Weeks Of Drinking Research Articles

Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:tdTomato Transgenic Rats.

In 2021, 131 million adult Americans reported drinking alcohol in the last month, despite the well-known consequences of alcohol consumption. While alcohol use disorders (AUDs) are associated with both mood and chronic pain disorders, the relationship between alcohol drinking and affective and nociceptive behaviors remains unclear. Corticotropin releasing factor receptor-1 (CRF1) has been implicated in alcohol drinking, affective states, and pain sensitivity, often in a sex-dependent manner. In order to probe the effects of alcohol drinking on activity of CRF1+ cells and to also test the hypothesis that alcohol drinking is associated with both basal and subsequent affective and nociceptive readouts, we put male and female CRF1:cre:tdTomato rats through a battery of behavioral tests before and after intermittent access to alcohol. Following baseline testing, rats began alcohol (or water) drinking. Females consumed more alcohol in the first week, but there was no effect of sex on overall alcohol intake. Following three to four weeks of drinking, behavioral tests were repeated. Alcohol drinking decreased mechanical sensitivity, but no other effects of alcohol drinking were observed between experimental groups. Individual alcohol intake correlated with affective behavior in both sexes but only correlated with thermal sensitivity in males. There were no main effects of alcohol drinking or sex on CRF1+ neuronal activity in the medial prefrontal cortex (PFC) but final session alcohol intake correlated with activity in CRF1+ neurons in the infralimbic (IL) subregion. Together, our results suggest complex interplay between affective state, alcohol drinking, and the role of prefrontal CRF1+ neurons in mediating these behaviors.

Relationship between voluntary ethanol drinking and approach-avoidance biases in the face of motivational conflict: novel sex-dependent associations in rats.

Aberrant approach-avoidance conflict processing may contribute to compulsive seeking that characterizes addiction. Exploration of the relationship between drugs of abuse and approach-avoidance behavior remains limited, especially with ethanol. To investigate the effects of voluntary ethanol consumption on approach-avoidance conflict behavior and to examine the potential approach/avoidance bias to predict drinking in male and female rats. Long-Evans rats consumed ethanol for 5 weeks under the intermittent access two-bottle choice (IA2BC) paradigm. Approach-avoidance tendencies were assessed before and after IA2BC drinking using a previously established cued approach-avoidance conflict maze task and the elevated plus maze (EPM). Female rats displayed higher consumption of and preference for ethanol than males. In the conflict task, males showed greater approach bias towards cues predicting conflict than females. In females only, a median split and regression analysis of cued-conflict preference scores revealed that the more conflict-avoidant group displayed higher intake and preference for ethanol in the first few weeks of drinking. In both sexes, ethanol drinking did not affect cued-conflict preference, but ethanol exposure led to increased time spent in the central hub in the males only. Finally, anxiety levels in EPM predicted subsequent onset of ethanol drinking in males only. Our results highlight sex and individual differences in both drinking and approach-avoidance bias in the face of cued conflict and further suggest that cued-conflict preference should be examined as a potential predictor of ethanol drinking. Ethanol exposure may also affect the timing of decision-making in the face of conflict.

Additive influences of acute early life stress and sex on vulnerability for aversion-resistant alcohol drinking.

Acute early life stress (ELS) alters stress system functioning in adulthood and increases susceptibility to posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). The current study assessed the effects of acute, infant ELS on alcohol drinking, including aversion-resistant drinking, in male and female Long Evans rats. Acute ELS was induced using a stress-enhanced fear learning (SEFL) protocol that consisted of 15 footshocks delivered on postnatal day (PND) 17. Alcohol drinking during adolescence and adulthood was measured with a two-bottle choice intermittent alcohol access paradigm. Aversion-resistant drinking was assessed in adulthood by adding quinine (0.01, 0.1, and 1.0 g/L) to the alcohol bottle after 5 to 6 weeks and 11 to 12 weeks of drinking. ELS had minimal influences on adolescent and adult alcohol consumption and preference. However, ELS, sex, and alcohol exposure history all influenced aversion-resistant alcohol drinking in an additive fashion. Higher concentrations of quinine were tolerated in females, ELS-exposed rats, and after 11 to 12 weeks of drinking. Tests of quinine sensitivity in a separate cohort of animals found that rats can detect concentrations of quinine as low as 0.001 g/L in water and that quinine sensitivity is not influenced by sex or ELS exposure. These results agree with reports of sex differences in aversion-resistant drinking and are the first to demonstrate an influence of ELS on this behavior. Our results also suggest that a single traumatic stress exposure in infancy may be a promising model of comorbid PTSD and AUD and useful in studying the interactions between ELS, sex, and alcohol dependence.

Weighing the Pros and Cons of Using Alcohol Protective Behavioral Strategies: A Qualitative Examination among College Students

ABSTRACTBackground: Alcohol protective behavioral strategies (PBS) are behaviors engaged in immediately prior to, during, after, or instead of drinking with the explicit goal of reducing alcohol use, intoxication, and/or alcohol-related harms. Despite the quantitative support for alcohol PBS as a protective factor among college student drinkers, we know of no qualitative research aimed at determining college student drinkers' perceptions regarding the advantages and disadvantages of using PBS. Objectives: In the style of a decisional balance exercise, we asked college student drinkers (analytic n = 113) to identify 5 reasons they would not use PBS (cons) and 5 reasons they would use PBS (pros). Method: Participants (majority female, 77.0%) were recruited from a psychology department participant pool at a large, southeastern university in the United States. Within our analytic sample, participants on average consumed 6.38 (SD = 8.16) drinks per typical week of drinking and reported consuming alcohol on average 7.5 days (SD = 5.83) in the last 30 days. Results: Using a descriptive phenomenological approach, we identified 2 themes for pros (prevention of specific negative alcohol-related consequences and general safety) and 4 themes for cons (goal conflict, ineffectiveness, difficulty of implementation, and negative peer/social repercussions). Overall, participants reported more pros than cons and this discrepancy (i.e., number of PBS pros minus number of PBS cons) was positively related to self-reported frequency of PBS use. Conclusions/Importance: Taken together, we hope that clinicians/researchers will probe individual's reasons for choosing to use (or not use) PBS in order to tailor or improve existing PBS-based interventions.

Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism.

Episodic bouts of social stress can precede the initiation, escalation, or relapse to disordered alcohol intake. Social stress may engender neuroadaptations in the hypothalamic-pituitary-adrenal (HPA) axis and in extrahypothalamic stress circuitry to promote the escalation of alcohol intake. We aimed to (1) confirm a pattern of escalated drinking in socially defeated mice and to (2) test drugs that target distinct aspects of the HPA axis and extrahypothalamic neural substrates for their effectiveness in reducing murine, stress-escalated drinking. Male C57BL/6J (B6) mice were socially defeated by resident Swiss-derived males for ten consecutive days receiving 30 bites/day. Ten days after the final defeat, cohorts of B6 mice received continuous or intermittent access to 20% EtOH (w/v) and water. After 4weeks of drinking, mice were injected with weekly, systemic doses of the CRF-R1 antagonist, CP376395; the glucocorticoid receptor antagonist, mifepristone; the 11-beta-hydroxylase inhibitor, metyrapone; or the 5-alpha-reductase inhibitor, finasteride. Prior to drug treatments, defeated mice reliably consumed more EtOH than non-defeated controls, and mice given alcohol intermittently consumed more EtOH than those with continuous access. CP376395 (17-30mg/kg) reduced continuous, but not intermittent EtOH intake (g/kg) in socially defeated mice. Mifepristone (100mg/kg), however, increased drinking by defeated mice with intermittent access to alcohol while reducing drinking during continuous access. When administered finasteride (100mg/kg) or metyrapone (50mg/kg), all mice reduced their EtOH intake while increasing their water consumption. Mice with a history of episodic social defeat stress were selectively sensitive to the effects of CRF-R1 antagonism, suggesting that CRF-R1 may be a potential target for treating alcohol use disorders in individuals who escalate their drinking after exposure to repeated bouts of psychosocial stress. Future studies will clarify how social defeat stress may alter the expression of extrahypothalamic CRF-R1 and glucocorticoid receptors.

A single alcohol drinking session is sufficient to enable subsequent aversion-resistant consumption in mice.

Addiction is mediated in large part by pathological motivation for rewarding, addictive substances, and alcohol-use disorders (AUDs) continue to extract a very high physical and economic toll on society. Compulsive alcohol drinking, where intake continues despite negative consequences, is considered a particular obstacle during treatment of AUDs. Aversion-resistant drives for alcohol have been modeled in rodents, where animals continue to consume even when alcohol is adulterated with the bitter tastant quinine, or is paired with another aversive consequence. Here, we describe a two-bottle choice paradigm where C57BL/6 mice first had 24-h access to 15% alcohol or water. Afterward, they drank quinine-free alcohol (alcohol-only) or alcohol with quinine (100μM), in a limited daily access (LDA) two-bottle-choice paradigm (2h/day, 5 days/week, starting 3h into the dark cycle), and achieved nearly binge-level blood alcohol concentrations. Interestingly, a single, initial 24-h experience with alcohol-only enhanced subsequent quinine-resistant drinking. In contrast, mice that drank alcohol-quinine in the 24-h session showed significantly reduced alcohol-quinine intake and preference during the subsequent LDA sessions, relative to mice that drank alcohol-only in the initial 24-h session and alcohol-quinine in LDA sessions. Thus, mice could find the concentration of quinine we used aversive, but were able to disregard the quinine after a single alcohol-only drinking session. Finally, mice had low intake and preference for quinine in water, both before and after weeks of alcohol-drinking sessions, suggesting that quinine resistance was not a consequence of increased quinine preference after weeks of drinking of alcohol-quinine. Together, we demonstrate that a single alcohol-only session was sufficient to enable subsequent aversion-resistant consumption in C57BL/6 mice, which did not reflect changes in quinine taste palatability. Given the rapid development of quinine-resistant alcohol drinking patterns, this model provides a simple, quick, and robust method for uncovering the mechanisms that promote aversion-resistant consumption.

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The effect of red wine consumption on hormonal reproductive parameters and total antioxidant status in young adult male rats.

Very little is known about the effects of red wine consumption on male reproductive functions. Here we report the effect of regular drinking of different types of red wine on hormonal reproductive parameters and total antioxidant status in young adult male rats. Dry red wine (D-RW) exerted higher antioxidant activity and was characterized by higher concentration of phenolic compounds compared to semi-dry (SD-RW), sweet (S-RW) and semi-sweet (SS-RW) wines. No differences in total antioxidant status of rat plasma after six weeks of drinking of the wines were detected. Increased plasma follicle-stimulating hormone levels in S-RW versus control and D-RW (5.26 vs. 3.06 and 3.21 ng mL(-1)) groups were found. The plasma testosterone concentration was lower in D-RW compared to control, SD-RW, S-RW and SS-RW groups (0.25 vs. 1.12, 1.09, 1.54 and 1.25 ng mL(-1)). Higher plasma 17β-estradiol level in S-RW versus SD-RW and SS-RW (10.94 vs. 7.18 and 6.72 pg mL(-1)) group was stated. The prolactin level was higher in plasma of S-RW versus D-RW and SS-RW (17.35 vs. 9.74 and 8.59 ng mL(-1)) rats. The effects of red wine drinking on the hormonal regulation of the male reproductive system depend on the type and the dose of red wine. Chemical compounds naturally occurring in red wines (i.e. phenolics) may modulate the effects of ethyl alcohol, but also directly affect the male reproduction.

Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water

BackgroundHydrogen has been reported to relieve damage in many disease models, and is a potential additive in drinking water to provide protective effects for patients as several clinical studies revealed. However, the absence of a dose–response relationship in the application of hydrogen is puzzling. We attempted to identify the dose–response relationship of hydrogen in alkaline electrolyzed drinking water through the aspirin induced gastric injury model.MethodsIn this study, hydrogen-rich alkaline water was obtained by adding H2 to electrolyzed water at one atmosphere pressure. After 2 weeks of drinking, we detected the gastric mucosal damage together with MPO, MDA and 8-OHdG in rat aspirin induced gastric injury model.ResultsHydrogen-dose dependent inhibition was observed in stomach mucosal. Under pH 8.5, 0.07, 0.22 and 0.84 ppm hydrogen exhibited a high correlation with inhibitory effects showed by erosion area, MPO activity and MDA content in the stomach. Gastric histology also demonstrated the inhibition of damage by hydrogen-rich alkaline water. However, 8-OHdG level in serum did not have significant hydrogen-dose dependent effect. pH 9.5 showed higher but not significant inhibitory response compared with pH 8.5.ConclusionsHydrogen is effective in relieving the gastric injury induced by aspirin-HCl, and the inhibitory effect is dose-dependent. The reason behind this may be that hydrogen-rich water directly interacted with the target tissue, while the hydrogen concentration in blood was buffered by liver glycogen, evoking a suppressed dose–response effect. Drinking hydrogen-rich water may protect healthy individuals from gastric damage caused by oxidative stress.

P01-127 - Psychophysiological abstinence

How the psychophysiological functions (cognition, attention, memory, neuropsychic functions) change after alcohol use at different doses remains poorly understood. This study examines the extent to which the psychophysiological functions are restored after moderate dose of alcoholic beverages. University students (non-alcohol users; alcohol users after 1–2 weeks and 3–6 weeks of drinking) approved their participation on a consent form after the aims and objectives of the study had been explained. Continuous Tests using psychphysiological methods were applied to produce maximum stressed condition for the participants. The statistical value for significance was set at p < 0.05. No significant changes in the psychophysiological functions were noted among the non-alcohol users. There was a significant decrease in psychophysiological functions of alcohol users in course of the study. Restoration of the psychophysiological functions was recorded only among drinkers of 3–6 weeks after alcohol use. Restoration of psychophysiological functions after alcohol use may take 3–6 weeks interval (abstinence time frame i.e. psychophysiological abstinence).

Impact of Alcohol Use Patterns on Clinical Outcomes in Patients with Chronic Pancreatitis

Purpose: While it is well known that chronic pancreatitis (CP) is commonly caused by alcohol consumption, the relationship between amount and duration of alcohol consumption and development of CP is unclear. Moreover, there is no information on patterns of drinking in CP patients and how they relate to outcomes such as pain, development of exocrine failure and diabetes mellitus (DM). This study: (1) Characterized recent and lifetime alcohol use in subjects with CP; and (2) Assessed impact of alcohol use on CP outcomes (pain, exocrine failure, DM). Methods: Participants were consecutive patients with CP who provided informed consent. Quantity and frequency of recent (past 90 days) drinking was measured with the Timeline Follow-Back Interview. In addition, drinking patterns for a typical week prior to most recent abstinence and for the period of heaviest alcohol use (lifetime) were recorded. Pain was characterized as type A (flares of pain with normal intervening periods) and type B (chronic continuous pain). Exocrine insufficiency was defined by presence of steatorrhea or fecal elastase < 200 mcg/gm. CP participant subgroups were compared using Students t-tests in SPSS. To-date 36 CP subjects (56% male; mean age 44.9 yrs; 50% African-American) have been enrolled. Results: In a preliminary analysis, average drinks per day during a typical week prior to most recent abstinence and during a week of heaviest drinking were 10.2 and 10.9, respectively. Subjects with type A pain had higher drinking amounts and total drinks, but a trend toward fewer days suggesting more binge patterning (P= 0.006) during heavier as well as typical drinking weeks, respectively (8.4 vs 6.6 drinks/day) (P= 0.007). CP patients with DM (DM+) reported histories of heavier drinking than CP subjects without DM (DM-). DM+ patients also consumed more than twice as many drinks per day (18.4. vs 7.9, respectively); twice as many drinks on the days they drank (21.8 vs 11.8, respectively) and nearly 3 times as many total drinks per week (129 vs 56) (P= 0.038) as DM- patients. Similarly patterns were seen for heaviest week of drinking (P= 0.002). In contrast, comparisons of CP patients with and without exocrine failure found no group differences in patterns of alcohol consumption (recent or heaviest ever). Conclusion: CP subjects who indulge in binge drinking are at greater risk for being DM+ and for having type A pain than non-binge drinking CP subjects.

A phenotype-driven ENU mutagenesis screen for the identification of dominant mutations involved in alcohol consumption

The aim of this study was the application of a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice for the identification of dominant mutations involved in the regulation and modulation of alcohol-drinking behavior. The chemical mutagen ENU was utilized in the generation of 131 male ENU-mutant C57BL/6J mice (G0). These ENU-treated mice were paired with wild-type C57BL/6J mice to generate G1 and subsequent generations. In total, 3327 mice were generated. Starting with G1, mice were screened for voluntary oral self-administration of 10% (v/v) alcohol vs. water in a two-bottle paradigm. From these mice, after a total period of 5 weeks of drinking, 43 mutants fulfilled the criteria of an "alcohol phenotype," that is, high or low ethanol intake. They were then selected for breeding and tested in a "confirmation cross" (G2-G4) for inheritance. Although we did not establish stable high or low drinking lines, several results were obtained in the context of alcohol consumption. First, female mice drank more alcohol than their male counterparts. Second, the former demonstrated greater infertility. Third, all animals displayed relatively stable alcohol intake, although significantly different in two different laboratories. Finally, seasonal and monthly variability was observed, with the highest alcohol consumption occurring in spring and the lowest in autumn. In conclusion, it seems difficult to identify dominant mutations involved in the modulation or regulation of voluntary alcohol consumption via a phenotype-driven ENU mutagenesis screen. In accordance with the findings from knockout studies, we suggest that mainly recessive mutations contribute to an alcohol-drinking or alcohol-avoiding phenotype.

Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons

Hippocampal neurogenesis is known as the formation of new neurons from the proliferating neural progenitor cells (NPC) at the dentate gyrus. Cell proliferation, survival, differentiation and maturation are critical stages leading to the generation of healthy neurons. As all of these stages can be influenced by alcohol exposure, we studied the effects of chronic alcohol on each process by immunocytochemistry for stage-specific antigens and prelabelling newborn cells with bromodeoxyuridine (BrdU). Rats were administered alcohol liquid diet or control diet for one, two or four weeks. We found that cell proliferation was inhibited as proliferating cell nuclear antigen (PCNA) expression was reduced by approximately 50% in alcohol-treated animals at all time points. Doublecortin (DCX), a microtubule protein expressed early in differentiating neurons, was progressively decreased over the duration of exposure and significantly reduced after two and four weeks of drinking. Morphological analyses of DCX-positive cells revealed that four weeks of alcohol treatment reduced the size of the dendritic tree including the total length of apical dendrites, number of nodes and endings. Furthermore, BrdU labelling demonstrated a dramatic decrease in cell survival after four weeks of drinking, while cell death was increased by such treatment. Confocal analysis indicated that over 80% of BrdU+ cells colabelled with NeuN suggesting that alcohol reduced neurogenesis. In conclusion, chronic alcohol exposure disrupts neurogenesis by decreasing NPC proliferation, inhibiting cell survival and altering morphological maturation of newborn neurons. These data implicate impaired hippocampal neurogenesis with the cognitive and affective dysfunction associated with chronic alcoholism.