Working memory, executive processes and the effects of alcohol on Go/No-Go learning: testing a model of behavioral regulation and impulsivity

Rationale: Impulsivity is associated with increased risk for alcoholism. Alcohol also may increase impulsive behavior, although little is known about the processes underlying this effect. Objectives: This study tested a model proposing that the executive processes of working memory (WM) and conditional associative learning (CAL) modulate behavioral inhibition. Subjects had either a positive (FHP) or a negative (FHN) family history of alcoholism. Hypotheses were that alcohol would increase Go/No-Go impulsive responding but only in subjects with low working memory capacity (low-WM), low-CAL ability, or FHP for alcoholism. The model also predicted that WM and CAL modulate inhibitory responses to contingency reversal on a Go/No-Go task. Methods: A Go/No-Go learning task with a midway contingency reversal was administered to 71 FHP and 78 FHN subjects when sober and after drinking one of two moderate doses of alcohol. WM (digits backward) and CAL (conditional spatial association task) were also assessed when sober. Results: Alcohol resulted in more false alarms but only in low-WM subjects. Both WM and CAL modulated learning to inhibit behavior after contingency reversal, suggesting separate modulation mechanisms for WM and CAL. Subjects with low- capacity WM and subjects with low-capacity CAL ability had more difficulty learning response inhibition after contingency reversal. FHPs and FHNs did not differ in their response to alcohol. Conclusions: The results support our model of the modulatory role of WM and CAL in the ongoing regulation of behavioral inhibitory systems. The results also suggest that individuals with low capacity WM are more susceptible to alcohol’s effect of increasing impulsive behavior, suggesting that alcohol reduces the capacity of working memory to modulate response inhibition. Received: 3 March 1999 / Final version: 28 May 1999     

Impulsivity is not always associated with student drinking: a moderation study of impulsivity and drinking by positive alcohol expectancies

Student drinking is a major problem on North American campuses and impulsivity is a significant risk factor for heavy drinking. The present study investigates the moderation of the impulsivity-drinking relationship by the expectation that having a drink will lead to positive experiences. Undergraduate drinkers (n=292) completed measures of impulsivity (Barratt Impulsiveness Scale 11; BIS-11), positive drinking expectancies, and alcohol use. Expectancies moderated the relationship between BIS-11 scores and alcohol use. BIS-11 scores were significantly related to typical alcohol quantity, frequency, quantity X frequency, and binge drinking frequency for individuals with average and high levels of positive expectancies, but not for those with few positive expectancies. Implications for interventions targeted at highly impulsive students, using expectancy modification are discussed.     

Personality and alcohol use: the role of impulsivity

Research has shown that personality traits associated with impulsivity influence alcohol use during emerging adulthood, yet relatively few studies have examined how distinct facets of impulsivity are associated with alcohol use and abuse. We examine the influence of impulsivity traits on four patterns of alcohol use including frequency of alcohol use, alcohol-related problems, binge drinking, and alcohol use disorders (AUDs) in a community sample of young individuals (N = 190). In multivariate regression analyses that controlled for peer and parental alcohol use, psychological distress, and developmental correlates (i.e., college, marriage, employment) in emerging adulthood, we found that urgency and sensation seeking were consistently related to all four constructs of alcohol use. The present study suggests that distinct impulsivity traits may play different roles in escalation of alcohol use and development of AUDs during emerging adulthood.     

Selected impulsivity facets with alcohol use/problems: the mediating role of drinking motives

Impulsivity is associated with alcohol use and related problems, yet limited research has examined the different facets of impulsivity with these outcomes. This study aimed to examine whether sensation seeking, positive urgency, and negative urgency, as separate constructs, would differentially predict alcohol use/problems, and to investigate whether specific drinking motives would mediate these relationships. Self-reported data from an online survey of undergraduate drinkers (n=317) was used in the current study. Findings indicate that sensation seeking and the urgency traits represent unique personality constructs in the prediction of alcohol use/problems, and should be considered separately in future research and when designing prevention and intervention strategies.     

Long-term effects of frequent cannabis use on working memory and attention: an fMRI study

Rationale Excessive use of cannabis may have long-term effects on cognitive abilities. Mild impairments have been found in several cognitive domains, particularly in memory and attention. It is not clear, however, whether these effects also occur with moderate, recreational use of cannabis. Furthermore, little is known about underlying brain correlates.Objectives The aim of this study is to assess brain function in frequent but relatively moderate cannabis users in the domains of working memory and selective attention.Methods Functional magnetic resonance imaging was used to examine verbal working memory and visuo-auditory selective attention in ten frequent cannabis users (after 1 week of abstinence) and ten non-using healthy controls. Groups were similar in age, gender and estimated IQ.Results Cannabis users and controls performed equally well during the working memory task and the selective attention task. Furthermore, cannabis users did not differ from controls in terms of overall patterns of brain activity in the regions involved in these cognitive functions. However, for working memory, a more specific region-of-interest analysis showed that, in comparison to the controls, cannabis users displayed a significant alteration in brain activity in the left superior parietal cortex.Conclusion No evidence was found for long-term deficits in working memory and selective attention in frequent cannabis users after 1 week of abstinence. Nonetheless, frequent cannabis use may affect brain function, as indicated by altered neurophysiological dynamics in the left superior parietal cortex during working memory processing.     

Radial maze as a tool for assessing the effect of drugs on the working memory of rats

The effect of physostigmine (0.2 mg/kg), scopolamine (0.1 mg/kg), d,l-amphetamine (1 mg/kg), apomorphine (0.05 mg/kg), and piracetam (100 mg/kg) on working memory was examined in 12 rats that were highly overtrained in the radial maze. In experiment 1, drugs administered 10 min before the trial did not worsen performance of rats in the 12-arm maze. In experiment 2, insertion of a 5-min delay between the sixth and seventh choices increased the number of errors over choices 7–12. Performance was unaffected by pretreatment with physostigmine or apomorphine, but was significantly impaired by scopolamine, amphetamine, and piracetam. In experiment 3, performed in a 24-arm maze, the number of errors and trial duration increased, but performance was not decreased by amphetamine or piracetam. It is concluded that the uninterrupted radial maze task is relatively resistant to pharmacological disruption, but that scopolamine, amphetamine, and piracetam enhance the effect of stimuli interfering with the storage of spatial information over delays.     

Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction

Rationale Disturbances in critical cognitive processes, such as working memory, are now regarded as core features of schizophrenia, but available pharmacological treatments produce little or no improvement in these cognitive deficits. Although other explanations are possible, these cognitive deficits appear to reflect a disturbance in executive control, the processes that facilitate complex information processing and behavior and that include context representation and maintenance, functions dependent on the dorsolateral prefrontal cortex (DLPFC). Studies in non-human primates indicate that normal working memory function depends upon appropriate GABA neurotransmission in the DLPFC, and alterations in markers of GABA neurotransmission are well documented in the DLPFC of subjects with schizophrenia.Objectives Thus, the purpose of this paper is to review the nature of the altered GABA neurotransmission in the DLPFC in schizophrenia, and to consider how these findings might inform the search for new treatments for cognitive dysfunction in this illness.Results and conclusions Postmortem studies suggest that markers of reduced GABA neurotransmission in schizophrenia may be selective for, or at least particularly prominent in, the subclass of GABA neurons, chandelier cells, that provide inhibitory input to the axon initial segment of populations of pyramidal neurons. Given the critical role that chandelier cells play in synchronizing the activity of pyramidal neurons, the pharmacological amelioration of this deficit may be particularly effective in normalizing the neural network activity required for working memory function. Because GABA_A receptors containing the a² subunit are selectively localized to the axon initial segment of pyramidal cells, and appear to be markedly up-regulated in schizophrenia, treatment with novel benzodiazepine-like agents with selective activity at GABA_A receptors containing the a² subunit may be effective adjuvant agents for improving working memory function in schizophrenia.     

Positive alcohol expectancies mediate the influence of the behavioral activation system on alcohol use: a prospective path analysis

Gray's (1975, 1987) behavioral activation (BAS) and behavioral inhibition systems (BIS) are thought to underlie sensitivity to reinforcement and punishment, respectively. Consistent with Gray's theory and the Acquired Preparedness model, BAS may facilitate the learning of positive alcohol expectancies (PAEs) over time, leading to increases in drinking. Yet, no prospective tests of this pathway have been reported. The present study investigated whether BAS prospectively predicted PAEs and whether PAEs mediated the association between BAS and subsequent alcohol use. We hypothesized that BAS would influence drinking specifically via enhancement-related PAEs. We also explored the role of BIS in PAEs and drinking. College students (N=557) completed online BAS, PAE, and alcohol use measures in September of their first (T1), second (T2), and third (T3) years of college. We conducted autoregressive path analyses with three BAS subscales and BIS (T1) as predictors, four PAE types (T2) as mediators, and quantity and frequency of drinking (T3) as outcomes. The BAS Fun-Seeking scale was prospectively associated with PAEs, and there was a significant indirect path from Fun-Seeking to alcohol use mediated specifically through activity enhancement PAEs. BIS was positively associated with some PAE types, but did not have indirect effects on drinking. Findings are consistent with both the theory of the BAS and the Acquired Preparedness model, as individuals high on BAS Fun-Seeking may find the rewarding properties of alcohol more reinforcing, leading to stronger enhancement PAEs and increased drinking over time. The prospective design helps establish the temporal association between BAS and alcohol-related learning, and points to the need for prevention efforts that target these at-risk students.     

Assessment of working memory in rats using spatial alternation behavior with variable retention intervals: effects of fixed-ratio size and scopolamine

The effects of fixed-ratio (FR) size, scopolamine, and the interactions between FR size and scopolamine were investigated in male F344 rats on working memory as assessed by spatial alternation behavior maintained under FR schedules of food presentation where the interval between trials was varied among values of 2, 4, 8, 16, and 32 s within each session. The magnitude of the FR size on the correct and incorrect levers was varied systematically from 1 response to 2, 4, 8, or 16 responses in order to determine whether the FR size influenced either the percentage of correct responding, rates of responding, or both. Under the primary baseline condition, that is when the FR size on both the correct and incorrect levers was one response (designated FR1 FR1), the percentage of correct responses decreased with increasing retention interval duration. Increasing the FR size on the correct lever produced FR-dependent increases in the percentage of correct responding as well as in rates of responding. Increasing the FR size on the incorrect lever produced FR-dependent decreases in correct responding, but had little effect on rates of responding. Dose-effect curves for scopolamine were determined on performance maintained under FR values on the correct and incorrect levers, respectively, of FR1 FR1, FR1 FR10, FR10 FR1, and FR10 FR10. In general, scopolamine produced dose-related decreases in the percentage of correct responding, although the magnitude of the effects of scopolamine varied not only with dose, but also with the length of the retention interval and with changes in FR size. Rates of responding during trials were dose-dependently decreased by scopolamine under all schedule parameters. The present results are consistent with the interpretation that scopolamine can selectively impair time-dependent memory processes such as working memory, but also can impair time-independent variables which affect performance, dependent on dose and schedule maintaining the behavior.     

Chronic nicotine working and reference memory effects in the 16-arm radial maze: interactions with D1 agonist and antagonist drugs

Chronic nicotine infusion has been found in a series of studies in our laboratory to significantly improve choice accuracy of rats in the eight-arm radial maze. The current study was designed to compare the effects of chronic nicotine infusion on working and reference memory in a 16-arm radial maze. Nicotine was administered to female Sprague-Dawley rats at approximately 5 mg/kg per day SC via osmotic minipumps. Controls received saline infusions. Chronic nicotine infusion significantly lowered the number of working memory errors compared to controls, whereas the number of reference memory erros was not significantly affected. The modest nicotine-induced reduction in working memory errors was seen as a main effect over the 4 weeks of infusion, but the clearest effect was seen in weeks 3–4 of nicotine administration. For the 2 weeks after withdrawal, the nicotine effect was no longer evident. Acute D₁ challenges were given with the D₁ agonist dihydrexidine (0, 0.25, 0.5 and 1 mg/kg) and the D₁ antagonist SCH 23390 (0, 0.005, 0.015 and 0.05 μg/kg) during weeks 3–4 of chronic nicotine administration and weeks 1–2 after withdrawal from nicotine. Dihydrexidine caused a modest dose-related increase in reference memory errors but not working memory errors in the nicotine-treated, but not the control rats. The D₁ antagonist SCH 23390 caused a modest though significant decrease in reference memory errors but not working memory errors in the control, but not the nicotine-treated rats. The behavioral specificity of chronic nicotine infusion was demonstrated with selective improvement in working memory function. Pharmacological interactions were seen with chronic nicotine treatment increasing responsivity to D₁ agonist and decreasing responsivity to a D₁ antagonist with regard to reference memory. The mechanisms of this interaction are still undiscovered.     

The roman strains of rats as a psychogenetic tool for pharmacological investigation of working memory: example with RU 41656

This study examined the effects of RU 41656, a dopaminergic D₂ agonist, on the differential working memory performances and on the differential activities of the neurochemical systems of the Roman high (RHA) and Roman low (RLA) avoidance strains of rats. Compared with RLA, RHA performed worse in three tests of working memory (spontaneous alternation, radial maze and object recognition) and had higher levels of exploratory locomotor activity. Hippocampal and frontal cortex choline acetyltransferase (ChAT) activities were loer in RHA. Frontal cortex DA and DOPAC levels, hippocampal and striatal 5-HT and NA levels were higher in RHA. RU 41656 induced a significant improvement in working memory performance of RHA, whereas in RLA it had no effect. It decreased exploratory locomotor activity in both strains. ChAT activity in hippocampus was not affected by RU 41656 in either strain, whereas in frontal cortex it was increased in RHA but not in RLA. Hippocampal NA levels were decreased by RU 41656 in RHA but not in RLA. These results confirm previous data concerning the promnesic effect of RU 41656 and extend the finding that the Roman strains are a psychogenetic model for the behavioural, neurochemical and psychopharmacological study of the working memory in rats.     

Associations of the DRD2 TaqIA polymorphism with impulsivity and substance use: Preliminary results from a clinical sample of adolescents

Background

The A1 allele of the TaqIA polymorphism (rs1800497) in the dopamine D2 receptor gene (DRD2) has been associated with substance use. It is unclear whether this allele is a marker for an underlying propensity for specifically developing a substance use disorder, or more generally to developing an externalizing psychiatric disorder highly correlated with substance use. It is also possible that DRD2 is related to a behavioral phenotype common to externalizing disorders and substance use.

Method

Data was obtained from 104 psychiatrically hospitalized adolescents in a larger assessment study. Adolescents were genotyped for the DRD2 TaqIA site, grouped as carriers of the A1 allele (A1+) or homozygous for the A2 allelle (A1−). Associations of the presence of the A1 allele with externalizing disorders, the intermediate phenotype of impulsivity, and measures of alcohol and drug use were examined.

Results

A diagnosis of conduct disorder and impulsive behavior were both associated with severity of problem drinking and/or drug use. Further, interaction effects were found between the DRD2 TaqIA polymorphism and conduct disorder (trend level) as well as A1+ status and impulsivity, such that adolescents who were carriers of the A1 allele, and had conduct disorder or impulsive behavior, reported higher levels of problematic alcohol use than those who were non-carriers (A2/A2 or A1−). The same interaction effect between this polymorphism and impulsivity was found for severity of problem drug use. In contrast, no interaction effects were found between the DRD2 allele status and ADHD on severity of problem drinking or drug use.

Discussion

These results suggest that the well documented relationship between conduct disorder, the behavioral phenotype of impulsivity, and problematic alcohol/drug use among adolescents may be moderated by A1 carrier status of the DRD2 gene.     

Haloperidol increases the disruptive effect of alcohol on spatial working memory in rats: a dopaminergic modulation in the medial prefrontal cortex

Rationale The prefrontal cortex (PFC) has been considered the anatomic site for working memory. The medial portion of the PFC (mPFC) is also part of a "brain reward circuit" as constituted by the mesocorticolimbic dopaminergic system. Objective This study examined the effects of acute administration of alcohol (ETOH) in the mPFC or systemically on the performance of 5-s or 1-h delayed tasks in an eight-arm radial maze. Effects of haloperidol (HAL), a dopamine antagonist, combined with ETOH, were also examined in a 1-h delayed task. Methods Male Wistar rats trained in the radial maze and with bilateral cannulae implanted in the mPFC received intraperitoneal (IP) or intracortical (IC) drug administration. Results As compared to saline (SAL) IC, ETOH IC in doses of 100 μg and 180 μg (5 min before session) increased significantly the number of errors in the 1-h and 5-s post-delay performance, respectively. HAL in doses with little or no effect alone IC (10 or 32 μg, 10 min before session) or IP (3.2 mg/kg, 35 min before session) increased the disruptive effect of ETOH IC (100 μg) on 1-h delayed task. Conclusions These results showed that ETOH administered directly in the mPFC disrupts short- and long-term spatial working memory. The increase of the disruptive effect of ETOH produced by a dopaminergic blockage, particularly in the mPFC, suggests that the dopaminergic neurotransmission in this cortical area might modulate ETOH effects on spatial working memory.     

Roman strains as a psychogenetic model for the study of working memory: behavioral and biochemical data.

Performances of male rats of the Roman High- (RHA), Roman Control- (RCA) and Roman Low- (RLA) Avoidance strains were compared in two working memory tests, a spatial one, the radial maze, and a nonspatial one, an object recognition test. The same rats were subjected to measures of emotional reactivity and of different forms of motor activity and finally to measures of cholinergic and aminergic activities in the hippocampus, frontal cortex and striatum. Compared to RHA, RLA performed better in the two working memory tests, displayed "anxiety" and had also lower levels of exploratory locomotor activity. Hippocampal ChAT activity was higher in RLA than in RHA. Levels of DA and DOPAC in the striatum were higher in RLA compared to RHA, whereas in the frontal cortex they were lower. For most of these measures, RCA were intermediate between RLA and RHA. These results confirm and extend the finding that the Roman strains are not only a genetic model for two-way avoidance conditioning but also for working memory.     

Work stress and alcohol use: Examining the tension-reduction model as a function of worker's parent's alcohol use

In an effort to identify groups who may be more vulnerable to tension-reduction drinking [Frone, M. (2003). Predictors of overall and on-the-job substance use among young workers. Journal of Occupational Health Psychology, 8, 39-54.], we examine whether drinking alcohol in response to work stress varies as a function of whether workers were raised in homes where (a) both parents abstained from alcohol, (b) at least one parent drank nonproblematically, (c) at least one parent drank problematically, or (d) both parents drank problematically. Employees participating in a large, longitudinal study who reported using alcohol in the previous year (N=895) completed various measures of work stressors, alcohol use, and alcohol problems. We found few mean group differences for either the work stressor or alcohol measures, but we did find a greater number of significant and moderate correlations between work stressors and alcohol for those reporting that both parents drank alcohol problematically. Interestingly, a number of significant correlations were found for those reporting that both parents abstained from alcohol; few were found for the two groups reporting that at least one parent drank with or without alcohol problems. Results are interpreted in light of where and how alcohol expectancies and other coping methods are learned.     

Cigarette and alcohol use in the UK Armed Forces, and their association with combat exposures: a prospective study

Retrospective studies of military personnel and survivors of community disasters suggest a link between traumatic exposure and substance use. This is the first study to investigate this association prospectively in a military population. A representative cohort of members of the UK Armed Forces was recruited into a longitudinal study, with 1382 people surveyed at baseline, and 941 followed up around three years later. Alcohol and cigarette use were assessed on both occasions, and combat exposures during this time were assessed at follow-up. Alcohol consumption and the prevalence of binge-drinking increased over the course of the study. The increase in alcohol consumption was greater in those subjects who had been deployed, in particular in those who thought they might be killed (p=.010), or who experienced hostility from civilians while on deployment (p=.010). The effects of these combat exposures were strongest in those most recently deployed. In contrast, cigarette smoking declined during the three years of the study.     

Reducing the risks of alcohol use among urban youth: three-year effects of a computer-based intervention with and without parent involvement

OBJECTIVE: This study tested a CD-ROM intervention with and without a parent involvement component to reduce risk of alcohol use among an urban sample of early adolescents. METHOD: Youths (N = 514, mean age 11.5 years at recruitment) were assigned randomly by community site to receive the CD-ROM intervention, the CD-ROM plus parent intervention, or no intervention. All youths completed pretest, posttest and three annual follow-up measurements. After pretesting, youths and parents received their respective interventions. RESULTS: Main effects of the intervention and for measurement occasion as well as interaction effects of the intervention by measurement occasion were seen for substance use and related outcomes. Over time, youths in all 3 groups reported increased use of alcohol, tobacco and marijuana; youths who received the interventions reported smaller increases than control youths. At 3-year follow-up, alcohol use was lower for CD-ROM plus parent intervention youths than for CD-ROM only youths, who, in turn, reported less use than controls. Cigarette use was lower for youths in either intervention group than in the control group at posttest and at 1-, 2- and 3-year follow-ups. Marijuana use was lower for youths in either intervention than for controls at 1-, 2- and 3-year follow-ups. Youths in both intervention groups outperformed control youths at posttest and at 1- and 3-year follow-ups on levels of negative and peer influence toward substance use. Finally, at the 3-year follow-up, youths in the CD-ROM plus parent intervention group reported more family involvement in their alcohol use prevention efforts than did youths in the CD-ROM group, who, in turn, reported more positive levels of family involvement than youths in the control group. CONCLUSIONS: Study findings modestly support the CD-ROM intervention with and without the parent intervention to reduce alcohol use risks among urban early adolescents.     

Model minority stereotype and the diagnosis of alcohol use disorders: Implications for practitioners working with Asian Americans

This study investigated the priming effects of the model minority stereotype on 122 clinicians in training regarding their diagnostic accuracy on Asian Americans compared to Whites. It was hypothesized that clinicians in training would be less likely to diagnose Asian Americans with alcohol use disorder and would perceive them to have fewer clinical symptoms than Whites due to the model minority stereotype. Consistent with the hypotheses, clinicians in training were less likely to assign alcohol use disorder to Asian Americans compared to Whites, as well as to the unprimed condition versus the condition primed with the stereotype. Implications regarding cultural competence and future research are discussed.