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Individual Differences in the Biphasic Effects of Ethanol

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Abstract

Ethanol exerts both stimulant-like and sedative-like subjective and behavioral effects in humans depending on the dose, the time after ingestion and, we will argue, also on the individual taking the drug. This study assessed stimulant-like and sedative-like subjective and behavioral effects of ethanol during the ascending and descending limbs of the blood alcohol curve across a range of doses in nonproblem social drinkers. Forty-nine healthy men and women, 21 to 35 years old, consumed a beverage containing placebo or ethanol (0.2, 0.4, or 0.8 g/kg) on four separate laboratory sessions, in randomized order and under double-blind conditions. Subjective and behavioral responses were assessed before and at regular intervals for 3 hr after ingestion of the beverage. The lowest dose of ethanol (0.2 g/kg) only produced negligible subjective effects compared to placebo. The moderate dose (0.4 g/kg) increased sedative-like effects 90 min after ethanol ingestion but did not increase ratings of stimulant effects at any time. The highest dose (0.8 g/kg) increased ratings of both stimulant- and sedative-like effects during the ascending limb and produced only sedative-like effects during the descending limb. Closer examination of the data revealed that individual differences in response to the highest dose of ethanol accounted for this unexpected pattern of results: about half of the subjects reported stimulant-like effects on the ascending limb and sedative-like effects on the descending limb after 0.8 g/kg ethanol, whereas the other half did not report stimulant-like effects at any time after administration of ethanol. These results challenge the simple assumption that ethanol has biphasic subjective effects across both dose and time, and extend previous findings demonstrating individual differences in response to ethanol.

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... Zebrafish larvae treated with low-dose ethanol (1%) showed an increased locomotor activity [83,84,96,97] whereas those treated with higher dose ethanol showed a decreased locomotor activity as compared with the controls. This effect of ethanol in zebrafish larvae is similar to that in humans, where low-dose ethanol acts as a CNS stimulant, whereas high-dose ethanol act as a CNS depressant [107]. ...
... Zebrafish larvae treated with low-dose ethanol (1%) showed an increased locomotor activity [83,84,96,97] whereas those treated with higher dose ethanol showed a decreased locomotor activity as compared with the controls. This effect of ethanol in zebrafish larvae is similar to that in humans, where low-dose ethanol acts as a CNS stimulant, whereas high-dose ethanol act as a CNS depressant [107]. Figure 2. Swimming pattern of AB wild type zebrafish larvae after drug treatment. ...
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Zebrafish larvae show a clear and distinct pattern of swimming in response to light and dark conditions, following the development of a swim bladder at 4 days post fertilization. This swimming behavior is increasingly employed in the screening of neuroactive drugs. The recent emergence of high-throughput techniques for the automatic tracking of zebrafish larvae has further allowed an objective and efficient way of finding subtle behavioral changes that could go unnoticed during manual observations. This review highlights the use of zebrafish larvae as a high-throughput behavioral model for the screening of neuroactive compounds. We describe, in brief, the behavior repertoire of zebrafish larvae. Then, we focus on the utilization of light-dark locomotion test in identifying and screening of neuroactive compounds.
... Nonetheless, there have been numerous demonstrations of the alcohol-specific PIT construct in the human laboratory. Instrumental responding for alcohol, measured as ingested alcohol volume or ingestion speed in bogus beverage evaluation tasks or number of alcohol beverage-earning responses in computerized tasks, has been shown to increase following isolated presentation of alcoholic beverage cues within specific sensory modalities (Field and Eastwood, 2005;Field and Jones, 2017;Hodgson et al., 1979;Martinovic et al., 2014;Roehrich and Goldman, 1995;Rose et al., 2018;Stein et al., 2000;Van Dyke and Fillmore, 2015), but see: (Carter and Tiffany, 1999;Field et al., 2007Field et al., , 2005Jones and Field, 2013;Kersbergen and Field, 2017;Stautz et al., 2017) as well as following presentation of alcoholic beverages and/or the interoceptive stimuli produced by ingestion ( (Amlung and MacKillop, 2014;Bigelow et al., 1977;Blaine et al., 2019;Christiansen et al., 2017;Chutuape et al., 1994;Corbin et al., 2008;Farris and Ostafin, 2008;Fernie et al., 2012;Fromme and Dunn, 1992;Hodgson et al., 1979;Holdstock and de Wit, 1998;Johnson and Fromme, 1994;Larsen et al., 2012;Leeman et al., 2009;Ludwig et al., 1978Ludwig et al., , 1974MacKillop and Lisman, 2005;Marlatt et al., 1973;Perkins et al., 2003;Rose and Duka, 2006;Stockwell et al., 1982;Wetherill and Fromme, 2009;Williams and Brown, 1985), but see: (Paredes et al., 1973)). In keeping with ISST, these PIT effects have been found to differ in magnitude based on AUD status ( (Higgins and Marlatt, 1973;Hodgson et al., 1979;Ludwig et al., 1978;Marlatt et al., 1973;Stockwell et al., 1982), but see: (Bujarski et al., 2018)) as well as individual differences in typical alcohol use levels ( (Blaine et al., 2019;Corbin et al., 2008;Leeman et al., 2009;Van Dyke and Fillmore, 2015), but see: (Kersbergen and Field, 2017;Martinovic et al., 2014)). ...
... Specifically, some individuals may have (an initially) low level of subjective response (LLR)-they recollect having required more drinks to feel any effect, dizziness, or stumbling than other individuals in questionnaire-based studies (Schuckit et al., 1997). Similarly, some individuals appear to be less sensitive to alcohol's sedative-like properties yet more sensitive to its stimulant-like properties (LSedHStim)-they feel less "down" or "sluggish" or "slow thoughts" and more "excited" or "excited" or "up" than other individuals after equivalent alcohol doses in controlled laboratory studies (Davidson et al., 2002;Holdstock and de Wit, 1998;King et al., 2002;Martin et al., 1993;Newlin and Thomson, 1990;Rueger et al., 2009;Rueger and King, 2013) Given differences in how these groups of individuals (LLR versus HLR and LSedHStim versus HSedLStim) were identified, it remains to be seen whether they stem from different or overlapping subpopulations. However, we can tentatively treat LLR and LSedHStim individuals as belonging to one population-the low sensitivity (LS) ASR phenotype population-and HLR and HSedLStim individuals as belonging a different population-the high sensitivity (HS) ASR phenotype population. ...
Article
Cofresí, R. C., B. D. Bartholow and T. M. Piasecki. Evidence for incentive salience sensitization as a pathway to alcohol use disorder. NEUROSCI BIOBEHAV REV 21(1) XXX-XXX, 1998. - The incentive salience sensitization (ISS) theory of addiction holds that addictive behavior stems from the ability of drugs to progressively sensitize the brain circuitry that mediates attribution of incentive salience (IS) to reward-predictive cues and its behavioral manifestations. In this article, we establish the plausibility of ISS as an etiological pathway to alcohol use disorder (AUD). We provide a comprehensive and critical review of evidence for: (1) the ability of alcohol to sensitize the brain circuitry of IS attribution and expression; and (2) attribution of IS to alcohol-predictive cues and its sensitization in humans and non-human animals. We point out gaps in the literature and how these might be addressed. We also highlight how individuals with different alcohol subjective response phenotypes may differ in susceptibility to ISS as a pathway to AUD. Finally, we discuss important implications of this neuropsychological mechanism in AUD for psychological and pharmacological interventions attempting to attenuate alcohol craving and cue reactivity.
... For example, alcohol has a predominant stimulant effect during the ascending limb of the BAC curve, and a predominant sedative/anxiolytic effect during the descending limb of the BAC curve (e.g. Addicott et al., 2007;Hendler et al., 2011;Holdstock & de Wit, 1998). This variation in the pharmacological effects of alcohol across the ascending and descending limbs of the BAC curve is referred to as alcohol's biphasic effects. ...
... This variation in the pharmacological effects of alcohol across the ascending and descending limbs of the BAC curve is referred to as alcohol's biphasic effects. Finally, individual differences exist in the extent to which the stimulant vs. sedative/anxiolytic effects of alcohol use are experienced (Hendler et al., 2011;Holdstock & de Wit, 1998). ...
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This study developed and tested a moderated-mediation model of work stress and alcohol use, based on the biphasic (stimulant and sedative) effects of alcohol and the self-medication and stress-vulnerability models of alcohol use. The model proposes that exposure to work stressors can increase both negative affect and work fatigue, and that these 2 sources of strain can subsequently motivate the use of alcohol. However, the relations of negative affect and work fatigue to alcohol use are conditional on the joint moderating effects of alcohol outcome expectancies and gender. Data were collected from a national probability sample of 2808 U.S. workers. Supporting the model, the results indicated that work stressor exposure was conditionally related via negative affect to heavy alcohol use among both men and women holding strong tension-reduction alcohol expectancies and to after work alcohol use among men holding strong tension-reduction alcohol expectancies. Also, work stressor exposure was conditionally related via work fatigue to both heavy alcohol use and workday alcohol use among men holding strong fatigue-reduction alcohol expectancies. The results have application in the identification of individuals at higher risk of problematic alcohol use and are relevant to workplace safety and to the design of appropriate interventions.
... Previous research has identified several other variables that influence how responsive individuals are to the acute subjective effects of alcohol. For instance, studies suggest that the sedative effects of alcohol tend to be more pronounced at higher blood alcohol concentrations (Holdstock & de Wit, 1998;Leeman et al., 2014;Pohorecky, 1977). Furthermore, heavier drinkers typically report more pronounced stimulation with ascending BAC levels and less sedation with declining BAC than lighter drinkers (Holdstock, King, & de Wit, 2000;King, de Wit, McNamara, & Cao, 2011;King et al., 2014). ...
... However, our results indicate that greater punishment sensitivity was only marginally associated with initial feelings of sedation and did not influence changes in sedation across levels of intoxication. Sedative effects of alcohol tend to be more pronounced at higher blood alcohol concentrations (Holdstock & de Wit, 1998;Leeman et al., 2014;Pohorecky, 1977), and thus, a higher dose of alcohol may be required to detect an association between punishment sensitivity and subjective sedation. It is also plausible that the relation of punishment sensitivity and sedation is dependent on important moderators not included in this study. ...
Article
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Individual differences in subjective response to alcohol play a crucial role in the development of heavy drinking and related problems. In light of this, a growing focus of research has been identifying factors that contribute to differences in response. The aim of the present study was to determine whether individual differences in the subjective experience of rewarding and aversive effects of alcohol are a specific manifestation of general differences in reward and punishment sensitivity. Eighty-nine participants (M age = 22.4, SD = 1.9; 47.2% women) consumed a moderate dose of alcohol, i.e., peak breath alcohol concentration (BrAC) ≈ 0.080 g%, and rated their level of stimulation and sedation at seven timepoints over the BrAC curve. Sensitivity to reward and punishment were assessed by a self-report questionnaire prior to consumption. Multilevel growth models showed that post-consumption changes in stimulation ratings varied as a function of participants' level of reward and punishment sensitivity. Drinkers more sensitive to reward reported feeling more stimulated shortly after drinking and exhibited an attenuated rate of decline in stimulation over the blood alcohol curve, relative to drinkers with less strong reward sensitivity. Reward sensitivity was not related to subjective ratings of sedation, and punishment sensitivity was not related to either stimulation or sedation ratings. Findings suggest that reward sensitivity may increase risk for alcohol misuse among young adult social drinkers by increasing their subjective feelings of stimulation while drinking.
... In the present study, the stimuli were administered immediately following the initial BrAC reading to ensure completion on the ascending limb of the BAC curve which is associated with the stimulant effects of alcohol and increased likelihood of aggression relative to the descending limb (Giancola & Zeichner, 1997;Holdstock & de Wit, 1998). A neutral scenario was presented first and depicted a dating couple returning home from a party and having an ordinary conversation about what happened at the party as well as their upcoming plans. ...
... Alcohol may also have served to disinhibit aggressive behavior in response to the conflict scenario, especially because assessments were taken on the ascending limb of the BAC curve. The ascending limb is associated with the stimulant effects of alcohol and has been associated with increased aggression in the TAP relative to the descending limb, which is associated with the sedative effects of alcohol (Giancola & Zeichner, 1997;Holdstock & de Wit, 1998). Thus, both alcohol-impaired attentional processes and the disinhibiting effects of alcohol likely influenced participants' aggression intentions. ...
Article
Verbal and physical dating aggression is prevalent among college-aged men and women, especially a pattern of mutual aggression in which both partners engage in aggression. Alcohol intoxication and anger arousal have been implicated in the occurrence of aggression, and the ability to regulate one's emotions may interact with both alcohol intoxication and emotional arousal to predict dating aggression. The current study is the first known experimental investigation to examine the effects of alcohol intoxication, alcohol expectancies, emotion regulation, and emotional arousal on dating aggression. Participants were randomized to receive alcohol (n = 48), placebo (n = 48), or no alcohol (n = 48). Intoxicated men and women expressed more verbal and physical aggression intentions than those in the no-alcohol condition, and individuals in the placebo condition did not significantly differ from those in the alcohol and no-alcohol conditions. These results suggest that the pharmacological effects of alcohol were important to the occurrence of dating aggression, whereas the effects of expectancy are less clear. Among those less able to engage in cognitive reappraisal, individuals who consumed or believed they consumed alcohol expressed more verbal and physical aggression intentions than those who received no alcohol. Those with higher arousal who were better able to suppress their emotions expressed fewer verbal and physical aggression intentions than those with lower arousal. In addition to reducing alcohol consumption, interventions for dating aggression might incorporate emotion regulation skills, with a focus on understanding the circumstances in which cognitive reappraisal and emotion suppression are relatively more effective. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
... When the correlation between BAC and the scores of stimulant feelings was examined, the stimulant feeling did not show a correlation with the BAC, but the scores of sedative feelings showed a significant positive correlation, proving that the intensity of stimulant feelings did not depend on the degree of BAC elevation. A previous report indicated that stimulant feeling was similar between 0.2 g/kg and 0.4 g/kg of alcohol ingestion, but sedative feeling was significantly stronger with 0.4 g/kg of alcohol than 0.2 g/kg of alcohol when healthy adults ingested moderate amounts of alcohol [28]. The results of the present study are in agreement with that of the abovementioned study. ...
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The change in physiological parameters and subjective feelings according to the speed of drinking alcohol has not been reported to date. The aim of this randomized crossover pilot study was to investigate the objective and subjective effects of different speeds of alcohol ingestion in healthy volunteers. Accordingly, 11 male and 7 female healthy Japanese adults were asked to consume 480 mL of beer at three different drinking speeds (80, 40, and 20 mL/5 min). According to the objective measurement, the transient increase in blood alcohol and serum uric acid concentrations was most inhibited at a drinking speed of 20 mL/5 min. Acetate, lactate, pyruvate, and lactate/pyruvate ratios did not differ between the three drinking speeds. Stimulant feelings measured by the subjective scores of the Brief Biphasic Alcohol Effects Scale did not differ between the three speeds. However, the sedative feeling score obtained at a drinking speed of 20 mL/5 min (the slowest speed of alcohol consumption) was significantly weakened in comparison with those obtained at drinking speeds of 40 and 80 mL/5 min. Therefore, a slower consumption of alcohol mitigated the subjective sedative feeling. The effects of slower alcohol consumption may be caused by the slower slope of the increasing trend of blood alcohol concentration.
... Similar to previous rodent research we reported BECs over time to create a BEC profile (Livy et al., 2003). BEC profiles can be used by researchers to identify the ascending and descending limbs of the BEC curve and can be used to determine whether there is evidence of acute tolerance (LeBlanc et al., 1975;Martin and Moss, 1993) and/or a biphasic effect of ethanol (Holdstock and de Wit, 1998). ...
Article
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Ethanol is one of the most widely used and abused drugs. Following ethanol consumption, ethanol enters the bloodstream from the small intestine where it gets distributed to peripheral tissues. In the bloodstream, ethanol is cleared from the system by the liver. The primary metabolism of ethanol uses alcohol dehydrogenase (ADH). In mammals, females appear to have higher ADH activity in liver samples than males. The purpose of the first experiment was to analyze sex differences in ADH levels following 12 days of ethanol administration (i.e., water or 2 g/kg) in male and female quail. Following the last daily treatment of ethanol, quail were euthanized, their livers were extracted, and ADH was analyzed in liver homogenate samples. Results showed that female quail had higher ADH levels, heavier livers, and a greater liver to body weight ratio than male quail. In a second experiment, we aimed to develop a blood ethanol concentration (BEC) profile for both male and female quail. Quail were administered 0.75 or 2 g/kg of ethanol and blood was collected at 0.5, 1, 2, 4, 6, 8, 12, 24 hours after gavage administration. Blood ethanol concentration was analyzed using an Analox. We found that quail had a fairly rapid increase in BECs followed by a steady and slow disappearance of ethanol from the blood samples. Female quail had a lower peak of ethanol concentration and a smaller area under the curve (AUC) than male quail. The current research suggests that higher ADH levels in female quail may be responsible for increased metabolism of ethanol. In general, quail appear to eliminate ethanol more slowly than rodents. Thus, as a model, they may allow for a prolonged window with which to investigate the effects of ethanol.
... First, we did not consider individual differences. Numerous studies, including our own, indicate that individuals vary in their subjective responses to alcohol (Weafer et al., 2018;Holdstock & Wit, 1998;King et al., 2020). However, the sample size was not sufficient to examine inter-subject variability, and the correlates of neural responses to the drug will be examined in detail in future, with a larger data set. ...
Article
Alcohol abuse and dependence remain significant public health issues, and yet the brain circuits that are involved in the rewarding effects of alcohol are poorly understood. One promising way to study the effects of alcohol on neural activity is to examine its effects on functional connectivity between brain areas involved in reward and other functions. Here, we compared the effects of two doses of alcohol (0.4 and 0.8 g/kg) to placebo on resting-state functional connectivity in brain circuits related to reward in 19 healthy young men without histories of alcohol problems. The higher, but not the lower, dose of alcohol, significantly increased connectivity from reward-related regions to sensory and motor cortex, and between seeds associated with cognitive control. Contrary to expectation, alcohol did not significantly change connectivity for the ventral striatum at either dose. These findings reveal unrecognized effects of alcohol on connectivity from reward-related regions to visual and sensory cortical areas.
... Several lines of evidence suggest that positive stimulant-like subjective effects of alcohol are related to actions of the drug on the brain's reward circuitry. First, stimulant-like subjective effects are associated with behavioral preference for alcohol in laboratory studies (Holdstock and de Wit, 1998;King et al., 2011), as well as with escalation of alcohol consumption over years (King et al., 2014;Ray et al., 2010). Both preclinical and clinical studies indicate alcohol, like other drugs of abuse (Di Chiara and Imperato, 1988;Koob and Bloom, 1988), activates the corticostriatal reward circuit, including brain regions such as the ventral tegmental area (VTA), nucleus accumbens (NAcc), aymgdala, and prefrontal cortex (Alasmari et al., 2018;Koob and Volkow, 2016;. ...
Article
Background Alcohol use disorder (AUD) remains an unresolved source of morbidity and mortality. Psychopharmacological challenge studies and neuroimaging experiments are two methods used to identify risk of problematic substance use. The present study combined these two approaches by examining associations between self-reported stimulation, sedation, liking or wanting more after a dose of alcohol and neural-based responses to anticipation of monetary gain and loss. Methods Young adult binge drinkers (N = 56) aged 21–29, with no history of Substance Use Disorder completed five experimental sessions. These included four laboratory sessions in which they rated their subjective responses to alcohol (0.8 g/kg for men, 0.68 g/kg for women) or placebo, and a single functional magnetic resonance imaging session in which they completed a monetary incentive delay task. During the scan, we recorded neural signal related to anticipation of winning $5 or $1.50 compared to winning no money (WinMoney-WinZero), losing $5 or $1.50 compared to losing no money (LoseMoney-LoseZero), and winning $5 or $1.50 compared to losing $5 or $1.50 (WinMoney-LoseMoney), in reward related regions. Results There were no significant associations between subjective ratings of “Feel Drug Effect”, “Like Drug Effect”, “Want More”, stimulation or sedation following the acute alcohol challenge and neural activation in reward related regions during anticipation of monetary gain or loss. Conclusions These results suggest that sensitivity of neural reward circuits is not directly related to rewarding subjective experiences from alcohol. Taken together with previous studies, the present findings indicate that the association between the subjective effects of drugs and reward-related brain activity depends on the drugs, tasks or subject samples under study.
... Ethanol acts, paradoxically, as both a sedative and a stimulant drug across both dose and time (Addicott, Marsh-Richard, Mathias, & Dougherty, 2007;Correa et al., 2009;Fern andez et al., 2016;Rodd et al., 2004;S anchez-Catal an, Hip olito, Zornoza, Polache, & Granero, 2009;Tambour, Didone, Tirelli, & Quertemont, 2006). The stimulatory effects in humans are thought to be more rewarding than the sedative ones, and thus ethanol may play a more prominent role in determining addiction (Holdstock & de Wit, 1998). ...
Article
Highly sensitive detection of ethanol concentrations in discrete brain regions of rats voluntarily accessing ethanol, with high temporal resolution, would represent a source of greatly desirable data in studies devoted to understanding the kinetics of the neurobiological basis of ethanol's ability to impact behavior. In the present study, we present a series of experiments aiming to validate and apply an original high-tech implantable device, consisting of the coupling, for the first time, of an amperometric biosensor for brain ethanol detection, with a sensor for detecting the microvibrations of the animal. This device allows the real-time comparison between the ethanol intake, its cerebral concentrations, and their effect on the motion when the animal is in the condition of voluntary drinking. To this end, we assessed in vitro the efficiency of three different biosensor designs loading diverse alcohol oxidase enzymes (AOx) obtained from three different AOx-donor strains: Hansenula polymorpha, Candida boidinii, and Pichia pastoris. In vitro data disclosed that the devices loading H. polymorpha and C. boidinii were similarly efficient (respectively, linear region slope [LRS]: 1.98 ± 0.07 and 1.38 ± 0.04 nA/mM) but significantly less than the P. pastoris-loaded one (LRS: 7.57 ± 0.12 nA/mM). The in vivo results indicate that this last biosensor design detected the rise of ethanol in the nucleus accumbens shell (AcbSh) after 15 minutes of voluntary 10% ethanol solution intake. At the same time, the microvibration sensor detected a significant increase in the rat's motion signal. Notably, both the biosensor and microvibration sensor described similar and parallel time-dependent U-shaped curves, thus providing a highly sensitive and time-locked high-resolution detection of the neurochemical and behavioral kinetics upon voluntary ethanol intake. The results overall indicate that such a dual telemetry unit represents a powerful device which, implanted in different brain areas, may boost further investigations on the neurobiological mechanisms that underlie ethanol-induced motor activity and reward.
... (b) Expression of various NOX components increases from embryonic Day 5.5-11 and remains constant from Day 14 to 19. Modified from Baehner et al. (1999) the levels of which may differ among individuals (Holdstock & de Wit, 1998;Pohorecky, 1977). ...
Article
This review covers molecular mechanisms involving oxidative stress and DNA damage that may contribute to morphological and functional developmental disorders in animal models resulting from exposure to alcohol (ethanol, EtOH) in utero or in embryo culture. Components covered include: (a) a brief overview of EtOH metabolism and embryopathic mechanisms other than oxidative stress; (b) mechanisms within the embryo and fetal brain by which EtOH increases the formation of reactive oxygen species (ROS); (c) critical embryonic/fetal antioxidative enzymes and substrates that detoxify ROS; (d) mechanisms by which ROS can alter development, including ROS‐mediated signal transduction and oxidative DNA damage, the latter of which leads to pathogenic genetic (mutations) and epigenetic changes; (e) pathways of DNA repair that mitigate the pathogenic effects of DNA damage; (f) related indirect mechanisms by which EtOH enhances risk, for example by enhancing the degradation of some DNA repair proteins; and, (g) embryonic/fetal pathways like NRF2 that regulate the levels of many of the above components. Particular attention is paid to studies in which chemical and/or genetic manipulation of the above mechanisms has been shown to alter the ability of EtOH to adversely affect development. Alterations in the above components are also discussed in terms of: (a) individual embryonic and fetal determinants of risk and (b) potential risk biomarkers and mitigating strategies. FASD risk is likely increased in progeny which/who are biochemically predisposed via genetic and/or environmental mechanisms, including enhanced pathways for ROS formation and/or deficient pathways for ROS detoxification or DNA repair.
... Ainsi on constate que la dose, mais aussi la « pente » de la consommation (ou plus exactement le taux plasmatique) jouent un rôle décisif : à faible dosage ou à pente croissante (augmentation de l'éthanolémie) l'effet produit va être stimulant. A contrario, à forte dose ou lorsque la pente est décroissante (éthanolémie descendante), l'effet va être sédatif, ou entraîner une dysphorie [10]. Cet effet de la pente et de la dose n'est d'ailleurs pas propre à l'éthanol. ...
Article
Si l’existence de liens entre consommation éthylique et symptômes thymiques paraît évidente, la nature et les mécanismes qui sous-tendent ces interactions s’avèrent en revanche très complexes et moins bien connus. Cet article, qui s’appuie essentiellement sur des données empiriques et destinées aux cliniciens, vise à décrire de quelle manière la compréhension de ces symptômes thymiques permet de dégager des pistes de travail ou leviers pour le travail clinique avec les patients alcoolo-dépendants. Nous développons en particulier la manière dont la consommation aiguë entraîne des réactions émotionnelles, hors contexte d’abus ou de dépendance (caractère syntone par rapport au cadre social de consommation, « binge-drinking »). Les consommations chroniques, menant à l’abus ou à la dépendance, sont par la suite abordées en détaillant de quelle manière leur interaction biologique avec le circuit de récompense cérébrale modifie notablement l’humeur, en fonction d’un principe d’allostasie. Nous mettons aussi en évidence le rôle de facteurs de personnalité tels que la conscience de Soi dans la relation qui peut exister entre dépression et « craving ». Nous insistons également sur des manifestations annexes aux symptômes thymiques que sont les troubles de cognition sociale fréquents chez les patients alcooliques, menant souvent à un isolement social ainsi qu’à des relations interpersonnelles conflictuelles qui peuvent à leur tour être des facteurs d’accentuation du vécu dépressif.
... Research suggests a biphasic response to alcohol such that stimulant effects occur on the ascending limb of the blood alcohol curve, while sedative effects occur on the descending limb (Holdstock and de Wit 1998). Further, characterizing drug expectancies as stimulant or sedative provides a more nuanced understanding of expectancies. ...
Article
Impulsivity and substance use covary. Smith and Anderson’s acquired preparedness model proposes that impulsivity predicts substance use through a mediational model such that substance use expectancies mediate the relation between impulsivity and drug use. The present study seeks to examine the relation between positive urgency, an important component of impulsivity with specific relations to substance use behavior, marijuana expectancies, and marijuana use patterns. The study focused on a sample of frequent marijuana users (n = 3,616) and assessed positive urgency using the UPPS-P, expectancies using the Biphasic Marijuana Effects Scale, an adapted form of the Biphasic Alcohol Effects Scale to measure the sedative and stimulant properties of marijuana, and also assessed use patterns. Findings suggest that stimulant expectancies predict heavier, more frequent marijuana use than sedative expectancies and that marijuana expectancies vary based on the limb of marijuana intoxication. Examination of the acquired preparedness model revealed that positive urgency’s link to marijuana use was fully mediated by expectancies.
... Specifically, heavy drinkers show greater alcohol-induced stimulation [35,36], and greater stimulation predicts subsequent binge drinking and number of AUD symptoms [3,37]. Even among young adults who have not yet developed AUD, greater stimulantlike subjective effects after alcohol are associated with greater preference for alcohol in a choice test [38]. However, until now, the neurobiological mechanisms underlying individual differences in stimulant responses were unknown. ...
Article
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Individuals who experience greater stimulation and less sedation from alcohol are at increased risk for alcohol-related problems. However, little is known regarding the neurobiological mechanisms underlying subjective response to alcohol. The current study examined the degree to which alcohol-induced brain activation correlates with ratings of stimulation and sedation, using a within-subjects, double-blind, placebo-controlled design. Participants (N = 34 healthy adults with no history of alcohol use disorder) completed three sessions: a calibration session to determine the duration of infusion needed to bring the breath alcohol to 80 mg/dl for each subject, and two counterbalanced fMRI sessions with placebo and alcohol administration. During the fMRI sessions, participants underwent 50 min scans, which included a 10 min baseline period, the IV infusion period needed to bring breath alcohol concentration (BrAC) to a peak 80 mg/dl (on the alcohol session), followed by a post-peak decline period. Participants rated their subjective stimulation and sedation at regular intervals throughout the scan. A priori VOI analyses showed that the time course of stimulation correlated with BOLD signal in the striatum. The time course of sedation did not correlate with BOLD signal in any VOIs. There were no correlations in primary visual cortex, which served as a control. These findings are the first to show that alcohol effects in the striatum are linked to the positive, stimulant-like effects of the drug and advance our understanding of the neurobiological mechanisms underlying individual differences in subjective responses to alcohol, and more broadly, risk for alcohol use disorders.
... The beverage was aliquoted into 2 equal volumes, and patients consumed each aliquot within consecutive 5-minute periods. During both conditions, 2 mL of alcohol were sprayed onto the surface of the cup to serve as a flavor mask [22]. An assessment of BAC estimated from breath samples (BrAC) was performed by using an Alco-Sensor IV (Intoximeters, Inc., St. Louis, MO, USA). ...
Article
Background While it is well established that Roux-en-Y gastric bypass (RYGB) causes a rapid and heightened peak blood alcohol concentration (BAC), results from previous studies on the effects of sleeve gastrectomy (SG) on alcohol pharmacokinetics are conflicting. Data from two studies found SG did not affect BAC, whereas another study found SG caused a heightened peak BAC after alcohol ingestion. Moreover, these three studies estimated BAC from breathalyzers, which might not reliably estimate peak BAC. Objectives To evaluate 1) the effect of SG, relative to RYGB and a pre-surgery group, on alcohol pharmacokinetics and subjective effects, and 2) whether breathalyzers are reliable in this population. Setting Single-center prospective nonrandomized trial. Methods We performed alcohol challenge tests in 11 women who had SG surgery 1.9±0.1 years ago (Body mass index (BMI)=35.1±6.6 kg/m²), 8 women who had RYGB surgery 2.2±0.4 years ago (BMI=30.0±5.2 kg/m²), and 9 women who were scheduled for bariatric surgery (BMI=44.1±4.0 kg/m²). BAC were estimated from breath samples (BrAC) and measured by gas chromatography at various times after consuming ~2 standard drinks. Results BAC increased faster, peak BAC was ~two-fold higher, and feelings of drunkenness were heightened in both SG and RYGB groups relative to the pre-surgery group (P’ values <.001). BrAC underestimated BAC by 27% (SD=13%) and missed peak BACs post-surgery. Conclusions SG, similar to RYGB, causes marked alterations in the response to alcohol ingestion manifested by a faster and higher peak BAC. The breathalyzer is invalid to assess effects of gastric surgeries on pharmacokinetics of ingested alcohol.
... Although this study used an adequate sample size for factor analysis (MacCallum et al. 1999), the generalizability of the findings to independent samples with differing demographics and alcohol use characteristics is uncertain. Specifically, one of the limitations of the current study is that the sample was relatively homogenous with regards to drinking behavior (moderate-to-heavy binge drinkers) and there is evidence that subjective alcohol responses (Holdstock and de Wit 1998;Holdstock et al. 2000;King et al. 2002) and factor structure of subjective alcohol responses (Bujarski et al. 2015) differ in heavy and light drinkers. Therefore, it is not yet clear whether the factor structure is stable across repeated alcohol administrations among lighter drinkers. ...
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RationaleAlcohol subjective experiences are multi-dimensional and demonstrate wide inter-individual variability. Recent efforts have sought to establish a clearer understanding of subjective alcohol responses by identifying core constructs derived from multiple measurement instruments. Objective The aim of this study was to evaluate the temporal stability of this approach to conceptualizing alcohol subjective experiences across successive alcohol administrations in the same individuals. Methods Healthy moderate alcohol drinkers (n = 104) completed six experimental sessions each, three with alcohol (0.8 g/kg), and three with a non-alcoholic control beverage. Participants reported subjective mood and drug effects using standardized questionnaires before and at repeated times after beverage consumption. We explored the underlying latent structure of subjective responses for all alcohol administrations using exploratory factor analysis and then tested measurement invariance over the three successive administrations using multi-group confirmatory factor analyses. ResultsExploratory factor analyses on responses to alcohol across all administrations yielded four factors representing “Positive mood,” “Sedation,” “Stimulation/Euphoria,” and “Drug effects and Urges.” A confirmatory factor analysis on the separate administrations indicated acceptable configural and metric invariance and moderate scalar invariance. Conclusions In this study, we demonstrate temporal stability of the underlying constructs of subjective alcohol responses derived from factor analysis. These findings strengthen the utility of this approach to conceptualizing subjective alcohol responses especially for use in prospective and longitudinal alcohol challenge studies relating subjective response to alcohol use disorder risk.
... However, in both AUD patients and social drinkers, treatment with a dopamine D2 receptor antagonist has been shown to reduce alcohol craving and to increase control over alcohol intake (Borg 1983;Modell et al. 1993;Peters and Faulds 1994;Enggasser and de Wit 2001;Martinotti et al. 2010). The effect of treatment with dopaminergic drugs on the subjective effects of alcohol has been shown to differ among individuals (Holdstock and de Wit 1998;Holdstock and de Wit 1999;Enggasser and de Wit 2001;Holdstock and de Wit 2001). For example, the dopamine D2 receptor antagonist haloperidol reduced the alcohol-induced euphoric effects in subjects who experienced stimulant effects upon alcohol intake, whereas these effects were absent in individuals who primarily reported sedative-like effects (Enggasser and de Wit 2001). ...
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RationaleIndividual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission. Objectives The aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats that differ in individual levels of alcohol intake. Methods The effects of the dopamine D1 receptor agonist SKF 82958, the dopamine D1 receptor antagonist SCH 23390, the dopamine D2 receptor agonist sumanirole and the dopamine D2 receptor antagonist L741,626 on alcohol consumption and preference were assessed at different time points after treatment in subgroups of low and high alcohol drinking rats (LD and HD) using an intermittent alcohol access paradigm. ResultsSKF 82958 decreased alcohol intake and alcohol preference throughout the 24-h session. Sumanirole decreased alcohol intake during the first 2 h, but increased alcohol intake during the remainder of the session. The effects of SKF 82958 and sumanirole on alcohol intake and alcohol preference were comparable in LD and HD. By contrast, the dopamine receptor antagonists SCH 23390 and L741,626 did not alter alcohol consumption in either group at any time point. Conclusions These data indicate that stimulation of dopamine D1 receptors reduces alcohol intake, but that endogenous dopamine does not play a primary role in alcohol consumption. Moreover, the difference in alcohol consumption between LD and HD does not involve altered dopamine signaling.
... Another consideration in studying the effects of alcohol on memory is the presence of individual differences in sensitivity to alcohol reward. Individuals differ markedly in subjective and rewarding response to alcohol: some are more sensitive to the positive, rewarding effects of alcohol, experiencing euphoria, arousal and increased talkativeness, whereas others are more sensitive to the negative effects and report feeling down, sluggish, and tired (Holdstock and de Wit, 1998;Newlin and Thomson, 1990;Quinn and Fromme, 2011). Greater sensitivity to alcohol-induced stimulation is associated with greater alcohol consumption, and longitudinal evidence suggests that "stimulant responders" are at greater risk for developing alcohol use disorder symptoms (King et al., 2011(King et al., , 2014(King et al., , 2016Newlin and Thomson, 1990;Quinn and Fromme, 2011). ...
Article
Background: Drug and alcohol abusers develop strong memories for drug-related stimuli. Preclinical studies suggest that such memories are a result of drug actions on reward pathways, which facilitate learning about drug-related stimuli. However, few controlled studies have investigated how drugs affect memory for drug-related stimuli in humans. Methods: The current study examined the direct effect of alcohol on memory for images of alcohol-related or neutral beverages. Participants received alcohol (0.8 g/kg) either before viewing visual images (encoding condition; n = 20) or immediately after viewing them (consolidation condition; n = 20). A third group received placebo both before and after viewing the images (control condition; n = 19). Memory retrieval was tested exactly 48 hours later, in a drug-free state. Results: Alcohol impaired memory in the encoding condition and enhanced memory in the consolidation condition, but these effects did not differ for alcohol-related and neutral beverage stimuli. However, in the encoding condition, participants who experienced greater alcohol-induced stimulation exhibited better memory for alcohol-related, but not neutral beverage stimuli. Conclusions: These findings suggest that individual differences in sensitivity to the positive, rewarding effects of alcohol are associated with greater propensity to remember alcohol-related stimuli encountered while intoxicated. As such, stimulant responders may form stronger memory associations with alcohol-related stimuli, which might then influence their drinking behavior.
... Each participant received an acute dose of both alcohol and placebo across two sessions in a randomized, balanced, and double-blinded crossover design. A moderate dose (0.4 g/kg; Holdstock and de Wit, 1998) was chosen for this initial experiment since high doses (e.g., 0.8 g/kg) can cause global impairment (Bisby et al., 2010) which might have interfered with participants' ability to understand and engage with the Cyberball task. Based on a sample size of 32, α = 0.05, β = 0.8, 4 measurements, and a correlation between measures of 0.5, a power calculation conducted in G * Power * (3.1.9) ...
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Anecdotal and correlational evidence suggests a relationship between social ostracism and alcohol dependence. Furthermore, a recent fMRI investigation found differences in the neural correlates associated with ostracism in people with alcohol dependence compared to healthy controls. We predicted that acutely administered alcohol would reduce the negative effects of social ostracism. Alcohol (0.4 g/kg) or matched placebo was administered to a sample of 32 hazardous drinkers over two sessions in a randomized, double-blind, cross-over design. In each session, participants were exposed to an ostracism event via the computerized ball passing game, "Cyberball." In order to quantify the effects of ostracism, the fundamental needs questionnaire was completed twice on each testing session; immediately after (i) social inclusion and (ii) social exclusion. Ostracism caused robust changes to scores on the fundamental needs questionnaire, in line with previous literature. Alcohol administration did not influence the effects of simulated social ostracism, which was supported by a Bayesian analysis. Exploratory analyses revealed a negative relationship between age and ostracism induced fundamental needs threat across both sessions. In conclusion, a moderate dose of alcohol did not influence experience of simulated social ostracism in hazardous drinkers. Further research is needed to establish the effects of alcohol administration on social ostracism using different doses and populations of alcohol users.
... Another limitation of this study was the dose of alcohol used, as this moderate dose of alcohol (0.6 g/kg) may have been too low to produce robust conditioning, especially given the heterogeneity in drinking patterns within our sample (M = 11.1 drinks per week; SD = 6.3). The dose used here produces modest subjective effects (Holdstock & de Wit, 1998; Table 2) but fails to produce consistent stimulant-like effects that are the hallmark of alcohol reward (King et al., 2011). Interestingly, this same dose (0.6 g/kg) did sustain conditioning using measures of skin conductance and cardiac inter-beat interval (Glautier et al., 1994), and as noted above, a dose of 0.2 g/kg led to an increase in attention (Field & Duka, 2002). ...
Article
Objective: This study examined the acquisition of conditioning between novel stimuli and single doses of alcohol in social drinkers. Environmental stimuli present during the consumption of alcohol or other drugs come to elicit conditioned responses that subsequently increase drug seeking. However, relatively few studies have examined the process of acquisition of these conditioned drug responses in human subjects. Method: We used a procedure previously developed to study acquisition of conditioned responses to a methamphetamine-associated cue. In the present study we applied the paradigm to alcohol, pairing de novo neutral cues with alcohol in social drinkers (N = 36). We obtained measures of self-report, behavioral preference, emotional reactivity (assessed using facial electromyography), and attention to specific cues paired with administration of 0.6 g/kg 95% absolute alcohol or placebo. Results: After conditioning, participants showed an increase in attention toward the alcohol-paired cue, and this increase was associated with ratings of liking the alcohol-containing beverage during the conditioning sessions. In contrast to our previous findings with methamphetamine, the alcohol-paired cue did not elicit changes in emotional reactivity (measured by facial electromyography) or behavioral preference. Conclusions: This study extends our previous findings with a stimulant drug to alcohol and highlights possible similarities and differences in conditioning with different classes of drugs. Conditioning with alcohol was less robust than with methamphetamine, but in both cases the conditioning that did occur was related to positive subjective drug response.
... Alcohol produces both stimulation and sedation simultaneously and these two effects are essential to the understanding of the use and misuse of alcohol (Martin et al., 1993). Individuals differ in when, how much and under what conditions they feel stimulant and sedative effects (Holdstock and de Wit, 1998;Söderpalm and de Wit, 2002). The prominent sedative effects of alcohol after stress in those with an increased physiological stress response may, in turn, motivate for increased drinking in stressful situations. ...
Article
Aims: The present study was designed to examine the relationship between high and low cortisol response to an acute stressful situation and the subjective effects after different doses of alcohol, in healthy social drinkers. Method: Sixty-four subjects (32 men and 32 women) participated in one laboratory session. They performed a modified version of the Trier Social Stress Test (TSST) immediately before consumption of either placebo or alcohol (0.2, 0.4 or 0.8g/kg). Subjects in each dose group were then divided into high (HCR; n=32) or low (LCR; n=32) cortisol responders. Primary dependent measures were self-report questionnaires of mood. Results: The HCR reported increased ratings on Sedation on the Biphasic Alcohol Effects Scale (BAES) with increased dose in comparison with the LCR. This increase in sedation also correlated to the increase in cortisol levels. Conclusion: We conclude that a high cortisol response to stress modulates the subjective response to alcohol, dose-dependently. HCR subjects experience increased sedative effects of alcohol after consumption of higher doses of alcohol following stress compared to LCR subjects.
... All models included a random intercept of subject. Because the shape of the relationship between time and alcohol effects was expected to differ as a function of BrAC limb (Holdstock and Wit, 1998), a regression spline was included in each model. For each individual, the spline variable at time t is equal to p max (0, time t À time peakBrAC ). ...
Article
Background: Variability in sensitivity to the acute effects of alcohol is an important risk factor for the development of alcohol use disorder (AUD). The most commonly used retrospective self-report measure of sensitivity, the Self-Rating of the Effects of Alcohol form (SRE), queries a limited number of alcohol effects and relies on respondents’ ability to recall experiences that might have occurred in the distant past. Here, we investigated the construct validity of an alternative measure that queries a larger number of alcohol effects, the Alcohol Sensitivity Questionnaire (ASQ), and compared it to the SRE in predicting momentary subjective responses to an acute dose of alcohol. Method: Healthy young adults (N = 423) completed the SRE and the ASQ and then were randomly assigned to consume either alcohol or a placebo beverage (between-subjects manipulation). Stimulation and sedation (Biphasic Alcohol Effects Scale) and subjective intoxication were measured multiple times after drinking. Results: Hierarchical linear models showed that the ASQ reliably predicted each of these outcomes following alcohol but not placebo consumption, provided unique prediction beyond that associated with differences in recent alcohol involvement, and was preferred over the SRE (in terms of model fit) in direct model comparisons of stimulation and sedation. Conclusions: The ASQ compared favorably with the better-known SRE in predicting increased stimulation and reduced sedation following an acute alcohol challenge. The ASQ appears to be a valid self-report measure of alcohol sensitivity and therefore holds promise for identifying individuals at-risk for AUD and related problems. Key Words: Alcohol Sensitivity, Level of Response, Subjective Alcohol Effects, Alcohol Challenge, Model Comparison.
... (dosage = 1.00 mL alcohol/kg body weight; 1:6 alcohol to fruit juice ratio). Assessment of BrAC took place every three minutes until participants reached the target criterion (BrAC ≥ .06) to ensure that sexual stimuli was presented during the ascending limb of the alcohol curve (Holdstock & de Wit, 1998; Martin, Earleywine, Musty, Perrine, & Swift, 1993). In the no alcohol condition, participants were given the same volume of fruit juice as they would have received in the alcohol condition using a yoked control design (Giancola & Zeichner, 1997; Schacht, Stoner, George, & Norris, 2010aCSA severity was measured using the Childhood Trauma Questionnaire-Sexual Abuse Subscale (CTQ-Sexual Abuse; Bernstein & Fink, 1998). ...
Article
This study examined influences of alcohol intoxication, attentional control, and CSA severity on sex-related dissociation. Sex-related dissociation is defined here as dissociation (e.g., feeling as if the world is unreal and feeling disconnected from one's body) during sexual activity or in the presence of sexual stimuli. Women (N = 70) were randomized to a 2 (alcohol condition: none, .10% peak breath alcohol concentration) x 2 (attentional control instructions: none, "relax and maximize" sexual arousal) experiment and exposed to sexual stimuli. Alcohol intoxication was positively associated with sex-related dissociation. CSA severity and sex-related dissociation were positively associated in the no instruction condition but not in the "relax and maximize" condition. For some women, efforts to relax and maximize sexual arousal may buffer the association between CSA and sex-related dissociation.
... El alcohol, como sustancia sedante que es, también produjo un aumento en esta escala. En estudios controlados en los que se administró alcohol a voluntarios sanos, la PCAG del ARCI obtuvo puntuaciones significativamente más altas que el placebo (Holdstock y de Wit, 1998;) y cocaína (Foltin y cols., 1993) e incluso más altas que tras la administración de la combinación de cocaína y alcohol (Farré y cols., 1997). En un estudio más reciente, y al que ya se ha hecho referencia anteriormente, se administró alcohol y se comparó precisamente con la MDMA, la PCAG presentó puntuaciones significativamente superiores para el alcohol (Hernández-López y cols., 2002). ...
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The objective of this study was to construct an instrument capable of measuring the subjective effects produced by 3.4-methyilenedioxymethamphetamine (MDMA). After the construction of a bank of items, subsequent reductions and a factorial analysis, a 36-item questionnaire was obtained with a five-point Likert response. This questionnaire was called VESSPA-SEE (Evaluation of Subjective Effects of Substances with Abuse Potential) and contains 6 scales: Sedation, Physical Anxiety, Changes in Perception, Pleasure and Social Contact, Activity and Energy, and Psychotic Symptoms. For these scales, the coefficients of alpha ranged from 0.67 to 0.86, and the coefficients of test-retest reliability ranged from 0.79 to 0.91. The validity of the scale was investigated by the application of three tests: correlations with VESSPA and ARCI scales (Addiction Research Center Inventory-49 item short form), scores of the different scales in other simulated conditions (alcohol, cannabis, cocaine and LSD), and response of the questionnaire in an experimental situation in a clinical trial in where MDMA and alcohol were administered. The results showed that the VESSPA questionnaire is an instrument with an acceptable validity and reliability for measuring the pharmacological effects of the MDMA and other psychopharmacos. In addition, the questionnaire seems apropiate for use in a clinical trial context.
... doi:10.1371/journal.pone.0086199.g005 on the descending limb of the BAC curve, while we observed sedative effects directly after consumption [31,43,44]. However, Addicot et al. (2007) also observed sedative effects before BAC levels started to decline [45]. ...
... The timedependent biphasic effect of alcohol has been associated with changes in blood alcohol concentration. In humans, a single acute dose of alcohol induces stimulation during the ascending trajectory of the blood alcohol curve (BAC) and sedation during the descending trajectory of the BAC (Holdstock & de Wit, 1998). Similar time-dependent biphasic effects of alcohol have been shown in other mammalian species (Read et al., 1960) and now in zebrafish too (Tran & Gerlai, 2013a). ...
... Saccadic eye movement test The analysis of eye movements in response to changing visual stimuli provides a simple and reproducible method of detecting changes in attention and sedation in healthy subjects. This method was also demonstrated to be sensitive to both sedativelike and stimulant-like effects of various psychotropic drugs [44], including alcohol effects [45][46][47][48]. Different types of eye movements are sensitive to alcohol effects (for a review see [41]). ...
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AimThe pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g/kg alcohol using 40% vodka).Methods In a randomized, double-blind, double-dummy, cross-over trial, 24 healthy volunteers received randomly: a) 2.25 g of SMO.IR and placebo alcohol preparation, b) 2.25 g of SMO.IR and alcohol, c) 2.25 g of SMO.IR matching placebo and alcohol, d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events, vital signs were assessed before, 15 and 165 minutes after treatment administration.ResultsAlcohol produced the expected cognitive impairments and the expected subjective sedation rapidly after intake (from 15 min). Objective effects of SMO.IR were much less pronounced than those of alcohol; the reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 minutes after administration this sedation feeling was lesser with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol, at 15 min (i.e.; increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 minutes post dose after combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated.ConclusionSMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol; no deleterious interaction was observed.
... One of the sources of variability in alcohol's effects comes from the influence of biphasic effects on behavior across the time course of the alcohol dose-response curve (Holdstock and de Wit, 1998). Some aspects of performance appear to be more impaired during the ascending limb (i.e., acute tolerance, also known as the Mellanby effect) while performance on other aspects appears to be impaired to a greater degree during the descending limb (acute protracted error) (Cromer et al., 2010;Schweizer and Vogel-Sprott, 2008;Weafer and Fillmore, 2012). ...
Article
Previous research has shown that the effects of alcohol on drivers’ performance can differ depending on whether blood alcohol concentrations are increasing or decreasing. The present research used a more ecologically representative alcohol consumption protocol in order to determine whether the same pattern of driver impairment would occur when drinking occurred in social groups over a longer period of time. Forty-four participants were assigned to one of two alcohol dose conditions or a placebo control group and consumed alcohol in groups of three (typically one participant from each condition) such that they gradually reached their target BAC (.05 or .08) and maintained it for 1 h. The participants completed a series of cognitive tests (Cogstate test battery) and a simulated driving task (driver attention inhibition and reaction test) over the course of their intoxication curve (approximately 4 h). The results showed strong placebo effects on ratings of subjective intoxication. Driving and cognitive performance both showed dose-dependent alcohol impairment, and some measures displayed acute protracted error. The findings provide strong evidence of expectancy effects in contributing to self-perceptions of intoxication.
... Further, environmental factors may influence the effects of alcohol (Holdstock and de Wit, 1998;Lindman et al., 1987), and several authors (Behar, 1983;Kalin, 1972;Marlatt and Rohsenow, 1980;Polivy, 1976) have suggested that alcohol in itself is not enough to cause such effects, i.e. different contextual, cognitive and affective factors are necessary. It is also reasonable to assume that the different modes of alcohol administration (oral vs. intravenous) affected subjective experiences differently. ...
... It is also worth noting that we did not find differences in craving during different time points during BAC. Individual differences in the effects of alcohol are known to be both dose and time dependent (Holdstock & Wit, 1998). In the present study, participants' BAC peaked during the break, and began to drop before being exposed the second set of video cues. ...
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Non-daily smokers commonly smoke cigarettes following the consumption of alcohol, yet the reason(s) for this remains poorly understood. The present study examined the impact of alcohol consumption on responses in tobacco salient cues 49 male and 50 female non-daily smokers. After the administration of an alcohol, placebo, or control beverage, participants were exposed to series neutral video clips and tobacco smoking salient video clips, and their subjective states and heart rates were monitored. The timing of the exposure to the tobacco smoking clips was randomly determined to coincide with the timing of either the ascending limb or the descending limb of the blood alcohol concentration (BAC) curve of the alcohol beverage condition. The tobacco smoking clips were found to increase cigarette craving regardless of beverage condition or timing of exposure (p =.002). Alcohol consumption was associated with increased ratings of intoxication (p < .001), increased heart rate across participants (p <.001), and increased cigarette craving in female participants specifically (p = .017). Alcohol did not influence responses to the smoking videos. These results suggest that smoking salient cues and alcohol may impact cigarette craving in non-daily smokers through independent processes.
... Alcohol has a biphasic effect (stimulant and sedative), depending on the phase of the blood alcohol curve and the individual (Pohorecky, 1977;Holdstock and de Wit, 1998). Alcohol is incoordinating, anxiolytic, anticonvulsant, and sedative; in high doses, it is hypnotic, similar to many effects of positive modulators of GABA A receptors (Grobin et al., 1998). ...
... In zebrafish, ethanol initially acts as a stimulant by increasing activity in the first 30 min of acute exposure, which is followed by depressantlike effects in the subsequent 30 min. The biphasic effect of ethanol has been demonstrated in zebrafish [21,32] as well as mammalian species [11,33,34]. Chatterjee and Gerlai [30] previously described the temporal trajectory of changes in neurotransmitters and their metabolites during acute ethanol exposure and found that the neurochemical changes plateaued after 60 min of exposure. ...
... This biphasic pattern differs from studies in which alcohol is consumed without food in the early-late afternoon. Those studies found that sedative effects arose on the descending limb of the BAC curve, while we observed sedative effects directly after consumption [31,43,44]. However, Addicot et al. (2007) also observed sedative effects before BAC levels started to decline [45]. ...
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The pre-drinking mood state has been indicated to be an important factor in the mood effects of alcohol. However, for moderate alcohol consumption there are no controlled studies showing this association. Also, the mood effects of consuming alcohol combined with food are largely unknown. The aim of this study was to investigate the effects of moderate alcohol combined with a meal on ambiance-induced mood states. Furthermore effects on autonomic nervous system activity were measured to explore physiological mechanisms that may be involved in changes of mood state. In a crossover design 28 women (age 18-45 y, BMI 18.5-27 kg/m(2)) were randomly allocated to 4 conditions in which they received 3 glasses of sparkling white wine (30 g alcohol) or alcohol-free sparkling white wine while having dinner in a room with either a pleasant or unpleasant created ambiance. Subjects filled out questionnaires (B-BAES, POMS and postprandial wellness questionnaire) at different times. Skin conductance and heart rate variability were measured continuously. Moderate alcohol consumption increased happiness scores in the unpleasant, but not in the pleasant ambiance. Alcohol consumption increased happiness and stimulation feelings within 1 hour and increased sedative feelings and sleepiness for 2.5 hour. Skin conductance was increased after alcohol within 1 hour and was related to happiness and stimulation scores. Heart rate variability was decreased after alcohol for 2 hours and was related to mental alertness. Mood inductions and autonomic nervous system parameters may be useful to evaluate mood changes by nutritional interventions. Moderate alcohol consumption elevates happiness scores in an unpleasant ambiance. However, drinking alcohol during a pleasant mood results in an equally positive mood state. Clinicaltrials.gov NCT01426022.
... Mecamylamine decreased the rewarding effect of alcohol, alcohol-induced mood alterations and the self-reported desire to consume alcoholic beverages (Blomqvist et al., 2002). Selfreport measures included the Drug Effect Questionnaire (Holdstock and de Wit, 1998), the Alcohol Sensation Scale (Maisto et al., 1980), and the Biphasic Alcohol Effects Scale (Martin et al., 1993). Mecamylamine also modified the pharmacokinetic profile of alcohol, as evidenced by decreased blood alcohol concentrations (Blomqvist et al., 2002). ...
Article
Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat hypertension. Mecamylamine administration produces several deleterious side-effects at therapeutically relevant doses. As such, mecamylamine's use as an antihypertensive agent was phased out, except in severe hypertension. Mecamylamine easily traverses the blood-brain barrier to reach the central nervous system (CNS), where it acts as a nicotinic acetylcholine receptor (nAChR) antagonist, inhibiting all known nAChR subtypes. Since nAChRs play a major role in numerous physiological and pathological processes, it is not surprising that mecamylamine has been evaluated for its potential therapeutic effects in a wide variety of CNS disorders, including addiction. Importantly, mecamylamine produces its therapeutic effects on the CNS at doses 3-fold lower than those used to treat hypertension, which diminishes the probability of peripheral side-effects. This review focuses on the pharmacological properties of mecamylamine, the differential effects of its stereoisomers, S(+)- and R(-)-mecamylamine, and the potential for effectiveness in treating CNS disorders, including nicotine and alcohol addiction, mood disorders, cognitive impairment and attention deficit hyperactivity disorder.
... Correlational evidence also indicates some correspondence in the subjective effects of alcohol and AMPH in healthy volunteers (Holdstock and de Wit, 2001). Nevertheless, alcohol's most pronounced and consistent subjective effects are sedative (Holdstock and de Wit, 1998de Wit, , 2001 Schuckit et al, 1991; Walsh et al, 1991) consistent with its designation as a CNS depressant, whereas AMPH's primary effects are stimulant (de Wit et al, 2002; Heishman and Henningfield, 1991; Zacny et al, 1992). Research with animals further indicates that the discriminative stimulus properties of alcohol are unlike those of AMPH (Druhan et al, 1991). ...
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Previous research suggests that gambling can induce effects that closely resemble a psychostimulant drug effect. Modest doses of addictive drugs can prime motivation for drugs with similar properties. Together, these findings imply that a dose of a psychostimulant drug could prime motivation to gamble in problem gamblers. This study assessed priming effects of oral D-amphetamine (AMPH) (30 mg) in a within-subject, counter-balanced, placebo-controlled design in problem gamblers (n=10), comorbid gamblerdrinkers (n=6), problem drinkers (n=8), and healthy controls (n=12). Modified visual analog scales assessed addictive motivation and subjective effects. A modified rapid reading task assessed pharmacological activation of words from motivationally relevant and irrelevant semantic domains (Gambling, Alcohol, Positive Affect, Negative Affect, Neutral). AMPH increased self-reported motivation for gambling in problem gamblers. Severity of problem gambling predicted positive subjective effects of AMPH and motivation to gamble under the drug. There was little evidence that AMPH directly primed motivation for alcohol in problem drinkers. On the reading task, AMPH produced undifferentiated improvement in reading speed to all word classes in Nongamblers. By contrast, in the two problem gambler groups, AMPH improved reading speed to Gambling words while profoundly slowing reading speed to motivationally irrelevant Neutral words. The latter finding was interpreted as directly congruent with models, which contend that priming of addictive motivation involves a linked suppression of motivationally irrelevant stimuli. This study provides experimental evidence that psychostimulant-like neurochemical activation is an important component of gambling addiction.
... Although rodent models of ethanol consumption have clear translational value, we and others have focused some of our studies on the stimulant properties of ethanol due, in part, to the similarity in neurochemical pathways governing ethanol-induced stimulation and reward [18][19][20][21], and because increased stimulant sensitivity is associated with a history of increased ethanol consumption [22] and a family history of alcohol dependence [23,24]. This measure also avoids some of the complications associated with consumption studies, such as variation in ethanol intake, taste factors that can influence intake, and possible nonspecific drug effects, which can be assessed using the locomotor measure. ...
Article
Neural processes influenced by γ-aminobutyric acid B (GABA(B)) receptors appear to contribute to acute ethanol sensitivity, including the difference between lines of mice bred for extreme sensitivity (FAST) or insensitivity (SLOW) to the locomotor stimulant effect of ethanol. One goal of the current study was to determine whether selection of the FAST and SLOW lines resulted in changes in GABA(B) receptor function, since the lines differ in sensitivity to the GABA(B) receptor agonist baclofen and baclofen attenuates the stimulant response to ethanol in FAST mice. A second goal was to determine whether the baclofen-induced reduction in ethanol stimulation in FAST mice is associated with an attenuation of the mesolimbic dopamine response to ethanol. In Experiment 1, the FAST and SLOW lines were found to not differ in GABA(B) receptor function (measured by baclofen-stimulated [(35)S]GTPγS binding) in whole brain or in several regional preparations, except in the striatum in one of the two replicate sets of selected lines. In Experiment 2, baclofen-induced attenuation of the locomotor stimulant response to ethanol in FAST mice was not accompanied by a reduction in dopamine levels in the nucleus accumbens, as measured by microdialysis. These data suggest that, overall, GABA(B) receptor function does not play an integral role in the genetic difference in ethanol sensitivity between the FAST and SLOW lines. Further, although GABA(B) receptors do modulate the locomotor stimulant response to ethanol in FAST mice, this effect does not appear to be due to a reduction in tonic dopamine signaling in the nucleus accumbens.
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Background: Alcohol impairs response inhibition; however, it remains contested whether such impairments affect a general inhibition system, or whether affected inhibition systems are embedded in, and specific to, each response modality. Further, alcohol-induced impairments have not been disambiguated between proactive and reactive inhibition mechanisms, and nor have the contributions of action-updating impairments to behavioural 'inhibition' deficits been investigated. Methods: Forty Participants (25 female) completed both a manual and a saccadic stop-signal reaction time (SSRT) task before and after a 0.8g/kg dose of alcohol and, on a separate day, before and after a placebo. Blocks in which participants were required to ignore the signal to stop or make an additional 'dual' response were included to obtain measures of proactive inhibition as well as updating of attention and action. Results: Alcohol increased manual but not saccadic SSRT. Proactive inhibition was weakly reduced by alcohol, but increases in the reaction times used to baseline this contrast prevent clear conclusions regarding response caution. Finally, alcohol also increased secondary dual response times of the dual task uniformly as a function of the delay between tasks, indicating an effect of alcohol on action-updating or execution. Conclusions: The modality-specific effects of alcohol favour the theory that response inhibition systems are embedded within response modalities, rather than there existing a general inhibition system. Concerning alcohol, saccadic control appears relatively more immune to disruption than manual control, even though alcohol affects saccadic latency and velocity. Within the manual domain, alcohol affects multiple types of action updating, not just inhibition.
Article
Background. Variability in sensitivity to the acute effects of alcohol is an important risk factor for the development of alcohol use disorder (AUD). The most commonly used retrospective self-report measure of sensitivity, the Self-Rating of the Effects of Alcohol form (SRE), queries a limited number of alcohol effects and relies on respondents’ ability to recall experiences that might have occurred in the distant past. Here, we investigated the construct validity of an alternative measure that queries a larger number of alcohol effects, the Alcohol Sensitivity Questionnaire (ASQ), and compared it to the SRE in predicting momentary subjective responses to an acute dose of alcohol. Method. Healthy young adults (N = 423) completed the SRE and the ASQ and then were randomly assigned to consume either alcohol or a placebo beverage (between-subjects manipulation). Stimulation and sedation (Biphasic Alcohol Effects Scale) and subjective intoxication were measured multiple times after drinking. Results. Hierarchical linear models showed that the ASQ reliably predicted each of these outcomes following alcohol but not placebo consumption, provided unique prediction beyond that associated with differences in recent alcohol involvement, and was preferred over the SRE (in terms of model fit) in direct model comparisons of stimulation and sedation. Conclusions. The ASQ compared favorably with the better-known SRE in predicting increased stimulation and reduced sedation following an acute alcohol challenge. The ASQ appears to be a valid self-report measure of alcohol sensitivity and therefore holds promise for identifying individuals at-risk for AUD and related problems.
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Differential sensitivity to alcohol effects (e.g., increased stimulation and decreased sedation) is associated with heavier use and problems. Although genetic factors contribute to alcohol response (AR), environmental factors may also play a role. This study examined effects of physical context on AR using a between subjects placebo-controlled design. There were 157 (57% male) participants (ages 21-30) who were randomized to 1 of 4 conditions based on beverage (placebo or alcohol [target BrAC = .08 g%]) and physical context (simulated bar or traditional lab). AR was assessed using the Subjective Effects of Alcohol Scale and the Biphasic Alcohol Effects Scale, as well as behavioral tasks including the Balloon Analogue Risk Task (BART) and its negative reinforcement counterpart (MRBURNS). A beverage condition by context interaction emerged for low arousal positive subjective response (SR), and among women, for performance on the BART task. In the lab context only, alcohol (relative to placebo) was associated with stronger low arousal positive SR and, for women, with impaired performance on the BART task. This suggests that a less stimulating lab context may be better suited to differentiating positive alcohol effects from expectancies, whereas a bar context may be better suited to detecting expectancy effects. The findings also suggest that the ability to better appreciate positive alcohol effects (relative to expectations) in less stimulating contexts may lead to a strengthening of these effects among individuals who drink in these environments. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
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The belief that alcohol makes you cheerful is one of the main reasons for engaging in high-risk drinking, especially among young adults. The aim of the study was to investigate the association between blood alcohol content (BAC) and cheerfulness, focus distraction, and sluggishness among students attending high school parties. Participants included 230 students attending high school parties. BAC, measured by use of a breath analyzer, self-reported cheerfulness (on a score from 0 to 16), focus distraction (score from 0 to 8), and sluggishness (score from 0 to 4) were assessed several times during the party. Data were analyzed by means of linear regression, including robust standard errors and stratified on sex. For girls, cheerfulness increased up to a BAC of 0.113 g% and decreased at higher BACs. At BACs of 0.020, 0.050, 0.100, and 0.150 g% cheerfulness was 11.0 (95% confidence interval [CI]: 10.4 to 11.6), 12.4 (95% CI: 11.8 to 12.9), 13.5 (95% CI: 13.0 to 14.0), and 13.1 (95% CI: 11.9 to 14.4), respectively. For boys, the association was linear with an increase of 0.18 points in cheerfulness (95% CI: 0.01 to 0.36) for every 0.010 g% increase in BAC. Focus distraction increased with increasing BAC: 0.22 (95% CI: 0.16 to 0.28) and 0.24 (95% CI: 0.14 to 0.33) points for girls and boys, respectively, per 0.010 g% increase in BAC. The degree of sluggishness increased only slightly with increasing BAC with 0.02 (95% CI: 0.02 to 0.05) and 0.03 (95% CI: -0.01 to 0.07) points for every 0.010 g% increase in BAC for girls and boys, respectively. Cheerfulness increased up to a certain BAC value for girls, while it increased linearly for boys. Focus distraction increased with increasing BAC.
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Limiting alcohol consumption may help prevent alcohol-mediated smoking relapse in heavy drinking smokers. This pilot study examined whether combining a nicotine patch with nicotine nasal spray has stronger attenuating effects on alcohol response and consumption than a nicotine patch alone. Twenty-two non-alcohol dependent heavy drinking smokers completed the double-blind cross-over, placebo-controlled study (21 mg nicotine patch + nicotine or placebo nasal spray). Six hours after 21mg nicotine patch application, subjective and physiological responses to a priming drink (0.3 g/kg) were assessed, followed by two 1-hr alcohol self-administration periods, with possible consumption of up to 4 drinks per period (each 0.15 g/kg). Nasal spray (1 mg [active] or 0 mg [placebo] per dose) was administered 10 min prior to the priming dose and each self-administration period. Active nasal spray did not increase serum nicotine levels, compared with placebo administration. The number of drinks consumed did not differ by the nasal spray conditions. However, positive subjective responses to the priming drink were lower in the active nasal spray condition than the placebo nasal spray condition. During the self-administration period, urge to drink was also lower in the active spray condition than the placebo condition. Augmenting the nicotine patch with nicotine nasal spray attenuated positive subjective alcohol response and craving and suggests that future studies should investigate whether these findings translate to a clinical setting. (Am J Addict 2013;22:590-597).
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Children of alcoholics (COAs) have an increased risk of developing alcoholism themselves. The mechanisms responsible are not yet known. One compelling theory postulates that COAs may have an increased sensitivity to the stimulant effects of alcohol during the ascending limb of the blood alcohol curve combined with a decreased sensitivity to the putatively undesirable sedative effects of the drug during the descending limb, providing a particularly strong motivation to drink. Consistent with this theory, we hypothesized that compared to children of nonalcoholics (CONAs), COAs would display higher levels of ascending limb stimulation and lower levels of descending limb sedation. In the present study, 100 college students, who were either COAs (n=18) or CONAs (n=82), completed the Biphasic Alcohol Effects Scale (a self-report measure of stimulation and sedation): (1) before consuming 0.85n ml/kg ethanol; (2) during the ascending limb of their BAC, and; (3) during the descending limb of their BAC. Although findings indicated that COAs and CONAs had comparable levels of sedation at each time point, a significant Group×Time interaction (P
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γ-Hydroxybutyrate (GHB)-related compounds are most commonly described as depressants, with emphasis on somnolence, obtundation, stupor, and coma (SOSC). We sought to demonstrate the full spectrum of clinical presentations of GHB intoxication, including agitation and other nonsedative effects. Our observational study identified 66 patients with GHB toxicity, 40 of whom manifested agitation; 25 had agitation before or after SOSC, 10 had agitation alternating abruptly with SOSC, and 5 had agitation only. Fourteen presentations also included “bizarre” or self-injurious behaviors. Of 40 presentations with agitation, 19 had stimulant co-intoxicants confirmed by screen (14) or history (5). The remaining 21 patients with agitation were negative for stimulants by screen (12) or history (9). Gas chromatography/mass spectrometry detected GHB in 25 cases; 12 manifested agitation, 4 of which also screened negative for stimulants. Clinicians should broaden their definitions of GHB toxicity to include nonsedative effects such as agitation, combativeness, and bizarre or self-injurious behavior.
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Delay discounting and probability discounting are behavioral economic indices of impulsive and risky decision making that have been associated with addictive behavior, but the acute biphasic effects of alcohol on these decision-making processes are not well understood. This study sought to investigate the biphasic effects of alcohol on delay and probability discounting across the ascending and descending limbs of the breath alcohol concentration (BAC) curve, which are respectively characterized by the stimulant and sedative effects of alcohol. Delay and probability discounting were measured at four time points (Baseline, Ascending, Descending, and End point) across the BAC curve at two target alcohol doses (40 mg/dl and 80 mg/dl) in healthy adults (n = 23 and 27, for both doses, respectively). There was no significant effect of alcohol on delay discounting at either dose. Alcohol significantly affected probability discounting, such that reduced discounting for uncertain rewards was evident during the descending limb of the BAC curve at the lower dose (p < .05) and during both the ascending and descending limb of the BAC curve at the higher dose (p < .05). Thus, alcohol resulted in increased risky decision making, particularly during the descending limb, which is primarily characterized by the sedative effects of alcohol. These findings suggest that the biphasic effects of alcohol across the ascending and descending limbs of the BAC have differential effects on behavior related to decision-making for probabilistic, but not delayed, rewards. Parallels to and distinctions from previous findings are discussed. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
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Heroin dependence is associated with a stressful environment and with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The present study examined the acute effects of intravenous heroin versus placebo on the HPA axis response in heroin-dependent patients.Twenty-eight heroin-dependent patients in heroin-assisted treatment and 20 age- and sex-matched healthy participants were included in a controlled trial in which patients were twice administered heroin or saline in a crossover design, and healthy controls were only administered saline. The HPA axis response was measured by adrenocorticotropic hormone (ACTH) levels and by cortisol levels in serum and saliva before and 20 and 60 minutes after substance administration. Craving, withdrawal, and anxiety levels were measured before and 60 minutes after substance application. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography.Heroin administration reduces craving, withdrawal, and anxiety levels and leads to significant decreases in ACTH and cortisol concentrations (P < 0.01). After heroin administration, cortisol concentrations did not differ from healthy controls, and ACTH levels were significantly lower (P < 0.01). In contrast, when patients receive saline, all hormone levels were significantly higher in patients than in healthy controls (P < 0.01).Heroin-dependent patients showed a normalized HPA axis response compared to healthy controls when they receive their regular heroin dose. These findings indicate that regular opioid administration protects addicts from stress and underscore the clinical significance of heroin-assisted treatment for heroin-dependent patients.
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Schizophrenia is a major mental illness that is characterized by psychosis, social withdrawal, and cognitive impairment. High comorbidity rates with substance use disorders have consistently been found – especially with abuse of cannabis and psychostimulants. While the role of these drugs in the onset of psychosis and schizophrenia has received much attention, relatively few studies have been conducted on the impact of psychoactive substances on the course of schizophrenia. In this review, study findings measuring the effects of psychoactive substances with structural and functional magnetic resonance imaging methods are described in patients suffering from substance use disorder and schizophrenia. Both Schizophrenia and substance abuse are associated with different functional brain alterations. In addicted individuals, drug-related cues and drug administration lead to increased neurofunctional activity in limbic and prefrontal brain regions compared to healthy controls. Chronic drug abuse is associated with gray matter loss in these areas. In schizophrenic patients, cognitive imaging in the frontal and temporal brain areas has showed decreased neural activity during the resting state. In chronic schizophrenic patients, the greatest loss of brain volume was found in those patients with additional substance abuse. Neuroimaging studies highlight the significance of regular drug use in schizophrenia. Whereas schizophrenic patients with and without substance abuse may not differ in structural imaging at the onset of illness, regular drug abuse seems to be a significant risk factor for severe loss of brain volume in the course of schizophrenia.
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Ambiguous biochemical and subjective responses to alcohol may relate to preexisting individual differences in alcohol expectations, experience, or impulsivity. This study examined cortisol and alpha-amylase responses to alcohol and their association with trait impulsivity, alcohol expectancy, and subjective reports of alcohol's effects. Eighty-seven males assigned to an alcohol, sober, or placebo group provided biochemical and self-report measures. Both cortisol and alpha-amylase increased following alcohol administration. Impulsivity correlated with cortisol changes, and the greatest rise in cortisol correlated with high stimulating effects in the alcohol group. These findings emphasize the importance of individual differences in alcohol responses and support a relationship between hormonal responses and alcohol use.
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Five studies were conducted, employing three independent samples of high school students, leading to the development and assessment of the reliability and validity of a Drug Attitudes Scales. The results of these studies support the conclusions that this scale shows substantial reliability and validity, and promises considerable utility in drug treatment and education research. The Drug Attitudes Scale consists of 60 attitude items dealing with drugs and drug use, and is comprised of 10 six-item subscales referring to tranquilizers, barbiturates, heroin, opiates other than heroin, "speed," alcohol, cannabis, hallucinogens, tobacco, and general drug use.
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Clinical, genetic, and neuropsychopharmacological studies of developmental factors in alcoholism are providing a better understanding of the neurobiological bases of personality and learning. Studies of the adopted-away children of alcoholics show that the predisposition to initiate alcohol-seeking behavior is genetically different from susceptibility to loss of control after drinking begins. Alcohol-seeking behavior is a special case of exploratory appetitive behavior and involves different neurogenetic processes than do susceptibility to behavioral tolerance and dependence on the antianxiety or sedative effects of alcohol. Three dimensions of personality have been described that may reflect individual differences in brain systems modulating the activation, maintenance, and inhibition of behavioral responses to the effects of alcohol and other environmental stimuli. These personality traits distinguish alcoholics with different patterns of behavioral, neurophysiological, and neuropharmacological responses to alcohol.
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The theory is advanced that the common denominator of a wide range of addictive substances is their ability to cause psychomotor activation. This view is related to the theory that all positive reinforcers activate a common biological mechanism associated with approach behaviors and that this mechanism has as one of its components dopaminergic fibers that project up the medial forebrain bundle from the midbrain to limbic and cortical regions. Evidence is reviewed that links both the reinforcing and locomotor-stimulating effects of both the psychomotor stimulants and the opiates to this brain mechanism. It is suggested that nicotine, caffeine, barbiturates, alcohol, benzodiazepines, cannabis, and phencyclidine-each of which also has psychomotor stimulant actions-may activate the dopaminergic fibers or their output circuitry. The role of physical dependence in addiction is suggested to vary from drug to drug and to be of secondary importance in the understanding of compulsive drug self-administration.
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Reviews recent behavioral and neuropharmacological findings, which suggest that opiate and stimulant drugs act on common neurochemical systems of the brain to generate positive appetitive states that maintain drug-taking behavior. CSs associated with these drugs arouse neural states that mimic features of those produced by the drugs themselves and thereby serve to increase the effectiveness of drug-related stimuli and to increase the probability of drug-related thoughts and actions. This positive incentive account of compulsive drug use contrasts with the drive-reduction view that continued drug use depends primarily on efforts to reduce or to avoid symptoms of withdrawal, and that conditioned stimuli initiate and maintain drug-taking behavior through the elicitation of withdrawal-like, drug-opposing CRs. (4 p ref)
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Group-housed female mice were injected IP with 0, 0.5, 1.0 or 2.0 g/kg of ethanol. Twenty min after injection, the animal's responses in a neutral cage to a docile male "standard opponent" were videotaped for 500 sec. The tapes were subsequently analysed in terms of the total times allocated by the females to non-social, social/sexual, aggressive and timid activities. The frequency of occurrence of acts and postures associated with the above categories was also determined. Similar females given the same doses were used to assess the blood alcohol concentrations 20 min after injection. Timid behaviour was greatly increased by high doses of ethanol, especially as a consequence of increases in the element 'cringe'; at the low dose 'cringe' was decreased in frequency. Social/sexual behaviour was also influenced in a biphasic manner, low doses increasing and high doses reducing such activity. The drug modified some elements of non-social behaviour in a manner suggesting motor impairment at high doses. There was no evidence that any dose of ethanol induced aggressiveness in these animals. There did not seem to be a simple dose-response effect.
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Whole-cell and single-channel recording techniques were used to investigate the acute, in vitro effects of ethanol on the function of voltage-activated Ca2+ channels in cultured neurons derived from dorsal root ganglia (DRG) of embryonic mice. Although 5.4 MM ethanol produced a sustained increase of the amplitude of the whole-cell Ca2+ current (ICa), 43.2 mM ethanol had a time-dependent biphasic effect. That is, within 0.5 min of exposure to 43.2 MM ethanol, the maximal amplitude of ICa initially increased before declining to a new steady-state value. As anticipated, the facilitatory and inhibitory effects of ethanol on ICa were associated with an increase and decrease, respectively, in the probability of single-channel open events. Pretreatment of DRG with 200 ng/ml of pertussis toxin abolished the inhibitory, but not the facilitatory, effect of 43.2 mM ethanol on ICa Pretreatment with pertussis toxin also prevented the reduction of the probability of single-channel opening caused by 43.2 mM ethanol. Similarly, dialysis of neurons with polyclonal antibodies against the a-subunit of Go but not G., abolished the inhibitory effect of 43.2 mM ethanol on ICa These data demonstrate concentration- and time-dependent biphasic effects of ethanol on the activity of Ca2+ channels. The inhibitory effect of ethanol requires activation of the a-subunit of Go, which then decreases the probability of Ca2+ channel opening.
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We investigated the behavioral effects of alcohol, especially those on aggression, on members of established groups of squirrel monkeys. A continuous measurement of monkey behavior in groups revealed consistent differences between dominant and subordinate animals. Dominant monkeys aggressed more frequently than subordinate monkeys, and spent less time in stationary postures. Alcohol produced dose-related biphasic changes in the number of threats, grasps, and displacements exhibited by dominant but not subordinate monkeys. Low doses of alcohol (0.1, 0.3, 0.6 g/kg) increased the frequency of aggressive behavior, and high doses (1.0 g/kg) decreased these behaviors. The largest change in behavior was evident in the first 20–40 min after injection, with a return to baseline 60–120 min later. The aggression-enhancing effect of alcohol in dominant monkeys required a stable baseline, which was obtained by daily administration of distilled water. Low levels of aggressive and associative behavior in subordinate monkeys were relatively unaffected at any dose of alcohol. They were associated with and aggressed against more often by untreated members of the group. The status-dependent effects of alcohol may be related to the neuroendocrine and neurotransmitter profiles characteristic of dominant and subordinate monkeys.
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The course of alcohol absorption and elimination was investigated in seven women and nine men administered a moderate (0.66 ml/kg) dose of 95% ethanol. Women were tested during the postmenstrual phase (Day 6–7), when levels of estrogen and progesterone were estimated to be relatively low. Data reflecting alterations in physical sensations, perceived levels of intoxication, and positive and negative mood states were also collected. Women reached significantly higher peak blood alcohol concentrations (BAC's) than men (p<0.01). However, differences in peak BAC's between men and women could be explained by differences in body water content between the sexes. When the raw data on BAC's were corrected for differences in body water content between men and women, no difference in the amount of alcohol metabolized, or in the length of time necessary to metabolize that amount of alcohol, could be found between the sexes. Although women attained higher blood and, presumably, brain levels of ethanol, men did not differ from women in perceived levels of intoxication, physical sensations and mood states. Acute alcohol intoxication appeared to elevate positive mood states during the ascending limb of the BAC curve, but was associated with increased negative affect during the descending limb.
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The relationship between subjective effects and drug preferences in normal volunteers was explored in a meta-analysis of several previously published studies. Subjective effects of, and preference for, ethanol and diazepam vs. placebo were measured using a choice procedure. Subjects were grouped according to their drug choices: ‘non-choosers’ never chose drug, whereas ‘choosers’ always chose drug. The two groups were compared on their subjective responses to drug and on demographic variables. Ethanol decreased Arousal, Elation, Positive Mood and Vigor, and increased Anxiety, Depression and Fatigue in the non-choosers, whereas it increased Arousal and Vigor in the choosers. Ethanol choosers were also more likely to be males and/or full-time students than non-choosers. Diazepam produced sedative-like effects in both choosers and non-choosers, but markedly decreased Anxiety and increased Friendliness in choosers only. Diazepam choice was also associated with more frequent recreational use of marijuana and stimulants. Thus, both demographic variables and subjective drug effects were related to drug preference.
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Ten male and 10 female nonalcoholic college students were given drinks having alcohol levels of 0, 0.5, 0.8, and 1.2 g/kg. They were then given four complex psychomotor tests, immediately before and after which they were given the Spielberger State Anxiety Inventory, and asked to rate their performance on a five-point scale. Mean anxiety change scores were -.90, .75, 4.75, and 5.55 for the four alcohol doses, respectively. There was no significant correlation between anxiety change and actual performance on the visual vigilance task, but for males there was a significant correlation between anxiety change and perceived level of impairment.
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Ethanol effects on two types of motor activity and on lever responding for food delivered on a fixed-ratio 20 (FR 20) reinforcement schedule were compared using C57BL/6 (C57) mice. Low doses of ethanol (1-2 g/kg) transiently elevated horizontal activity and high doses (2.5 and 3.0 g/kg) reduced this behavior throughout testing with a slight recovery toward the end of a 16-min test period. In contrast, similar ethanol doses produced a monotonic reduction in both vertical activity and lever responding for food under the FR 20 schedule. The ethanol-induced reduction in FR 20 lever responding was less prolonged than the reduction in vertical activity but was more prolonged than the reduction in horizontal activity. Because vertical activity and lever responding for food delivered on the FR 20 schedule were never elevated, were reduced at ethanol doses that either stimulated or depressed horizontal activity, and were unaffected by low ethanol doses that did not affect horizontal activity, it is unlikely that either are sensitive to the stimulatory effects of ethanol. Accountable mechanisms for the different effects of ethanol on the three behaviors are unknown; however, the present study eliminates ethanol dose, postinjection time, testing time, and food deprivation condition as possible reasons for the differences.
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Seventh-generation selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats were trained to make differential responses for ethanol (0.75 g/kg, IP) and saline vehicle, following postadministration intervals (PI) of 2 min (HAD-2 and LAD-2 animals) and 30 min (HAD-30 and LAD-30 animals). ED50 values of 0.395 and 0.352 g/kg, respectively, for HAD-2 and LAD-2 animals and 0.269 and 0.314 g/kg, respectively, for HAD-30 and LAD-30 animals reflect the absence of any phenotypic difference for the discriminative stimulus effects of ethanol. HAD-2 animals were more responsive than LAD-2 animals to the stimulating effects of ethanol as measured by total response rates during training sessions. The differential ethanol response generalized to pentobarbital in all four groups but not to morphine, an alternative CNS depressant. The specific antagonist of 5-hydroxytryptamine3 receptors, 3-tropanyl-3,5-dichlorobenzoate (MDL 72222), up to doses of 14.0 mg/kg failed to antagonize the discriminative effects of ethanol. Ethanol sleep times did not differ between groups.
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Nifedipine (10.0 mg/kg) was administered to mice together with graded doses of ethanol (0, 2.5, 3.0, 3.5, 4.0 and 4.5 g/kg), and activity measured over a 2-hr period following administration. Low ethanol doses increased activity, whereas the highest dose decreased it. By itself, nifedipine had no effect on activity, but when combined with ethanol it produced a consistent decrease in comparison with ethanol alone. This occurred irrespective of whether the ethanol dose alone increased or decreased activity. These results demonstrate a clear interaction between nifedipine and ethanol which cannot be characterized as simple potentiation or antagonism. Time-course data showed that the effects of nifedipine were apparent within 10-20 min of drug administration, but, in the case of the highest ethanol dose, increased toward the end of the 2-hr period. Retardation of the development of acute tolerance may contribute to the interaction between ethanol and nifedipine.
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This paper represents a comprehensive review of laboratory studies investigating the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective effects of these drugs, most of which are either barbiturates or benzodiazepines, have been measured using various self-report questionnaires and their reinforcing effects have been studied using self-administration and choice procedures. Studies using both subjective and reinforcing effects reveal orderly relations between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates are associated with higher abuse liability than benzodiazepines), between different doses of the drugs (e.g. higher doses are usually associated with higher abuse liability) and among different compounds within a class. The subjective and reinforcing effects of barbiturates and benzodiazepines depend critically upon the subject populations that are tested and it is argued that individuals with histories of drug abuse provide a more sensitive indicator of abuse liability than healthy volunteers. Several principles of abuse liability testing are discussed, including the selection of an appropriate subject population, the use of blind drug administration procedures, the comparison of a test compound to an appropriate standard, the inclusion of a placebo and a wide range of doses of the test drug and the use of multiple measures of likelihood of abuse.
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Estimates of the likelihood that a drug will be abused have generally been based on the subjective effects engendered by that drug. With the development of standardized subjective effects questionnaires in the 1960s and 1970s, researchers have been able to carefully evaluate self-reported effects of drugs, generally making measures before and repeatedly after administration of a single dose of drug. The use of multiple doses under controlled laboratory conditions in which physiological measures are also taken, and both the investigator and the subject are blind to the dose administered, has been suggested as most likely to yield useful data about the abuse liability of a test compound. Although questions remain about the specific subjective effects measures to be used, there has been general agreement among researchers in this area that scores on scales from the Profile of Mood States, Addiction Research Center Inventory, and Visual Analog Scales which include measures of 'high' or 'liking' all provide predictive utility. The addition of a measure of actual drug-taking to this predictive model appears to provide important information about the conditions under which these two behaviors (self-reported effects and drug self-administration) vary, and strengthens the model substantially.
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Subjective feelings of intoxication help determine drinking-related behavior. Most experiments in this area have examined levels of intoxication at different blood alcohol concentrations (BACs) rather than the rate of change of these variables over time. In the present experiments, the rate of change of BACs and of intoxication ratings were compared on both the ascending and the descending limbs of these variables after alcohol challenge. BACs and intoxication ratings reached peak values at the same time when alcohol consumption took 55 min. However, when consumption was rapid (10 min), intoxication ratings reached peak values earlier than did BACs. In both experiments, intoxication ratings returned to baseline sooner than did BACs. The results suggest that internal cues to the effects of alcohol decline rapidly on the descending limb of the blood alcohol curve. The present methodology provides a way to compare the rate of change of variables with different measurement scales.
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The present research assessed the conditions under which subjects who consume alcohol and those who consume a placebo beverage, and who report consuming alcohol on a manipulation check question, are equivalent with respect to subjective responses to alcohol. Male subjects were told that they were drinking alcohol and consumed one of four beverages: alcoholic beer, nonalcoholic beer, vodka and tonic with lime, or tonic with lime. Measures of subjective intoxication, body sensations and breath alcohol were taken at different times during and after beverage consumption. Subjective intoxication ratings were higher for subjects who received alcohol, compared to subjects who received a placebo and reported consuming alcohol, when alcohol subjects achieved blood alcohol concentrations at and above .04%. These two groups did not differ in subjective intoxication ratings when alcohol subjects achieved blood alcohol concentrations below .04%. These data suggest that the orthogonal manipulation of alcohol consumption and expectancy effects is problematic at and above blood alcohol concentrations of .04%.
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Preference for ethanol versus a placebo was assessed in 12 normal volunteers usina a cumulative dosing preference test. The test consisted of four sampling sessions followed by three choice sessions. During the sampling sessions subjects received either five cumulating oral doses of ethanol (0.1 g/kg per dose) or equal volumes of placebo, at 15-min intervals. Subjective and observer-rated drug effects, psychomotor performance, drug liking ratings, and breath ethanol levels were measured at regular intervals. During choice sessions, subjects first chose which of the two substances (drug or placebo) they wished to take and ingested one unit dose. Then, at 15-min intervals throughout the session, they could ingest up to ten additional unit doses of the same substance (i.e., up to 1.1 g/kg ethanol). On average, the subjects chose the ethanol-containing beverage on 75% of the choice sessions, and they self-administered a mean total dose of 0.8 g/kg per session. Subjects varied in the amount of ethanol ingested on choice sessions, and the amount they chose was related to their subjective responses to the drug during sampling. Subjects who chose the most ethanol, whereas the subjects who chose ethanol less frequently and ingested lower doses reported primarily sedative-like effects from the drug. The results demonstrate that the cumulative dosing procedure can be used effectively to evaluate drug preferences and dose preferences in normal volunteers.
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Ethanol had biphasic effects on jump-up avoidance extinction with low doses (1 g/kg) increasing, and high doses (2.5 g/kg) decreasing number of trials to extinction criterion. In Experiment 1 these doses of ethanol were studied alone, and in combination with RO 15-4513 (0.3, 3 or 6 mg/kg). The stimulation of responding produced by low ethanol doses was reversed by 3 and 6 mg/kg doses of RO 15-4513 which had intrinsic suppressive effects, but the depressed responding produced by higher ethanol doses was not attenuated by RO 15-4513. Experiment 2 analysed the interaction between ethanol and benzodiazepine antagonists RO 15-1788 and CGS 8216. RO 15-1788 did not have intrinsic action and did not interact with ethanol. CGS 8216 showed an intrinsic suppressive action much like RO 15-4513, and also reversed the stimulation produced by low dose ethanol, but not the effects of the high dose. Experiment 3 showed that the benzodiazepine agonist, chlordiazepoxide, had effects much like low dose ethanol which were reversed by CGS 8216 and RO 15-4513. The major conclusions were that RO 15-4513 and CGS 8216 possess inverse agonist properties which may cancel out the effects of alcohol under certain circumstances.
Article
Thirty-four subjects in the Colorado Alcohol Research on Twins and Adoptees (CARTA) were brought back between 30 to 60 days after their initial testing to be retested on all the CARTA procedures. As before, subjects were given a dose of ethanol (0.8 g/kg) calculated to bring their blood alcohol concentration (BAC) to near 0.10 g/dl. Additional doses were given at the end of each of the next 2 hr to maintain their BAC near peak for approximately 3 hr. During both testings, subjects' self-reports of their emotional responses and perceived intoxication following alcohol dosing were only minimally correlated with their alcohol metabolism parameters and reported average level of alcohol use. Repeatabilities (test-retest correlations) for subjects' self-reports of positive affect and of intoxication following alcohol dosing were consistently high, in contrast to earlier reports of minimal repeatabilities for alcohol metabolism and responses to alcohol on physiological, motor coordination, reaction time, and perceptual speed measures. Tester ratings of the subjects' levels of intoxication were also moderately stable between the two testings.
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The effect of the i.p. administration of ethanol on the release of dopamine (DA) and on the output of its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, was estimated in the rat by transcerebral dialysis of two terminal dopaminergic areas, the nucleus accumbens and the dorsal caudate. Low doses of ethanol (0.25-0.5 g/kg i.p.) stimulated DA release specifically in the n. accumbens and elicited pure behavioral stimulation. Higher doses of ethanol (1.0-2.5 g/kg) elicited sedation and hypnosis and stimulated further DA release and dihydroxyphenylacetic acid and homovanillic acid output in the accumbens and, although less, also in the caudate. High doses of ethanol (5 g/kg i.p.) elicited long-lasting hypnosis and sedation and induced a depression followed by stimulation of DA release in the accumbens. DA release in the caudate was stimulated further. Low doses of apomorphine (0.05 mg/kg s.c.) reversed completely the stimulant effect of 0.5 g/kg of ethanol on behavior and on DA release in the accumbens. Moreover, the stimulation of behavior and of DA release in the accumbens elicited by 0.5 g/kg of ethanol were abolished completely by pretreatment with 700 mg/kg of gamma-butyrolactone, an agent which blocks DA firing and DA release. The results indicate that ethanol preferentially stimulates DA transmission in the mesolimbic system probably by activating the firing activity of mesolimbic DA neurons and provide direct evidence that these changes are involved in the motor stimulant effects of ethanol.
Article
Human responses to alcohol—especially sensitivity and acute behavioral tolerance—are being studied within a behavioral genetic design involving comparisons of scores from monozygotic twins, dizygotic twins, nontwin siblings, and unrelated (adoptee) pairs reared in the same family from infancy. The planned genetic analyses must await completion of data collection. The present sample is, however, adequate for analyses of means and for some analyses of individual differences in responses. For most of the measures being used, we find the usual mean decrement in performance after alcohol dosing to 0.100 BAC, but individual differences in response to alcohol are large, and a few individuals actually improve in performance after dosing. Also, on two tests, Cancellation and Block Rotations, there is a significant mean improvement in performance immediately after dosing. As yet we do not have a satisfactory explanation for this phenomenon. On most but not all of the tests, performance improves after the initial decrement during a 3‐hour period in which blood alcohol levels are maintained by additional hourly doses. This improvement may be due in part to practice effects, as well as to the development of acute behavioral tolerance to ethanol (ABTE). We are still exploring ways in which these effects may be disentangled, using data from concurrent placebo control subjects and from pre‐dosing test sessions. It is already apparent, nevertheless, that most of the variability in sensitivity and ABTE is related to pre‐existing individual variability rather than to gender, age, height, weight, or drinking history. By mailing annual questionnaires to all participants, we hope to be able to test the hypothesis that those who were relatively insensitive to ethanol or who showed a relatively large amount of ABTE during the test sessions may be at increased risk for heavy alcohol consumption.
Article
Contemporary theorists view many alcohol effects as complex functions of a number of interacting variables ranging from pharmacological factors (e.g., limb of the blood alcohol curve), environmental factors (e.g., setting) and dispositional factors (e.g., individually held expectations concerning the effects of alcohol). To examine this general model, the joint effects on subjective state of beverage (alcohol vs placebo), of setting (alone vs group) and of individual differences in alcohol expectancies were examined in a sample of 98 men social drinkers. Assessment of subjective state included measures of both mood and perceived physical sensations. The results demonstrated the complex determinants of subjective effects of alcohol and illustrated the difficulty of making strong generalizations concerning the subjective effects of alcohol. Alcohol consumption, alcohol expectancies and setting appear to have both independent and interacting effects on subjective state. These effects appear to vary in importance across the types of effects considered and the time since drinking.
Article
Rats were trained to discriminate between the interoceptive cues produced by 6.0 mg/kg pentobarbital and 0.8 mg/kg d-amphetamine, both administered intraperitoneally, using a two-lever drug discrimination task. Once trained, intraperitoneal administration of 200 mg/kg ethanol produced pentobarbital-like lever selection at 5 and 15 min post-injection with a return to random levels at 30, 45 and 60 min post-administration. In contrast, administration of 100 mg/kg ethanol produced a significantly greater number of amphetamine-appropriate lever selections at 15 min post-injection. Time-course experiments using 6.0 mg/kg pentobarbital indicated the production of predominantly pentobarbital lever selection for 60 min with a return to random responding (50% on each of the two levers) at 90 min post-administration. These results indicate that a low dose of ethanol can produce more amphetamine-like subjective cues than a higher dose and this effect is time-dependent. Neurochemical evidence is cited to illustrate the biphasic effect of ethanol as it is seen in animals and man.
Article
Doses of 0.41, 0.63, and 0.85 g alcohol/kg body weight were administered using a double-blind Latin square design to subjects who made mood ratings at seven points in time during 3h subsequent to administration. The subjects felt more euphoric and extraverted and less tense at mainly the highest dose levels. Lower dose levels tended to induce more negative feelings. Frequent consumers of alcohol derived greater affective benefit than rare drinkers. Intercorrelations between ratings of subjective intoxication and mood variables indicated that the meaning of the variable "subjective intoxication" was different for the three dose levels and for different points in time.
Article
A group of ten normal human volunteers participated in choice experiments comparing d-amphetamine or diazepam with placebo and with each other. Although amphetamine was preferred to placebo by most subjects, 2 mg diazepam and placebo were chosen equally. However, placebo was chosen over higher doses (5 and 10 mg) of diazepam and 5 mg d-amphetamine was preferred to 2 mg diazepam. Subjective effects were assessed using the Profile of Mood States (POMS) before drug was taken and 1, 3, and 6 h later. Compared to placebo, amphetamine produced changes in mood on the POMS including increases in Vigor and Arousal. Doses of 5 and 10 mg diazepam produced decreases in Vigor and Arousal and increases in Fatigue and Confusion. The effects of diazepam were most pronounced 1 h after ingestion and appeared dose-dependent. For one subject who consistently chose diazepam, its subjective effects were similar to placebo and he stated that he could not distinguish them. These results are discussed in terms of the abuse liability of diazepam.
Article
The reinforcing and subjective effects of two doses of ethanol [0.5 g/kg (LOW) and 0.8 g/kg (HIGH)] were evaluated under two conditions, a social condition (SOC), in which subjects were tested with two or three other subjects, and a socially isolated condition (ISO), in which subjects were tested alone. Forty-one social drinkers participated in a double-blind, seven-session choice procedure. Subjects were randomly assigned to one of four experimental groups: SOC-LOW, SOC-HIGH, ISO-LOW, or ISO-HIGH. On the first four sessions, subjects sampled ethanol (0.5 or 0.8 g/kg) on two occasions and placebo on the other two occasions. On the three remaining sessions, subjects selected and consumed whichever of the two previously sampled substances they preferred. The number of sessions on which they chose ethanol was the primary measure of the reinforcing effects of ethanol. Standardized self-report questionnaires and a psychomotor test were used to measure subjective and objective drug effects. Subjects in the SOC condition chose ethanol over placebo on significantly more sessions than subjects in the ISO condition. Ethanol produced positive subjective effects (e.g., increased ratings of drug liking and euphoria) for subjects in the SOC condition, but for subjects in the ISO condition, it produced apparently negative effects (e.g., increased ratings of dysphoria). These results extend previous reports that the behavioral effects of ethanol depend upon the social condition in which it is consumed.
The present investigation examined the effects of placebo (P), low dose (LD) and high dose (HD) ethanol on EEG activity in two groups of males. One group consisted of individuals at high risk for the development of alcoholism (HR, N = 21) while the other consisted of matched, low risk (LR, N = 21) controls. Only one condition (P, LD or HD) was presented each day and condition order was randomized. For each subject, both blood alcohol level(s) (BAL) measured via breathalyzer and EEG activity, using the entire 10/20 international system, were recorded prior to and at intervals of 35, 70, 105 and 140 min after P, LD or HD administration. The Fast Fourier Transform (FFT) was used to calculate power spectral densities (PSD). Measures of relative area under the power spectral curve were obtained for each of the following frequency bands: slow alpha (SA, 7.5-10 Hz), fast alpha (FA, 10.5-13.0 Hz), slow beta (SB, 13.5-19.5 Hz) and fast beta (FB, 20-26 Hz) at electrodes: F3, F4, C3, C4, P3, P4, O1 and O2. The results of repeated measures MANOVA conducted on the normalized values of relative areas revealed that at each electrode examined, ethanol elicited significant changes only in SA activity. Risk group differences in SA activity were observed only at electrodes F3, F4 and P4. These differences were the consequence of differential ethanol effects rather than differences in baseline SA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Through selective breeding, rat lines exhibiting high and low alcohol drinking preference have been developed as useful animal models for studying the neurobiological basis of alcohol-seeking behavior. The identified differences between lines in neurotransmitter functioning allows the evaluation of receptor agonist/antagonist compounds that might be efficacious in the treatment of alcohol craving and dependence.
Article
Several lines of research have suggested a link between the reward value of a drug and its ability to stimulate locomotion. One goal of the present study was to determine whether ethanol preferentially stimulates locomotor activity in lines of rat that show a preference for ethanol. A secondary goal was to determine the extent to which the benzodiazepine-like and NMDA antagonistic action of ethanol accounted for its effect on locomotor activity. To meet these goals, the effects of varying doses of ethanol (0.125-1.0 g/kg), MK-801 (0.1-0.3 mg/kg), and chlordiazepoxide (0.3-3 mg/kg) on locomotor activity were studied in several lines of rats that had been habituated to the testing procedure. The effect of low doses of ethanol on motor activity in the Alcohol-Preferring (P) and Fawn-Hooded rats, which show a strong ethanol preference, were similar to those of the alcohol-nonpreferring (NP), Flinders Sensitive Line, and Flinders Resistant Line rats. Only the Flinder Resistant Line rats showed a small, but significant increase in locomotor activity after the administration of ethanol. The highest dose of ethanol (1.0 g/kg) produced locomotor depression in all lines except the P and NP lines, which were not tested at this dose. These findings do not support a link between locomotor stimulation by ethanol and ethanol preference. In contrast, all lines exhibited locomotor stimulation after moderate (0.1-0.3 mg/kg) doses of MK-801, but did not exhibit increases in activity following any dose of chlordiazepoxide. These data indicate that the profiles of activity after MK-801 and chlordiazepoxide were distinct from that of ethanol in the various rat lines.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Previous studies have demonstrated that a moderate dose of ethanol induced a significant increase in the plasma beta-endorphin content of subjects from families with a history of alcoholism (high risk (HR)), but not subjects from families without a history of alcoholism (low risk (LR)). The objective of this study was to examine the response of the pituitary beta-endorphin and adrenal cortisol systems to various concentrations of ethanol in male and female subjects at high and low risk of the future development of alcoholism. All subjects participated in four experimental sessions. In each session the subjects were given a drink containing one of the following doses of ethanol: 0, 0.25, 0.50, and 0.75 g of ethanol per kilogram of body weight (for a 60- to 70-kg individual). Blood samples were taken at 0 minutes and at 15, 45, 120, and 180 minutes after the drink for estimation of the blood alcohol, plasma beta-endorphin, and plasma cortisol levels. The concentration of alcohol in the blood at various intervals after the drink was similar among the subjects, regardless of the risk group. Ethanol increased the plasma level of beta-endorphin-related peptides of the HR but not of the LR subjects in a dose-dependent manner. All subjects showed a small decrease in plasma cortisol level with time, but ethanol ingestion did not significantly alter the plasma cortisol levels. This study indicates that the pituitary beta-endorphin system, but not the adrenal cortisol system, of the HR subjects shows an enhanced sensitivity to ethanol, which may be an important factor in controlling ethanol consumption.
Article
There is considerable evidence that serotonin-3 (5-HT3) receptor antagonists modulate some of the behavioral effects of alcohol, and may decrease alcohol consumption. To better clarify the mechanism of action of 5-HT3 antagonists on these behaviors, we investigated the effects of the 5-HT3 antagonist, ondansetron, on several subjective and objective measures of alcohol intoxication in social drinkers. Twelve nonalcoholic, social drinkers received either 8 mg ondansetron, p.o., or placebo during one of two test sessions in a crossover, double-blind protocol. Both conditions were followed by a standard, intoxicating dose of alcohol. Subjective and objective measures of intoxication including mood, physical sensations, performance changes, and alcohol pharmacokinetics were determined. To control for ondansetron effects, 10 additional subjects received either ondansetron or placebo, followed by a nonintoxicating, "placebo" dose of alcohol during a second crossover double-blind protocol. Ondansetron was found to augment certain stimulant, sedative, and discriminant effects of alcohol, without affecting psychomotor performance or alcohol pharmacokinetics. Ondansetron had minimal effects on subjects receiving placebo alcohol. These data suggest that the reductions in alcohol consumption observed in animals and humans treated with ondansetron may be mediated by increases in subjective intoxication, and/or increases in the aversive effects of alcohol.
Article
The locomotor stimulant effect produced by alcohol (ethanol) is one of a large number of measurable ethanol effects. Ethanol-induced euphoria in humans and locomotor stimulation in rodents, a potential animal model of human euphoria, have long been recognized and the latter has been extensively characterized. Since the euphoria produced by ethanol may influence the development of uncontrolled or excessive alcohol use, a solid understanding of the neurochemical substrates underlying such effects is important. Such an understanding for spontaneous locomotion and for ethanol's stimulant effects is beginning to emerge. Herein we review what is known about three neurochemical substrates of locomotion and of ethanol's locomotor stimulant effects. Several lines of research have implicated dopaminergic, GABAergic, and glutamatergic neurotransmitter systems in determining these behaviors. A large collection of work is cited, which strongly implicates the above-mentioned neurotransmitter substances in the control of spontaneous locomotion. A smaller, but persuasive, body of evidence suggests that central nervous system processes utilizing these transmitters are involved in determining the effects of ethanol on locomotion. Particular emphasis has been placed on the mesolimbic ventral tegmental area to nucleus accumbens dopaminergic pathway, and on the ventral pallidum/substantia innominata, where GABA and glutamate have been found to play a role in altering the activity of this dopaminergic pathway. Research on ethanol and drug locomotor sensitization, increased responsiveness to the substance with repeated administration, is also reviewed as a process that may be important in the development of drug addiction.
Article
Discriminative stimulus properties of low doses of ethanol were evaluated in humans using established behavioural drug discrimination procedures. Twenty-five moderate drinkers (12 females and 13 males) were trained to discriminate placebo from 0.2 g/kg ethanol in 200 ml tonic water mixed with Tabasco sauce and drunk in portions of 50 ml every 15 s. Seventeen of the subjects (ten females and seven males) were able to reach criterion performance (at least 80% correct responses). Generalisation responding across ethanol doses of 0 (placebo), 0.025, 0.05, 0.1 and 0.2 g/kg was examined the day after training using a procedure in which subjects reported the extent to which the test stimulus resembled the training dose. At the end of each generalisation session, self ratings of mood changes, physiological responses and performance in a working memory and a time estimation task were evaluated. Subjects were able to distinguish the three higher doses of ethanol from placebo. Self ratings indicated that subjects' ability to distinguish ethanol from placebo was related, at the highest dose, to change of taste, but to feelings of light-headedness at the lower doses. Ethanol administration influenced skin conductance measurements but there was no relationship found between changes in skin conductance and the ethanol discriminative stimulus. These data suggest a difference in the nature of the discriminative stimulus of ethanol between high (training) and low (generalising) doses as indicated in the subjective reports.