Alcohol effects on simulated driving in frequent and infrequent binge drinkers.

OBJECTIVE: Compared with non­bingers, binge drinkers are more likely to drive while intoxicated. The extent to which binge frequency impacts confidence in driving and subsequent driving impairment is unknown. This study compared the effects of an experimenter­delivered alcohol binge on subjective impairment and simulated driving ability in female high­frequency and low­frequency bingers. METHODS: Female drinkers were assigned to high­frequency (n = 30) or low­frequency (n = 30) binge groups based on their Alcohol Use Questionnaire responses. At 30­min intervals within a 2­h period, participants received either a placebo drink (n = 15 per group) or a 0.2 g/kg dose of alcohol (n = 15 per group; cumulative dose 0.8 g/kg). Self­reported impairment, driving confidence, and simulated driving were then measured. RESULTS: Self­reported confidence in driving was significantly lower after alcohol than after placebo in low­frequency but not highfrequency bingers. Self­reported impairment and collisions during simulated driving were significantly greater after alcohol than after placebo in both low­frequency and high­frequency bingers. CONCLUSIONS: The impairing effects of a single alcohol binge on driving ability in women are not influenced by binge frequency. However, high binge frequency may be associated with a less cautious approach to post­binge driving.

Response inhibition impairments predict alcohol-induced sedation.

AIMS: The aim of this study was to probe the relationship between the subjective effects of alcohol and impulsive behavior in social drinkers. METHODS: Fifty social drinkers performed a response-inhibition task before consuming alcohol. A 0.8-g/kg dose of alcohol was administered in a binge-like fashion (0.2 g/kg every 30 min) to the participants over a 2-h time period. Participants then completed questionnaires measuring stimulation, sedation and mood following consumption of alcohol. Linear regression analyses were performed by examining the relationship between performance on the response inhibition impulsivity task and subjective responses to alcohol (i.e. stimulation, sedation and arousal). RESULTS: There was a significant positive relationship found between impulsive responding and self-reported sedation following alcohol consumption. Additionally, there was a significant negative relationship between behavioral impulsivity and self-reported stimulation and arousal following alcohol consumption. CONCLUSION: These results suggest that higher levels of impulsivity are associated with experiencing greater sedating than stimulating effects of alcohol. Individuals with high levels of impulsivity may be less sensitive to the stimulating effects of a specified dose of alcohol, which could lead to these individuals consuming more alcohol to experience the stimulating effects of alcohol.

Brain activity associated with social exclusion overlaps with drug-related frontal-striatal circuitry in cocaine users: A pilot study.

BACKGROUND: Exposure to various types of stress can elevate craving for cocaine and hasten relapse among substance dependent individuals. This investigation evaluated the effects of social exclusion on brain activity in cocaine dependent individuals. METHOD: Forty three individuals (18 crack-cocaine users, 25 controls) were recruited from the community to participate in functional neuroimaging study in which they performed a simulated 3 person ball-tossing game (Cyberball). Each participant was told that the other 2 players were in nearby MRI scanners. Task blocks included: Inclusion (likelihood of our participant receiving the ball = 50%), Exclusion (likelihood gradually decreases to 0%), and Rest. Self-worth variables (e.g self-esteem, locus of control) were measured before and after the ball-tossing game. General linear model-based statistics were used to measure the brain response to inclusion and exclusion within and between the groups with respect to rest. RESULTS: Relative to controls, cocaine users had significantly more activity during Exclusion versus Inclusion in 3 areas: the right medial frontal gyrus (Brodmann Area 9,10), left ventral lateral frontal gyrus (Brodmann Area 10,47) and right caudate. This was driven by a higher response to social exclusion in the cocaine users. There was no difference between groups in the brain reactivity to social inclusion. CONCLUSION: Cocaine dependent individuals have an amplified brain response to social exclusion stress in cortical regions associated with emotional regulation, arousal, craving and perception of physical pain. These data suggest that there may be a neurological basis for the well-established relationship between social stress and addiction.

Teenagers do not always lie: characteristics and correspondence of telephone and in-person reports of adolescent drug use.

Because of the widespread use of drugs by adolescents, there is demand for scientific rigor in sampling and accuracy in methods for ascertaining drug use patterns. The present study: (1) characterized adolescents who responded to advertisements for marijuana users; (2) compared rates of drug use reported on the telephone versus an on-site interview; and (3) examined drug use patterns as a function of parental awareness of drug use. Adolescents, identifying themselves as marijuana users during telephone interviews, reported more use of other drugs than those denying marijuana use. There was a high degree of correspondence between telephone and on-site interviews for all drugs except alcohol, which was reported at a higher rate on-site. Of those reporting marijuana use in the past week, 69% tested positive for marijuana in their urine-drug screens. Finally, marijuana and alcohol use patterns were higher among adolescents whose parents were aware of drug use than those whose parents indicated that their adolescent did not use marijuana. These results indicate that adolescents are willing to self-identify as marijuana users and report drug and alcohol use during telephone interviews. Additionally, parents appear to become more aware of their adolescent's drug use with increased frequency of use.

Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (GABA(A)). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.

Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine.

RATIONALE: Social rank has been shown to influence dopamine (DA) D(2) receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D(1) receptors. OBJECTIVE: Examine the effects of a high-efficacy D(1) agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D(1) agonist on cocaine self-administration, as well as the effects of cocaine exposure on D(2) receptor function across social ranks, as determined by positron emission tomography (PET). METHODS: Effects of the high-efficacy D(1) agonist SKF 81297 and cocaine (0.3-3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D(1) agonist SKF 38393 (0.1-17 mg/kg) to decrease cocaine self-administration (0.003-0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D(2) receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET. RESULTS: SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D(2) receptor levels did not differ across social ranks. CONCLUSIONS: These results suggest that D(1) receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D(2) receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D(2) receptor levels such that D(2) receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.

Anxiety, sedation, and simulated driving in binge drinkers.

The current study evaluated the relationships among trait anxiety, subjective response to alcohol, and simulated driving following a simulated alcohol binge. Sixty drinkers with a binge history completed the State Trait Anxiety Inventory (STAI), the Alcohol Use Questionnaire, and subsequently completed a driving simulation. Participants were then administered 0.2 g/kg ethanol at 30-min intervals (cumulative dose 0.8 g/kg). Following alcohol consumption, the Biphasic Alcohol Effects Scale (BAES) and visual analog scales of subjective impairment and driving confidence were administered, after which simulated driving was reassessed. Due to the emphasis on simulated driving after drinking in the current study, subjective response to alcohol (i.e., self-reported sedation, stimulation, impairment, and confidence in driving ability) was assessed once following alcohol consumption, as this is the time when drinkers tend to make decisions regarding legal driving ability. Alcohol increased driving speed, speeding tickets, and collisions. Sedation following alcohol predicted increased subjective impairment and decreased driving confidence. Subjective impairment was not predicted by sensitivity to stimulation or trait anxiety. High trait anxiety predicted low driving confidence after drinking and this relationship was mediated by sedation. Increased speed after alcohol was predicted by sedation, but not by trait anxiety or stimulation. Anxiety, combined with the sedating effects of alcohol, may indicate when consumption should cease. However, once driving is initiated, sensitivity to sedation following alcohol consumption is positively related to simulated driving speed.

Impulsivity, attention, memory, and decision-making among adolescent marijuana users.

RATIONALE: Marijuana is a popular drug of abuse among adolescents, and they may be uniquely vulnerable to resulting cognitive and behavioral impairments. Previous studies have found impairments among adolescent marijuana users. However, the majority of this research has examined measures individually rather than multiple domains in a single cohesive analysis. This study used a logistic regression model that combines performance on a range of tasks to identify which measures were most altered among adolescent marijuana users. OBJECTIVES: The purpose of this research was to determine unique associations between adolescent marijuana use and performances on multiple cognitive and behavioral domains (attention, memory, decision-making, and impulsivity) in 14- to 17-year-olds while simultaneously controlling for performances across the measures to determine which measures most strongly distinguish marijuana users from nonusers. METHODS: Marijuana-using adolescents (n = 45) and controls (n = 48) were tested. Logistic regression analyses were conducted to test for: (1) differences between marijuana users and nonusers on each measure, (2) associations between marijuana use and each measure after controlling for the other measures, and (3) the degree to which (1) and (2) together elucidated differences among marijuana users and nonusers. RESULTS: Of all the cognitive and behavioral domains tested, impaired short-term recall memory and consequence sensitivity impulsivity were associated with marijuana use after controlling for performances across all measures. CONCLUSIONS: This study extends previous findings by identifying cognitive and behavioral impairments most strongly associated with adolescent marijuana users. These specific deficits are potential targets of intervention for this at-risk population.

Understanding how the brain perceives alcohol: neurobiological basis of ethanol discrimination.

Understanding the neurobiological mechanisms that regulate how the brain perceives the intoxicating effects of alcohol is highly relevant to understanding the development and maintenance of alcohol addiction. The basis for the subjective effects of intoxication can be studied in drug discrimination procedures in which animals are trained to differentiate the presence of internal stimulus effects of a given dose of ethanol (EtOH) from its absence. Research on the discriminative stimulus effects of psychoactive drugs has shown that these effects are mediated by specific receptor systems. In the case of alcohol, action mediated through ionotropic glutamate, gamma-aminobutyric acid, and serotonergic receptors concurrently produce complex, or multiple, basis for the discriminative stimulus effects of EtOH. These receptor systems may contribute differentially to the discriminative stimulus effects of EtOH based on the EtOH dose, species differences, physiological states, and genetic composition of the individual. An understanding of the receptor mechanisms that mediate the discriminative stimulus effects of EtOH can be used to develop medications aimed at decreasing the subjective effects associated with repeated intoxication. The goal of this symposium was to present an overview of recent findings that highlight the neurobiological mechanisms of EtOH's subjective effects and to suggest the relevance of these discoveries to both basic and clinical alcohol research.

Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.

Discriminative stimulus effects of ethanol in mice lacking the gamma-aminobutyric acid type A receptor delta subunit.

BACKGROUND: Genetically altered mice have been used to examine gene contributions to ethanol phenotypes. Recently, mice with a targeted deletion of the delta subunit of the gamma-aminobutyric acid (GABA)A receptor have been generated. These mice display decreased sensitivity to neuroactive steroids and altered responses to some behavioral effects of ethanol. Given the application of drug discrimination to characterize receptor-mediated stimulus effects of ethanol and given the data showing altered ethanol responses in mice lacking the delta subunit of the GABAA receptor, these mice were characterized in an ethanol-discrimination procedure. It has been shown that neurosteroids will substitute for the discriminative stimulus effects of ethanol, and this study aimed to determine whether the substitution patterns of neuroactive steroids or other GABAA-positive modulators would be altered in these mice. METHODS: Twelve adult delta +/+ and delta-/- mice were trained to discriminate between ethanol 1.5 g/kg and saline in daily 15-min food-reinforced operant sessions. Once the discrimination was trained, substitution tests with ethanol, pentobarbital, midazolam, androsterone, alphaxalone, pregnanolone, morphine, zolpidem, and MK-801 were conducted. RESULTS: Both delta+/+ and delta-/- mice acquired ethanol discrimination in a similar number of days. Ethanol, midazolam, alphaxalone, pregnanolone, and MK-801 fully substituted (>80%) for ethanol in both delta+/+ and delta-/- mice. Pentobarbital fully substituted for ethanol in delta-/- mice but only partially substituted (74%) for ethanol in delta+/+ mice. Androsterone, zolpidem, and morphine did not substitute for ethanol in either delta+/+ or delta-/- mice. There were no significant differences in the response rate-suppressing effects of any of the compounds between delta+/+ and delta-/- mice. CONCLUSIONS: The training dose of ethanol resulted in substitution of five GABAA receptor ligands, indicating a robust GABAA mediation of ethanol's discriminative stimulus effects. Deletion of the delta subunit of the GABAA receptor does not alter the acquisition of an ethanol/saline discrimination or the substitution patterns of GABAA-positive modulators. Therefore, the delta subunit is not necessary in the mediation of ethanol-like effects of any of the GABAA ligands tested, including sensitivity to ethanol, barbiturate, benzodiazepine, and neurosteroid discriminative stimulus effects.