Brandon G. Oberlin

High-Alcohol Preferring Mice Are More Impulsive Than Low-Alcohol Preferring Mice as Measured in the Delay Discounting Task

BACKGROUND Repeated studies have shown that high impulsivity, when defined as the tendency to choose small immediate rewards over larger delayed rewards, is more prevalent in drug addicts and alcoholics when compared with nonaddicts. Assessing whether impulsivity precedes and potentially causes addiction disorders is difficult in humans because they all share a history of drug use. In this study, we address this question by testing alcohol-naïve mice from lines showing heritable differences in alcohol intake. METHODS Replicated selected lines of outbred high-alcohol preferring (HAP) mice were compared to a low-alcohol preferring (LAP) line as well as the low-drinking progenitor line (HS/Ibg) on an adjusting amount delay discounting (DD) task. The DD task employs 2 levers to present subjects with a choice between a small, immediate and a large, delayed saccharin reward. By adjusting the quantity of the immediate reward up and down based on choice behavior, the task allows an estimate of how the subjective value of the delayed reinforcer decreases as delays increase. Latency to respond was also measured for each trial. RESULTS Both HAP2 and HAP1 lines of mice were more impulsive than the LAP2 and HS/Ibg lines, respectively. Hyperbolic curve-fitting confirmed steeper discounting in the high-alcohol drinking lines. In addition, the high-alcohol drinking lines demonstrated greater within-session increases in reaction times relative to the low-alcohol drinking lines. No other differences (consumption of saccharin, total trials completed) consistently mapped onto genetic differences in alcohol drinking. CONCLUSIONS Alcohol-naïve outbred mice selected for high-alcohol drinking were more impulsive with saccharin reinforcers than low-alcohol drinkers. These data are consistent with results seen using inbred strain descendents of high-alcohol drinking and low-alcohol drinking rat lines, and suggest that impulsivity is a heritable difference that precedes alcoholism.

Normal attention orienting but abnormal stimulus alerting and conflict effect in combined subtype of ADHD.

Recent pharmacological studies in animals and neuroimaging studies in normal humans suggest that the spatial and nonspatial cues in tasks measuring reflexive attention may be modulated by different neurotransmitter systems. The efficiency with which attention is oriented to explicit spatial cues may be altered by manipulating levels of brain acetylcholine, whereas reactions to nonspatial cues may be influenced by altering brain noradrenaline levels but not acetylcholine levels. In humans, however, previous attention studies have implicated dopamine when either explicit or implicit cueing is used. Some of the differences between animal and human work may be due to inadequate testing of nonspatial cues. To remedy this, we tested adult humans with ADHD that were primarily inattentive (ADHD/I) or combined inattentive/hyperactive (ADHD/C) and controls with the Attention Network Task that assesses both reflexive and voluntary attention and explicitly tests nonspatial cueing. Our results showed that spatial orienting in both subtypes was no different than controls. However, ADHD/C but not ADHD/I subjects had significantly slowed response times to nonspatial cues and cues with spatial conflict. Stimulant medication in a subset of ADHD/C subjects reduced these deficits to control levels. Based on these results, we conclude that ADHD/C subjects orient the focus of their attention normally but are impaired in their reactions both to abrupt visual cues and those that contain conflicting spatial cues.

Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism

Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol’s classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer’s flavor alone can reduce the binding potential (BP) of [11C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [11C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [11C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.

How Acute and Chronic Alcohol Consumption Affects Brain Networks: Insights from Multimodal Neuroimaging

BACKGROUND Multimodal imaging combining 2 or more techniques is becoming increasingly important because no single imaging approach has the capacity to elucidate all clinically relevant characteristics of a network. METHODS This review highlights recent advances in multimodal neuroimaging (i.e., combined use and interpretation of data collected through magnetic resonance imaging [MRI], functional MRI, diffusion tensor imaging, positron emission tomography, magnetoencephalography, MR perfusion, and MR spectroscopy methods) that leads to a more comprehensive understanding of how acute and chronic alcohol consumption affect neural networks underlying cognition, emotion, reward processing, and drinking behavior. RESULTS Several innovative investigators have started utilizing multiple imaging approaches within the same individual to better understand how alcohol influences brain systems, both during intoxication and after years of chronic heavy use. CONCLUSIONS Their findings can help identify mechanism-based therapeutic and pharmacological treatment options, and they may increase the efficacy and cost effectiveness of such treatments by predicting those at greatest risk for relapse.

Pharmacologic Dissociation Between Impulsivity and Alcohol Drinking in High Alcohol Preferring Mice

BACKGROUND Impulsivity is genetically correlated with, and precedes, addictive behaviors and alcoholism. If impulsivity or attention is causally related to addiction, certain pharmacological manipulations of impulsivity and/or attention may affect alcohol drinking, and vice versa. The current studies were designed to explore the relationship among impulsivity, drinking, and vigilance in selectively bred High Alcohol Preferring (HAP) mice, a line that has previously demonstrated both high impulsivity and high alcohol consumption. Amphetamine, naltrexone, and memantine were tested in a delay discounting (DD) task for their effects on impulsivity and vigilance. The same drugs and doses were also assessed for effects on alcohol drinking in a 2-bottle choice test. METHODS HAP mice were subjected to a modified version of adjusting amount DD using 0.5-second and 10-second delays to detect decreases and increases, respectively, in impulsive responding. In 2 experiments, mice were given amphetamine (0.4, 0.8, or 1.2 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) before DD testing. Another pair of studies used scheduled access, 2-bottle choice drinking to assess effects of amphetamine (0.4, 1.2, or 3.0 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) on alcohol consumption. RESULTS Amphetamine dose-dependently reduced impulsivity and vigilance decrement in DD, but similar doses left alcohol drinking unaffected. Naltrexone and memantine decreased alcohol intake at doses that did not affect water drinking but had no effects on impulsivity or vigilance decrement in the DD task. CONCLUSIONS Contrary to our hypothesis, none of the drugs tested here, while effective on either alcohol drinking or impulsivity, decreased both behaviors. These findings suggest that the genetic association between drinking and impulsivity observed in this population is mediated by mechanisms other than those targeted by the drugs tested in these studies.

Monetary discounting and ventral striatal dopamine receptor availability in nontreatment-seeking alcoholics and social drinkers

RationaleDopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood.ObjectivesTo determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD).MethodsNTS subjects (n = 10) and SD (n = 13) received PET scans at baseline with the D2/D3 radioligand [11C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND.ResultsAcross all subjects, greater impulsive choice for

Schedule of Passive Ethanol Exposure Affects Subsequent Intragastric Ethanol Self-Infusion

20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p = 0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST.ConclusionsPreference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures.

Externalizing personality traits, empathy, and gray matter volume in healthy young drinkers.

BACKGROUND Many studies have shown that chronic ethanol exposure can enhance later self-administration of ethanol, but only a few studies have identified critical parameters for such exposure. The present studies examined temporal and other parameters of chronic ethanol exposure on subsequent intragastric (IG) self-infusion of ethanol. METHODS Sprague-Dawley rats implanted with IG catheters were passively infused with ethanol for 5 to 6 days and then allowed to self-infuse ethanol or water using a procedure in which infusions were contingent upon licking fruit-flavored solutions. Experiment 1 examined the time interval between consecutive periods of passive infusion (Massed Group: 12 hours vs. Spaced Group: 36 hours). Experiment 2 studied the interval between the final passive infusion and onset of self-infusion (12 vs. 36 hours). Finally, Experiment 3 tested the effect of inserting self-infusion days within the passive infusion phase. RESULTS Passive ethanol exposure on consecutive days induced relatively large amounts of ethanol self-infusion (4.1 to 7.9 g/kg/d). Increasing the duration of the ethanol-free interval between periods of passive exposure to 36 hours significantly reduced ethanol self-infusion (2.2 g/kg/d; Exp. 1). The time delay between the last passive ethanol exposure and onset of self-infusion had no effect on self-infusion (Exp. 2). Moreover, inserting no-choice self-infusion days between the last few passive exposure days did not increase self-infusion (Exp. 3). CONCLUSIONS Measurement of withdrawal signs indicated that Massed passive exposure produced stronger dependence than Spaced passive exposure, suggesting that enhanced ethanol self-infusion in Massed Groups might be explained by the opportunity for greater negative reinforcement by ethanol. Although enhanced negative reinforcement might also explain why the Massed Group showed a weaker aversion for the ethanol-paired flavor than the Spaced Group, this observation could also be explained by the development of greater tolerance to ethanols aversive pharmacological effects in the Massed Group.

Family history of alcoholism and the human brain response to oral sucrose

Externalizing psychopathology has been linked to prefrontal abnormalities. While clinically diagnosed subjects show altered frontal gray matter, it is unknown if similar deficits relate to externalizing traits in non-clinical populations. We used voxel-based morphometry (VBM) to retrospectively analyze the cerebral gray matter volume of 176 young adult social to heavy drinkers (mean age=24.0±2.9, male=83.5%) from studies of alcoholism risk. We hypothesized that prefrontal gray matter volume and externalizing traits would be correlated. Externalizing personality trait components-Boredom Susceptibility-Impulsivity (BS/IMP) and Empathy/Low Antisocial Behaviors (EMP/LASB)-were tested for correlations with gray matter partial volume estimates (gmPVE). Significantly large clusters (pFWE<0.05, family-wise whole-brain corrected) of gmPVE correlated with EMP/LASB in dorsolateral and medial prefrontal regions, and in occipital cortex. BS/IMP did not correlate with gmPVE, but one scale of impulsivity (Eysenck I7) correlated positively with bilateral inferior frontal/orbitofrontal, and anterior insula gmPVE. In this large sample of community-dwelling young adults, antisocial behavior/low empathy corresponded with reduced prefrontal and occipital gray matter, while impulsivity correlated with increased inferior frontal and anterior insula cortical volume. These findings add to a literature indicating that externalizing personality features involve altered frontal architecture.

From anxiety to autism : spectrum of abnormal social behaviors modeled by progressive disruption of inhibitory neuronal function in the basolateral amygdala in Wistar rats

A heightened hedonic response to sweet tastes has been associated with increased alcohol preference and alcohol consumption in both humans and animals. The principal goal of this study was to examine blood oxygenation level dependent (BOLD) activation to high- and low-concentration sweet solutions in subjects who are either positive (FHP) or negative (FHN) for a family history of alcoholism. Seventy-four non-treatment seeking, community-recruited, healthy volunteers (22.8 ± 1.6 SD years; 43% men) rated a range of sucrose concentrations in a taste test and underwent functional magnetic resonance imaging (fMRI) during oral delivery of water, 0.83 M, and 0.10 M sucrose. Sucrose compared to water produced robust activation in primary gustatory cortex, ventral insula, amygdala, and ventral striatum. FHP subjects displayed greater bilateral amygdala activation than FHN subjects in the low sucrose concentration (0.10 M). In secondary analyses, the right amygdala response to the 0.10 M sucrose was greatest in FHP women. When accounting for group differences in drinks per week, the family history groups remained significantly different in their right amygdala response to 0.10 M sucrose. Our findings suggest that the brain response to oral sucrose differs with a family history of alcoholism, and that this response to a mildly reinforcing primary reward might be an endophenotypic marker of alcoholism risk.