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Item A critical review of front-loading: A maladaptive drinking pattern driven by alcohol's rewarding effects(Wiley, 2022) Ardinger, Cherish E.; Lapish, Christopher C.; Czachowski, Cristine L.; Grahame, Nicholas J.; Psychology, School of ScienceFront‐loading is a drinking pattern in which alcohol intake is skewed toward the onset of reward access. This phenomenon has been reported across several different alcohol self‐administration protocols in a wide variety of species, including humans. The hypothesis of the current review is that front‐loading emerges in response to the rewarding effects of alcohol and can be used to measure the motivation to consume alcohol. Alternative or additional hypotheses that we consider and contrast with the main hypothesis are that: (1) front‐loading is directed at overcoming behavioral and/or metabolic tolerance and (2) front‐loading is driven by negative reinforcement. Evidence for each of these explanations is reviewed. We also consider how front‐loading has been evaluated statistically in previous research and make recommendations for defining this intake pattern in future studies. Because front‐loading may predict long‐term maladaptive alcohol drinking patterns leading to the development of alcohol use disorder (AUD), several future directions are proposed to elucidate the relationship between front‐loading and AUD.Item Aberrations in Incentive Learning and Responding to Heroin in Male Rats After Adolescent or Adult Chronic Binge-Like Alcohol Exposure(Wiley, 2020-06) Galaj, Ewa; Barrera, Eddy; Morris, Debra; Ma, Yao-Ying; Ranaldi, Robert; Pharmacology and Toxicology, School of MedicineBackground and purpose: Binge drinking is a serious problem among adolescents and young adults despite its adverse consequences on the brain and behavior. One area that remains poorly understood concerns the impact of chronic intermittent ethanol (CIE) exposure on incentive learning. Methods: Here, we examined the effects of CIE exposure during different developmental stages on conditioned approach and conditioned reward learning in rats experiencing acute or protracted withdrawal from alcohol. Two or 21 days after adolescent or adult CIE exposure, male rats were exposed to pairings of a light stimulus (CS) and food pellets for 3 consecutive daily sessions (30 CS-food pellet pairings per session). This was followed by conditioned approach testing measuring responses (food trough head entries) to the CS-only presentations and by conditioned reward testing measuring responses on a lever producing the CS and on another producing a tone. We then measured behavioral sensitization to repeated injections of heroin (2 mg/kg/d for 9 days). Results: Adolescent and adult alcohol-treated rats showed significantly impaired conditioned reward learning regardless of withdrawal period (acute or prolonged). We found no evidence of changes to conditioned approach learning after adolescent or adult exposure to CIE. Finally, in addition to producing long-term impairments in incentive learning, CIE exposure enhanced locomotor activity in response to heroin and had no effect on behavioral sensitization to heroin regardless of age and withdrawal period. Conclusions: Our work sets a framework for identifying CIE-induced alterations in incentive learning and inducing susceptibility to subsequent opioid effects.Item Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion(Elsevier, 2017-09) Melón, Laverne C.; Nolan, Zachary T.; Colar, Delphine; Moore, Eileen M.; Boehm II, Stephen L.; Psychology, School of ScienceRecent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABAA receptor subtypes expressing the δ-subunit protein (δ-GABAARs). Indeed, administration of agonists that interact with these δ-GABAARs prior to alcohol access can abolish binge drinking behavior in male mice. These δ-GABAARs have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal gray. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with THIP, an agonist with high selectivity and efficacy at δ-GABAARs. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2h of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of THIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5α-reduced neurosteroids did not disrupt THIP's effects. Analysis of δ-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABAA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that δGABAARs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABAA receptor subtype.Item Acute drug effects on habitual and non-habitual responding in crossed high alcohol preferring mice(Springer Nature, 2018-07) Houck, Christa A.; Grahame, Nicholas J.; Psychology, School of ScienceRATIONALE: Drug reward plays a central role in acquiring drug-seeking behavior. However, subjects may continue using drugs despite negative consequences because self-administration becomes habitual, and divorced from outcome values. Although a history of drug and alcohol use expedite habit acquisition, and in spite of the fact that self-administration leads to intoxication, the acute effects of drugs on habitual responding are not well understood. OBJECTIVES: We sought to observe how acute ethanol and amphetamine affect the balance between habitual and goal-directed behavior, as measured by a fluid-reinforced operant conditioning task. METHODS: Selectively bred crossed high-alcohol-preferring (cHAP) mice were trained on an operant conditioning task reinforced on a variable interval schedule with 1% banana solution, which was subsequently devalued via LiCl pairing in half the animals. Ethanol (1.0 g/kg), amphetamine (2.0 mg/kg), or saline was administered prior to a post-devaluation test. RESULTS: Overall, mice showed habitual behavior, but when divided into high- or low-responding groups based on training response rates, saline-treated, low-responding animals devalued, while saline-treated high-responding animals did not. Furthermore, amphetamine elicited devaluation even in high-responding animals, while ethanol prevented devaluation even in low-responding animals. CONCLUSIONS: These data show that ethanol shifts animals toward behaving habitually. This may illuminate why alcohol-intoxicated individuals display impaired judgment about the relative merits of drinking, and potentially serve as a mechanism by which intoxicated subjects resume previously devalued behaviors, such as comorbid drug use. These findings also show that high variable interval response rates facilitate a shift from goal-directed to habitual behavior.Item Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium(Elsevier, 2022-12) Singh, Vikesh K.; Whitcomb, David C.; Banks, Peter A.; AlKaade, Samer; Anderson, Michelle A.; Amann, Stephen T.; Brand, Randall E.; Conwel, Darwin L.; Cote, Gregory A.; Gardner, Timothy B.; Gelrud, Andres; Guda, Nalini; Forsmark, Christopher E.; Lewis, Michele; Sherman, Stuart; Muniraj, Thiruvengadam; Romagnuolo, Joseph; Tan, Xiaoqing; Tang, Gong; Sandhu, Bimaljit S.; Slivka, Adam; Wilcox, C. Mel; Yadav, Dhiraj; Medicine, School of MedicineIntroduction: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. Methods: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. Results: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3–5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. Conclusions: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.Item Adaptation of the 5-choice serial reaction time task to measure engagement and motivation for alcohol in mice(Frontiers Media, 2022-09-16) Starski, Phillip; Maulucci, Danielle; Mead, Hunter; Hopf, Frederic; Psychiatry, School of MedicineAlcohol use disorder (AUD) is related to excessive binge alcohol consumption, and there is considerable interest in associated factors that promote intake. AUD has many behavioral facets that enhance inflexibility toward alcohol consumption, including impulsivity, motivation, and attention. Thus, it is important to understand how these factors might promote responding for alcohol and can change after protracted alcohol intake. Previous studies have explored such behavioral factors using responding for sugar in the 5-Choice Serial Reaction Time Task (5-CSRTT), which allows careful separation of impulsivity, attention, and motivation. Importantly, our studies uniquely focus on using alcohol as the reward throughout training and testing sessions, which is critical for beginning to answer central questions relating to behavioral engagement for alcohol. Alcohol preference and consumption in male C57BL/6 mice were determined from the first 9 sessions of 2-h alcohol drinking which were interspersed among 5-CSRTT training. Interestingly, alcohol preference but not consumption level significantly predicted 5-CSRTT responding for alcohol. In contrast, responding for strawberry milk was not related to alcohol preference. Moreover, high-preference (HP) mice made more correct alcohol-directed responses than low-preference (LP) during the first half of each session and had more longer reward latencies in the second half, with no differences when performing for strawberry milk, suggesting that HP motivation for alcohol may reflect "front-loading." Mice were then exposed to an Intermittent Access to alcohol paradigm and retested in 5-CSRTT. While both HP and LP mice increased 5-CSRTT responding for alcohol, but not strawberry milk, LP performance rose to HP levels, with a greater change in correct and premature responding in LP versus HP. Overall, this study provides three significant findings: (1) alcohol was a suitable reward in the 5-CSRTT, allowing dissection of impulsivity, attention, and motivation in relation to alcohol drinking, (2) alcohol preference was a more sensitive indicator of mouse 5-CSRTT performance than consumption, and (3) intermittent alcohol drinking promoted behavioral engagement with alcohol, especially for individuals with less initial engagement.Item Adenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice(Elsevier, 2015-08) Fritz, Brandon M.; Boehm II, Stephen L.; Department of Psychology, School of ScienceWe recently observed that the addition of caffeine (a nonselective adenosine receptor antagonist) to a 20% ethanol solution significantly altered the intoxication profile of male C57BL/6J (B6) mice induced by voluntary binge-like consumption in the 'Drinking-in-the-Dark' (DID) paradigm. In the current study, the roles of A1 and A2A adenosine receptor subtypes, specifically, in binge-like ethanol consumption and associated locomotor effects were explored. Adult male B6 mice (PND 60-70) were allowed to consume 20% ethanol (v/v) or 2% sucrose (w/v) for 6days via DID. On day 7, mice received a systemic administration (i.p.) of the A1 antagonist DPCPX (1, 3, 6mg/kg), the A2A antagonist MSX-3 (1, 2, 4mg/kg), or vehicle immediately prior to fluid access in DID. Antagonism of the A1 receptor via DPCPX was found to dose-dependently decrease binge-like ethanol intake and associated blood ethanol concentrations (p's<0.05), although no effect was observed on sucrose intake. Antagonism of A2A had no effect on ethanol or sucrose consumption, however, MSX-3 elicited robust locomotor stimulation in mice consuming either solution (p's<0.05). Together, these findings suggest unique roles for the A1 and A2A adenosine receptor subtypes in binge-like ethanol intake and its associated locomotor effects.Item Adolescent alcohol and nicotine exposure alters the adult response to alcohol use(Frontiers Media, 2023-11-22) Hauser, Sheketha R.; Waeiss, Robert A.; Deehan, Gerald A., Jr.; Engleman, Eric A.; Bell, Richard L.; Rodd, Zachary A.; Psychiatry, School of MedicineAdolescence through young adulthood is a unique period of neuronal development and maturation. Numerous agents can alter this process, resulting in long-term neurological and biological consequences. In the clinical literature, it is frequently reported that adolescent alcohol consumption increases the propensity to develop addictions, including alcohol use disorder (AUD), during adulthood. A general limitation of both clinical and human pre-clinical adolescent alcohol research is the high rate of co-using/abusing more than one drug during adolescence, such as co-using/abusing alcohol with nicotine. A primary goal of basic research is elucidating neuroadaptations produced by adolescent alcohol exposure/consumption that promote alcohol and other drug self-administration in adulthood. The long-term goal is to develop pharmacotherapeutics for the prevention or amelioration of these neuroadaptations. This review will focus on studies that have examined the effects of adolescent alcohol and nicotine exposure on adult alcohol consumption, the hypersensitivity of the mesolimbic dopaminergic system, and enhanced responses not only to alcohol but also to nicotine during adulthood. Again, the long-term goal is to identify potential cholinergic agents to prevent or ameliorate the consequences of, peri-adolescent alcohol abuse.Item Alcohol exposure decreases osteopontin expression during fracture healing and osteopontin-mediated mesenchymal stem cell migration in vitro(BMC, 2018-04-27) Natoli, Roman M.; Yu, Henry; Meislin, Megan Conti-Mica; Abbasnia, Pegah; Roper, Philip; Vuchkovska, Aleksandra; Xiao, Xianghui; Stock, Stuart R.; Callaci, John J.; Orthopaedic Surgery, School of MedicineBACKGROUND: Alcohol consumption is a risk factor for impaired fracture healing, though the mechanism(s) by which this occurs are not well understood. Our laboratory has previously shown that episodic alcohol exposure of rodents negatively affects fracture callus development, callus biomechanics, and cellular signaling which regulates stem cell differentiation. Here, we examine whether alcohol alters chemokine expression and/or signaling activity in the mouse fracture callus during early fracture healing. METHODS: A mouse model for alcohol-impaired tibia fracture healing was utilized. Early fracture callus was examined for alcohol-effects on tissue composition, expression of chemokines involved in MSC migration to the fracture site, and biomechanics. The effects of alcohol on MSC migration and cell adhesion receptors were examined in an in vitro system. RESULTS: Mice exposed to alcohol showed decreased evidence of external callus formation, decreased callus-related osteopontin (OPN) expression levels, and decreased biomechanical stiffness. Alcohol exposure decreased rOPN-mediated MSC migration and integrin β1 receptor expression in vitro. CONCLUSIONS: The effects of alcohol exposure demonstrated here on fracture callus-associated OPN expression, rOPN-mediated MSC migration in vitro, and MSC integrin β1 receptor expression in vitro have not been previously reported. Understanding the effects of alcohol exposure on the early stages of fracture repair may allow timely initiation of treatment to mitigate the long-term complications of delayed healing and/or fracture non-union.Item Alcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum(Nature Publishing group, 2018-04-03) Muñoz, Braulio; Fritz, Brandon M.; Yin, Fuqin; Atwood, Brady K.; Psychiatry, School of MedicineDrugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. Given the role of the µ-opioid receptor (MOR) in behavioral responding for alcohol, we explored the impact of alcohol on various forms of MOR-mediated synaptic depression that we find are differentially expressed at specific DS synapses. Corticostriatal MOR-mediated LTD (mOP-LTD) in the dorsolateral striatum occurs exclusively at inputs from anterior insular cortex and is selectively disrupted by in vivo alcohol exposure. Alcohol has no effect on corticostriatal mOP-LTD in dorsomedial striatum, thalamostriatal MOR-mediated short-term depression, or mOP-LTD of cholinergic interneuron-driven glutamate release. Disrupted mOP-LTD at anterior insular cortex–dorsolateral striatum synapses may therefore be a key mechanism of alcohol-induced neuroadaptations involved in the development of alcohol use disorders., µ-opioid receptors (MOR) are known to modulate the reward effects of drugs of abuse, and MOR activation induces long-term depression (LTD) at striatal synapses. Here the authors show that alcohol exposure disrupts MOR-induced LTD only at specific cortical inputs to the striatum.