Binge and high-intensity drinking-Associations with intravenous alcohol self-administration and underlying risk factors.

Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.

Translating preclinical models of alcohol seeking and consumption into the human laboratory using intravenous alcohol self-administration paradigms.

Preclinical models of alcohol use disorder (AUD) have advanced theoretical, mechanistic, and pharmacological study of the human condition. "Liking" and "wanting" behaviors reflect core processes underlying several models of AUD. However, the development and application of translational models of these preclinical approaches are at an incipient stage. The goal of this study was to examine how intravenous free-access and progressive-ratio, operant-response human alcohol self-administration paradigms can be used as translational human model parallels of preclinical "liking" and "wanting." Participants were 40 adults (mean age = 23.7, SD = 2.0; 45% female) of European descent who reported 12.6 drinking days (SD = 5.2) out of the previous 30 (average = 4.1 drinks per drinking day [SD = 1.7]). Individuals diverged in their alcohol self-administration behavior, such that free-access and progressive-ratio paradigm outcomes were not significantly correlated (p = 0.44). Free-access alcohol seeking was related to enjoying alcohol (p < 0.001), but not craving (p = 0.48), whereas progressive-ratio seeking at similar levels of alcohol exposure was related to craving (p = 0.02), but not enjoying (p = 0.30). Family history of alcoholism, venturesomeness traits, and disinhibition traits were unrelated (ps > 0.70) to preferred level of breath alcohol concentration (BrAC) in the free-access session, a measure of liking alcohol. Family history of alcoholism, disinhibition traits, and recent drinking history were significantly related (ps < 0.05) to alcohol seeking in the progressive-ratio paradigm, a measure of wanting alcohol. We conclude that intravenous alcohol self-administration paradigms show promise in modeling behaviors that characterize and parallel alcohol "liking" and "wanting" in preclinical models. These paradigms provide a translational link between preclinical methods and clinical trials.

Sex Differences in Motivation to Self-Administer Alcohol After 2 Weeks of Abstinence in Young-Adult Heavy Drinkers.

BACKGROUND: Studies in animal models document that forced abstinence from usual consumption of alcohol changes subsequent seeking and consumption, with increases or decreases depending on the species, duration of abstinence, number of deprivations, and sex. Human laboratory-based alcohol deprivation studies are rare. METHODS: We conducted a 2-session, within-participant, randomized-order comparison of intravenous, progressive ratio, alcohol self-administration during 2.5 hours of progressive work for alcohol and/or vehicle; once while the participants pursued their usual drinking habits and once after 2 weeks of closely monitored, voluntary outpatient abstinence from alcohol. The schedule of work for rewards and the incremental increases in breath alcohol concentration following completion of an alcohol work-set were identical across participants. Fifty young-adult (27 men), heavy-drinking participants completed both sessions. Our primary hypothesis was that motivation to work for alcohol after 2 weeks of abstinence would be greater in participants with a weekly binge pattern of drinking, compared to those who regularly drink heavily, and we intended to explore associations with biological family history of alcoholism and sex. RESULTS: We detected no change in work for alcohol associated with recent drinking history. However, females, on average, increased their work for alcohol upon resumption after 2 weeks of abstinence (mean ± SEM = +16.3 ± 9.6%), while males decreased that work (-24.8 ± 13.8%). The sex difference was substantial and significant (p < 0.03), with a medium effect size (Cohen's d = 0.63). CONCLUSIONS: We believe a more comprehensive study of mechanisms underlying the sex differences in the human postabstinence response is warranted.

Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking.

BACKGROUND: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS: One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS: Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS: Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.

Fat-free mass accounts for most of the variance in alcohol elimination rate in women.

BACKGROUND: Understanding how blood alcohol concentrations (BAC) achieved after drinking are determined is critical to predicting alcohol exposure to the brain and other organs and alcohol's effects. However, predicting end-organ exposures is challenging, as there is wide variation in BAC achieved after drinking a specified volume of alcohol. This variation is partly due to differences in body composition and alcohol elimination rates (AER), but there are limited data on how obesity affects AER. Here, we assess associations between obesity, fat-free mass (FFM), and AER in women and examine whether bariatric surgeries, which are linked to an increased risk of alcohol misuse, affect these associations. METHODS: We analyzed data from three studies that used similar intravenous alcohol clamping procedures to estimate AER in 143 women (21 to 64 years old) with a wide range of body mass index (BMI; 18.5 to 48.4 kg/m2 ). Body composition was measured in a subgroup using dual-energy X-ray absorptiometry (n = 42) or Bioimpedance (n = 60), and 19 of the women underwent bariatric surgery 2.1 ± 0.3 years before participation. We analyzed data using multiple linear regression analyses. RESULTS: Obesity and older age were associated with a faster AER (BMI: rs  = 0.70 and age: rs  = 0.61, both p < 0.001). Compared to women with normal weight, AER was 52% faster (95% Confidence Interval: 42% to 61%) in women with obesity. However, BMI lost predictive value when adding fat-free mass (FFM) to the regression model. Age, FFM, and its interaction explained 72% of individual variance in AER (F (4, 97) = 64.3, p < 0.001). AER was faster in women with higher FFM, particularly women in the top tertile of age. After controlling for FFM and age, bariatric surgery was not associated with differences in AER (p = 0.74). CONCLUSIONS: Obesity is associated with a faster AER, but this association is mediated by an obesity-related increase in FFM, particularly in older women. Previous findings of a reduced alcohol clearance following bariatric surgery compared with prior to surgery are likely explained by a reduction in FFM post-surgery.

Circadian entrainment by food and drugs of abuse.

Circadian rhythms organize behavior and physiological processes to be appropriate to the predictable cycle of daily events. These rhythms are entrained by stimuli that provide time of day cues (zeitgebers), such as light, which regulates the sleep-wake cycle and associated rhythms. But other events, including meals, social cues, and bouts of locomotor activity, can act as zeitgebers. Recent evidence shows that most organs and tissues contain cells that are capable of some degree of independent circadian cycling, suggesting the circadian system is broadly and diffusely distributed. Within laboratory studies of behavior, circadian rhythms tend to be treated as a complication to be minimized, but they offer a useful model of predictable shifts in behavioral tendencies. In the present review, we summarize the evidence that formed the basis for a hypothesis that drugs of abuse can entrain circadian rhythms and describe the outcome of a series of experiments designed to test that hypothesis. We propose that such drug-entrained rhythms may contribute to demonstrated daily variations in drug metabolism, tolerance, and sensitivity to drug reward. Of particular importance, these rhythms may be evoked by a single episode of drug taking, strengthen with repeated episodes, and re-emerge after long periods of abstinence, thereby contributing to drug abuse, addiction, and relapse.

Pre- and post-nicotine circadian activity rhythms can be differentiated by a paired environmental cue.

Previous studies have shown that addictive drugs presented daily at fixed times produce circadian (oscillator-driven) anticipatory and evoked activity rhythms in rats. Other studies have shown that environmental cues paired with addictive drugs produce tolerance to drug effects and elicit craving behavior when presented without the drug. The present study tested these circadian entrainment and paired-cue conditioning effects together. This study compared the ability of daily nicotine and saline injections at different fixed times to entrain pre-injection (anticipatory) and post-injection (evoked) circadian activity rhythms in two groups of female Sprague-Dawley rats. One group (Paired) had an environmental cue (a tone) paired with the effects of the nicotine injection, and the second group (Unpaired) had the tone paired with the effects of the saline injection. The rats were housed singly for 56 days in chambers with attached wheels under constant dim light and rate-limited food access. During three separate injection phases, nicotine and saline were administered daily at different fixed times, and the tone was presented at the second injection time. Three multi-day test phases examined circadian activity (a) without injections or tone, (b) with the tone alone at normal and novel times, and (c) with the tone absent and with injections occurring at normal and at novel times. The results showed that nicotine entrained both pre- and post-injection circadian oscillators, and the nicotine-paired tone interfered with pre-injection anticipatory activity.

Alcohol affects the P3 component of an adaptive stop signal task ERP.

BACKGROUND: The P3 component of the event-related potential (ERP) has been particularly useful in alcohol research for identifying endophenotypes of alcohol-use disorder (AUD) risk in sober subjects. However, practice and/or fatigue reduce P3 amplitude, limiting the ability to ascertain acute and adaptive effects of alcohol exposure. Here, we report acute alcohol effects on P3 amplitude and latency using an adaptive stop signal task (aSST). METHODS: One hundred forty-eight non-dependent moderate to heavy social drinkers, ages 21 to 27, participated in two single-blind, alcohol or placebo, counterbalanced sessions approximately 1 week apart. During each session, subjects performed an adaptive stop signal task (aSST) at 1) baseline, 2) upon reaching the target 60 mg/dL breath alcohol concentration or at the equivalent time during the placebo session, and 3) approximately 135 min later while the breath alcohol concentration was clamped. Here, we report on differences between baseline and first subsequent measurements across the experimental sessions. During each aSST run, the stop signal delay (SSD, the time between stop and go signals) adjusted trial-by-trial, based on the subject's performance. RESULTS: The aSST reliably generated a STOP P3 component that did not change significantly with repeated task performance. The pre-infusion SSD distribution was bimodal, with mean values several hundred msec apart (FAST: 153 msec and SLOW: 390 msec). This suggested different response strategies: FAST SSD favoring "going" over "stopping", and SLOW SSD favoring "stopping" over "going". Exposure to alcohol at 60 mg/dL differentially affected the amplitude and latency of the STOP P3 according to SSD group. Alcohol significantly reduced P3 amplitude in the SLOW SSD compared to the FAST SSD group, but significantly increased P3 latency in the FAST SSD compared to the SLOW SSD group. CONCLUSIONS: The aSST is a robust and sensitive task for detecting alcohol-induced changes in inhibition behavior as measured by the P3 component in a within-subject design. Alcohol was associated with P3 component changes, which varied by SSD group, suggesting a differential effect as a function of task strategy. Overall, the data support the potential utility of the aSST in the detection of alcohol response-related AUD risk.

Drugs of abuse can entrain circadian rhythms.

Circadian rhythms prepare organisms for predictable events in the 24 h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.

Amphetamine inhibits behavior-related neuronal responses in substantia nigra pars reticulata of rats working for sucrose reinforcement.

Changes in activity of basal ganglia neurons, especially those in the striatum, are thought to underlie the characteristic behavioral patterns produced by d-amphetamine (AMPH). To study the role of the substantia nigra pars reticulata (SNr), a major basal ganglia output nucleus, we recorded from SNr neurons before and after a behaviorally activating dose of AMPH (0.5 mg/kg) in rats trained to nosepoke for sucrose reinforcement. Before AMPH, task-related behaviors were associated primarily with increases or both increases and decreases in SNr firing. Although these same behavior-related patterns persisted after AMPH, their relative magnitude was significantly attenuated. Units unresponsive during task events were unaffected by AMPH. Thus, rather than change the overall level of SNr firing, a behaviorally active dose of AMPH exerts context-dependent effects on the activity of SNr neurons.

Nucleus accumbens single-unit activity in freely behaving male rats during approach to novel and non-novel estrus.

To assess the role of nucleus accumbens (NAcc) during approach to novel sexually arousing stimuli, we evaluated NAcc single-unit activity in male rats during the presentation of vaginal estrus extracted from novel and familiar female rats. After control stimulus presentations, animals were exposed to two estrous presentations from a female in the same or separate colony. A significantly larger proportion of units increased firing rate in the novel (11/32; 34%) than the familiar condition (2/28; 7%) during approach to the first but not the second presentation. Response magnitudes to novel but not familiar estrus were also greater than those during control trials. Collectively, these results provide further evidence of a role for the NAcc in the processing of novel sexually arousing information.

Intravenous alcohol self-administration in the P rat.

Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be temporally separate from time of intake) and the more temporally "relevant" effects (primarily olfactory and taste) that bridge the time from intake to onset of the pharmacological effects. Intravenous (IV) self-administration of ethanol limits the confounding "non-pharmacological" effects associated with oral consumption, allows for controlled and precise dosing, and bypasses first order absorption kinetics, allowing for more direct and better-controlled assessment of alcohol's effect on the brain. IV ethanol self-administration has been reliably demonstrated in mouse and human experimental models; however, models of IV self-administration have been historically problematic in the rat. An operant multiple-schedule study design was used to elucidate the role of each component of a compound IV-ethanol plus oral-sucrose reinforcer. Male alcohol-preferring P rats had free access to both food and water during all IV self-administration sessions. Animals were trained to press a lever for orally delivered 1% sucrose (1S) on a fixed ratio 4 schedule, and then surgically implanted with an indwelling jugular catheter. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5-min components across 30-min sessions. For the multiple schedule, two components were used: an oral 1S only and an oral 1S plus IV 20% ethanol (25 mg/kg/injection). Average total ethanol intake was 0.47 ± 0.04 g/kg. We found significantly higher earning of sucrose-only reinforcers and greater sucrose-lever error responding relative to the compound oral-sucrose plus IV-ethanol reinforcer. These response patterns suggest that sucrose, not ethanol, was responsible for driving overall responding. The work with a compound IV ethanol-oral sucrose reinforcer presented here suggests that the existing intravenous ethanol self-administration methodology cannot overcome the aversive properties of ethanol via this route in the rat.

Behavioral characteristics and pharmacological manipulations of a nicotine-entrainable circadian oscillator.

Chronic daily administration of nicotine and other drugs of abuse has been found to entrain pre- and post-drug circadian locomotor activity episodes that oscillate on a 24-h schedule and persist for several days after administration ceases. This drug-entrainable oscillator system could conceivably lead to circadian rhythms of drug seeking and drug use in human drug addicts. The present study (1) characterizes the ability of daily nicotine administration to entrain circadian wheel-running activity episodes in rats across a range of doses, lighting schedules, and food access; and (2) tests whether pre- and post-nicotine episodes can be altered through pharmacological manipulations. Adult female rats were housed in wheel boxes for 35-60 d, and both wheel-running and feeding-related behaviors were measured continuously. Following acclimation, nicotine or saline was administered for 16-24 d, and the rats were left undisturbed for several test days to observe the persistence of nicotine-entrained activity. The results showed that nicotine dose-dependently entrains wheel-running activity, and the highest dose of 1.0 mg/kg produces robust pre- and post-nicotine circadian activity episodes under constant, fixed, and variable light/dark schedules. In the pharmacological manipulation experiment, nicotine-entrained rats were administered one of seven pharmacological treatments (varenicline, mecamylamine, acamprosate, topiramate, naltrexone, SB-334867, or bupropion) in place of the nicotine injection for 2 d, and the rats were not disturbed for four subsequent days. Most of the treatment drugs significantly reduced post-nicotine activity episodes, but only three treatments affected pre-nicotine episodes: the µ- and κ-opioid receptor antagonist naltrexone, the orexin-1 receptor antagonist SB-334867, and the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)/kainate antagonist topiramate. These results show that chronic daily nicotine administration is a robust zeitgeber that dose-dependently entrains a nonphotic oscillator system that includes opioid, orexin, and glutamate pathways.

Effects of multiple daily nicotine administrations on pre- and post-nicotine circadian activity episodes in rats.

Administration of a single daily dose of nicotine has been shown to entrain circadian activity episodes both preceding and following the administration time that persist for several days after drug administration ceases. The present study tested the effects of multiple daily nicotine administrations on circadian activity episodes in adult female rats kept under constant light and rate-limited food access. Eight rats received 7 separate 7-day nicotine injection series, each followed by a 3-day test phase without injections. Subcutaneous nicotine was administered once a day during the 1st and 7th series, twice daily during the 2nd and 6th series, three times daily during the 3rd and 5th series, and four times daily during the 4th series. To control the cumulative daily dose throughout the study, 1.0 mg/kg nicotine was evenly divided among the injections within a single day. Pre- and post-administration effects of nicotine declined across the day, and significant entrainment of both pre- and post-nicotine episodes occurred for only one daily injection in each series. Additionally, post-nicotine episodes showed a different dose-response curve than the pre-nicotine episodes: post-nicotine wheel turns increased as the dose decreased, whereas pre-nicotine wheel turns remained relatively constant as the dose changed. These results provide evidence that nicotine-induced circadian entrainment to a single administration time does occur when the drug is administered multiple times a day, and pre- and post-nicotine circadian episodes are mediated at least partially by separate mechanisms.

Fentanyl, but not haloperidol, entrains persisting circadian activity episodes when administered at 24- and 31-h intervals.

Administration of several drugs of abuse on a 24-h schedule has been shown to entrain both pre-drug (anticipatory) and post-drug (evoked) circadian activity episodes that persist for several days when the drug is withheld. The present study tested the entrainment effects of fentanyl, an opioid agonist with a noted abuse liability, and haloperidol, an anti-psychotic dopamine antagonist without apparent abuse liability. Adult female Sprague-Dawley rats housed under constant light in cages with attached running wheels received repeated low, medium, or high doses of either fentanyl or haloperidol on a 24-h administration schedule followed by a 31-h schedule (Experiment 1) or solely on a 31-h schedule (Experiment 2). The results showed that all three doses of fentanyl entrained both pre-drug and post-drug episodes of wheel running when administered every 24h, and the combined pre- and post-fentanyl activity episodes persisted for at least 3 days when the drug was withheld during test days. On the 31-h schedule, fentanyl produced an "ensuing" activity episode approximately 24h post-administration, but failed to produce an anticipatory episode 29-31h post-administration. In contrast, haloperidol injections failed to produce both pre-drug episodes on the 24-h schedule and circadian ensuing episodes on the 31-h schedule, and post-haloperidol suppression of activity appeared to mask the free-running activity rhythm. Taken together, these results provide additional evidence that drugs of abuse share a common ability to entrain circadian activity episodes.

Nitrous oxide acutely suppresses ethanol consumption in HAD and P rats.

Nitrous oxide (N2O) has been reported to reduce post-withdrawal craving in alcoholic humans, aiding in their continued abstinence. This article assessed the ability of N2O to suppress alcohol drinking in genetically selected high alcohol-drinking (HAD) and alcohol-preferring (P) rats. Although water was available ad libitum, they were accustomed to a limited access (1 h/day) choice between 10% ethanol (EtOH) and water. When drinking stabilized, the rats were exposed for 30, 60, or 120 min to a mixture of N2O and pure oxygen, timed to end 1 h before the limited access. N2O suppressed EtOH consumption at 1, but not 25 h after exposure in both HAD and P rats. This result is consistent with the efficacy of N2O for acute reduction of EtOH drinking, and supports further research into the use of N2O as an adjunct to treatment.

Alcohol-related olfactory cues activate the nucleus accumbens and ventral tegmental area in high-risk drinkers: preliminary findings.

BACKGROUND: The mesocorticolimbic dopamine system is implicated in motivation and reward and may be involved in the development of alcoholism. METHODS: We used functional magnetic resonance imaging to study the blood oxygen level-dependent (BOLD) response to alcohol-related olfactory stimuli (AROS; odors of beer and whiskey) and non-alcohol-related olfactory stimuli (NAROS; odors of grass and leather) in 10 high-risk (HR) drinkers (average drinks per week, 19.99; SD, 6.99; all with > or = 2 first- or second-degree alcoholic relatives) and 5 low-risk (LR) social drinking controls (drinks per week, 2.82; SD, 2.87; 1 subject had 1 second-degree alcoholic relative). Data were analyzed with SPM99 and random effects analysis by using regions of interest and corrected cluster statistics (p < 0.05) to focus on the nucleus accumbens (NAc) and ventral tegmental area (VTA). RESULTS: In HR subjects, there was a greater BOLD signal increase in the NAc during AROS than during clean air. BOLD signal increases during AROS were also greater in the NAc than the signal increases induced by NAROS. The AROS signal was significantly greater than the NAROS signal in a small number of voxels in the VTA. Finally, the AROS/NAROS difference signal was larger in HR drinkers in both the NAc and VTA. CONCLUSIONS: Alcoholic olfactory cues may invoke the dopaminergic mesocorticolimbic system to a greater degree than nonalcoholic odors and could be effective tools in exploring the role of the dopamine system in susceptibility to alcoholism.