Alc-HighQ disordered bout generation and timing. Importantly, only fast-starting bouts persisted under Alc-HighQ, and while there were many fewer longer Alc-HighQ bouts, they still contributed >50 % of consumption. Also, longer bouts under Alc-HighQ had an early, several-second period with greater chance of stopping, but afterwards showed similar persistence and recovery from slow licking as other drinking conditions. Together, our findings elucidate novel behavioral indicators of successful and unsuccessful epochs of Alc-HighQ, compulsion-like intake. We also relate findings to congruent human and animal work implicating anterior insula and medial prefrontal cortices as critical for compulsion-like alcohol responding, and where ventral frontal cortex has been more associated with overall action plan and tongue control (retained under Alc-HighQ), with medial cortex more related to proximal action timing (disrupted under Alc-HighQ except after faster bout initiation).Item Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats(MDPI, 2022-08-05) Katner, Simon N.; Sentir, Alena M.; Steagall, Kevin B.; Ding, Zheng-Ming; Wetherill, Leah; Hopf, Frederic W.; Engleman, Eric A.; Psychiatry, School of MedicineWith the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes “inflexible” after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 h free-choice paradigm). Further, after 4−5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs.Item Nucleus Accumbens Shell Orexin-1 Receptors Are Not Needed For Single-Bottle Limited Daily Access Alcohol Intake in C57BL/6 mice(Elsevier, 2020-12) Lei, Kelly; Kwok, Claudina; Hopf, Frederic W.; Psychiatry, School of MedicineExcessive, binge drinking is a major contributor to the great harm and cost of alcohol use disorder. We recently showed, using both limited and intermittent-access two-bottle-choice models, that inhibiting nucleus accumbens shell (Shell) orexin-1-receptors (Ox1Rs) reduces alcohol intake in higher-drinking male C57BL/6 mice (Lei et al., 2019). Other studies implicate Ox1Rs, tested systemically, for several higher-drinking models, including the single-bottle, Rhodes Drinking-in-the-Dark paradigm. Here, we report studies examining whether Shell Ox1Rs contribute to alcohol intake in male mice using a single-bottle Limited Daily Access (LDA) drinking model modified from drinking-in-the-dark paradigms (2-h access starting 3 h into the dark cycle, 5 days per week). In addition, some previous work has suggested possible differences in circuitry for one- versus two-choice behaviors, and thus other mice first drank under a single-bottle schedule, and then an additional water bottle was included 2 days a week starting in week 3. Surprisingly, at the same time we were determining Ox1R importance for two-bottle-choice models, parallel studies found that inhibiting Shell Ox1Rs had no impact on drinking using the single-bottle LDA model, or when a second bottle containing water was added later during drinking. Furthermore, we have related Shell Ox1R regulation of intake to basal consumption, but no such pattern was observed with single-bottle LDA drinking. Thus, unlike our previous work showing the importance of Shell Ox1Rs for male alcohol drinking under several two-bottle-choice models, Shell Ox1Rs were not required under a single-bottle paradigm, even if a second water-containing bottle was later added. These results raise the speculations that different mechanisms could promote intake under single- versus two-bottle access conditions, and that the conditions under which an animal learns to drink can impact circuitry driving future intake.Item Recent perspectives on orexin/hypocretin promotion of addiction-related behaviors(Elsevier, 2020-05-15) Hopf, Frederic W.; Medicine, School of MedicineThe neuropeptide hypocretin/orexin plays a broad and important role in physiological functions ranging from addiction, stress, and anxiety to sleep, energy metabolism, and homeostatic regulation. A number of recent reviews addressing the importance of orexin for different addictive behaviors, especially the contribution of orexin-1-receptors (Ox1Rs) in responding for intoxicants in higher-motivation individuals and situations, and orexin-2-receptor (Ox2Rs) in stress-related aspects of addictive responding. This may parallel the importance of more lateral orexin neurons in the hypothalamus for reward and more medial for stress and arousal. However, there is clearly also some crossover, which may reflect, in part, where positive and negative conditioning (reward- and relief-seeking) are both present concurrently in established addiction, and also where orexin signaling can differ in subregions of a particular brain region. Here, we attempt to examine and synthesize some of the most recent work addressing orexin functions in addiction, including a particular role for Ox1Rs for driving responding in higher-motivation individuals and under higher levels of effort. While there are some commonalities across addictive substances addressed here (alcohol, cocaine, opiates), there are also some differences, which may relate to several factors including the speed of intoxication with a given substance. Together, recent findings have shed important insight and clues into what a more unified role of Ox1Rs might entail, and critical areas for future work. In addition, these many studies support the development of Ox1R blockers for use in humans to counteract addiction and other disorders of motivation. This article is part of the special issue on Neuropeptides.Item Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking(MDPI, 2021-04-06) Radke, Anna K.; Sneddon, Elizabeth A.; Frasier, Raizel M.; Hopf, Frederic W.; Psychiatry, School of MedicineAlcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment.Item The role of anterior insula-brainstem projections and alpha-1 noradrenergic receptors for compulsion-like and alcohol-only drinking(Springer Nature, 2021) De Oliveira Sergio, Thatiane; Lei, Kelly; Kwok, Claudina; Ghotra, Shahbaj; Wegner, Scott A.; Walsh, Margaret; Waal, Jaclyn; Darevsky, David; Hopf, Frederic W.; Psychiatry, School of MedicineCompulsion-like alcohol drinking (CLAD), where consumption continues despite negative consequences, is a major obstacle to treating alcohol use disorder. The locus coeruleus area in the brainstem and norepinephrine receptor (NER) signaling in forebrain cortical regions have been implicated in adaptive responding under stress, which is conceptually similar to compulsion-like responding (adaptive responding despite the presence of stress or conflict). Thus, we examined whether anterior insula (aINS)-to-brainstem connections and alpha-1 NERs regulated compulsion-like intake and alcohol-only drinking (AOD). Halorhodopsin inhibition of aINS-brainstem significantly reduced CLAD, with no effect on alcohol-only or saccharin intake, suggesting a specific aINS-brainstem role in aversion-resistant drinking. In contrast, prazosin inhibition of alpha-1 NERs systemically reduced both CLAD and AOD. Similar to systemic inhibition, intra-aINS alpha-1-NER antagonism reduced both CLAD and AOD. Global aINS inhibition with GABAR agonists also strongly reduced both CLAD and AOD, without impacting saccharin intake or locomotion, while aINS inhibition of calcium-permeable AMPARs (with NASPM) reduced CLAD without impacting AOD. Finally, prazosin inhibition of CLAD and AOD was not correlated with each other, systemically or within aINS, suggesting the possibility that different aINS pathways regulate CLAD versus AOD, which will require further study to definitively address. Together, our results provide important new information showing that some aINS pathways (aINS-brainstem and NASPM-sensitive) specifically regulate compulsion-like alcohol consumption, while aINS more generally may contain parallel pathways promoting CLAD versus AOD. These findings also support the importance of the adaptive stress response system for multiple forms of alcohol drinking.