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AIMS:Alcohol use disorder is highly heterogeneous. One approach to understanding this heterogeneity is the identification of drinker subtypes. A candidate classification consists of reward and relief subtypes. The current study examines a novel self-report measure of reward, relief, and habit drinking for its clinical correlates and subjective response (SR) to alcohol administration. METHODS:Non-treatment-seeking heavy drinkers (n = 140) completed the brief reward, relief, habit drinking scale (RRHDS). A subset of this sample (n = 67) completed an intravenous alcohol administration. Individuals were classified into drinker subtypes. A crowdsourced sample of heavy drinkers (n = 187) completed the RRHDS and a validated reward relief drinking scale to compare drinking classification results. RESULTS:The majority of the sample was classified as reward drinkers (n = 100), with fewer classified as relief (n = 19) and habit (n = 21) drinkers. Relief and habit drinkers reported greater tonic alcohol craving compared to reward drinkers. Reward drinkers endorsed drinking for enhancement, while relief drinkers endorsed drinking for coping. Regarding the alcohol administration, the groups differed in negative mood, such that relief/habit drinkers reported a decrease in negative mood during alcohol administration, compared to reward drinkers. The follow-up crowdsourcing study found a 62% agreement in reward drinker classification between measures and replicated the tonic craving findings. CONCLUSIONS:Our findings suggest that reward drinkers are dissociable from relief/habit drinkers using the brief measure. However, relief and habit drinkers were not successfully differentiated, which suggests that these constructs may overlap phenotypically. Notably, measures of dysphoric mood were better at detecting group differences than measures capturing alcohol's rewarding effects.

By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

RationaleDrug addiction can be described as aberrant allocation of effort toward acquiring drug, despite associated costs. It is unclear if this behavioral pattern results from an overvaluation of reward or to an altered sensitivity to costs.ObjectivePresent experiments assessed reward sensitivity and effortful choice in rats following 1 week of withdrawal from methamphetamine (mAMPH).MethodsRats were treated with either saline or an escalating dose mAMPH regimen, then tested after a week without the drug. In experiment 1, rats were given a free choice between water and various concentrations of sucrose solution to assess general reward sensitivity. In experiment 2, rats were presented with a choice between lever-pressing for sucrose pellets on a progressive ratio schedule or consuming freely-available chow.ResultsIn experiment 1, we found no differences in sucrose preference between mAMPH- and saline-pretreated rats. In experiment 2, when selecting between two options, mAMPH-pretreated rats engaged in less lever-pressing for sucrose pellets (p < 0.01) and switched from this preferred reward to the chow sooner than saline-pretreated rats (p < 0.05). This effect was not consistent with general reward devaluation or loss of motivation.ConclusionsThese findings demonstrate that mAMPH exposure and withdrawal lead to steeper discounting of reward value by effort, an effect that is consistent with the effect of mAMPH on discounting by delay, and which may reflect an underlying shared mechanism.

The relationship between risk-taking behavior and substance dependence has proven to be complex, particularly when examining across participants expressing a range of substance use problem severity. While main indices of risk-taking in the Balloon Analogue Risk Task (BART) positively associate with problematic alcohol use in adolescent populations (e.g., MacPherson, Magidson, Reynolds, Kahler, & Lejuez, 2010), several studies have observed a negative relationship when examining behavior within adult substance using populations (Ashenhurst, Jentsch, & Ray, 2011; Campbell, Samartgis, & Crowe, 2013). To examine potential mechanisms that underlie this negative relationship, we implemented multilevel regression models on trial-by-trial BART data gathered from 295 adult problem drinkers. These models accounted for participant behavior on trials following balloon bursts or cash outs as indices of loss and reward reactivity, respectively, and included control variables including age, IQ, and individual delay discounting rate. Results revealed that individual trial pumping was significantly predicted by trial number, and by whether or not the previous trial was a big burst or a big cash out (i.e., large magnitude of potential gains) in a manner consistent with a "near-miss" effect. Furthermore, severity of alcohol problems moderated the effect of a previous trial big burst, but not of a big cash out, on subsequent trial behavior such that those with greater severity demonstrated relative insensitivity to this "near-miss" effect. These results extend previous studies suggesting that alcohol abusers are less risky on the BART by specifying a mechanism underlying this pattern, namely, diminished reactivity to large magnitude losses.

The relationship between risk-taking behavior and substance dependence has proven to be complex, particularly when examining across participants expressing a range of substance use problem severity. While main indices of risk-taking in the Balloon Analogue Risk Task (BART) positively associate with problematic alcohol use in adolescent populations (e.g., MacPherson, Magidson, Reynolds, Kahler, & Lejuez, 2010), several studies have observed a negative relationship when examining behavior within adult substance using populations (Ashenhurst, Jentsch, & Ray, 2011; Campbell, Samartgis, & Crowe, 2013). To examine potential mechanisms that underlie this negative relationship, we implemented multilevel regression models on trial-by-trial BART data gathered from 295 adult problem drinkers. These models accounted for participant behavior on trials following balloon bursts or cash outs as indices of loss and reward reactivity, respectively, and included control variables including age, IQ, and individual delay discounting rate. Results revealed that individual trial pumping was significantly predicted by trial number, and by whether or not the previous trial was a big burst or a big cash out (i.e., large magnitude of potential gains) in a manner consistent with a "near-miss" effect. Furthermore, severity of alcohol problems moderated the effect of a previous trial big burst, but not of a big cash out, on subsequent trial behavior such that those with greater severity demonstrated relative insensitivity to this "near-miss" effect. These results extend previous studies suggesting that alcohol abusers are less risky on the BART by specifying a mechanism underlying this pattern, namely, diminished reactivity to large magnitude losses.

Attention deficit/hyperactivity disorder (ADHD) is encountered among patients with epilepsy at a significantly higher rate than in the general population. Mechanisms of epilepsy-ADHD comorbidity remain largely unknown. We investigated whether a model of chronic epilepsy in rats produces signs of ADHD, and thus, whether it can be used for studying mechanisms of this comorbidity. Epilepsy was induced in male Wistar rats via pilocarpine status epilepticus. Half of the animals exhibited chronic ADHD-like abnormalities, particularly increased impulsivity and diminished attention in the lateralized reaction-time task. These impairments correlated with the suppressed noradrenergic transmission in locus coeruleus outputs. The other half of animals exhibited depressive behavior in the forced swimming test congruently with the diminished serotonergic transmission in raphe nucleus outputs. Attention deficit/hyperactivity disorder and depressive behavior appeared mutually exclusive. Therefore, the pilocarpine model of epilepsy affords a system for reproducing and studying mechanisms of comorbidity between epilepsy and both ADHD and/or depression.

The procurement and consumption of palatable, calorie-dense foods is influenced by the nutritional and hedonic value of foods. Although many factors can influence the control over behavior by foods rich in sugar and fat, emerging evidence indicates that biological sex may play a particularly crucial role in the types of foods individuals seek out, as well as the level of motivation individuals will exert to obtain those foods. However, a systematic investigation of food-seeking and consumption that disentangles the effects of the major sex-biasing factors, including sex chromosome complement and organizational and activational effects of sex hormones, has yet to be conducted. Using the four core genotypes mouse model system, we separated and quantified the effects of sex chromosome complement and gonadal sex on consumption of and motivation to obtain a highly palatable solution [sweetened condensed milk (SCM)]. Gonadectomized mice with an XY sex chromosome complement, compared with those with two X chromosomes, independent of gonadal sex, appeared to be more sensitive to the reward value of the SCM solution and were more motivated to expend effort to obtain it, as evidenced by their dramatically greater expended effort in an instrumental task with progressively larger response-to-reward ratios. Gonadal sex independently affected free consumption of the solution but not motivation to obtain it. These data indicate that gonadal and chromosomal sex effects independently influence reward-related behaviors, contributing to sexually dimorphic patterns of behavior related to the pursuit and consumption of rewards.

RationalePoor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex.ObjectivesIn the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys.Materials and methodsAdult male Long-Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations.ResultsIn accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance.ConclusionsOur results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding i

Genome-wide gene expression studies may provide substantial insight into gene activities and biological pathways differing between tissues and individuals. We investigated such gene expression variation by analyzing expression profiles in brain tissues derived from eight different brain regions and from blood in 12 monkeys from a biomedically important non-human primate model, the vervet (Chlorocebus aethiops sabaeus). We characterized brain regional differences in gene expression, focusing on transcripts for which inter-individual variation of expression in brain correlates well with variation in blood from the same individuals. Using stringent criteria, we identified 29 transcripts whose expression is measurable, stable, replicable, variable between individuals, relevant to brain function and heritable. Polymorphisms identified in probe regions could, in a minority of transcripts, confound the interpretation of the observed inter-individual variation. The high heritability of levels of these transcripts in a large vervet pedigree validated our approach of focusing on transcripts that showed higher inter-individual compared with intra-individual variation. These selected transcripts are candidate expression Quantitative Trait Loci, differentially regulating transcript levels in the brain among individuals. Given the high degree of conservation of tissue expression profiles between vervets and humans, our findings may facilitate the understanding of regional and individual transcriptional variation and its genetic mechanisms in humans. The approach employed here-utilizing higher quality tissue and more precise dissection of brain regions than is usually possible in humans-may therefore provide a powerful means to investigate variation in gene expression relevant to complex brain related traits, including human neuropsychiatric diseases.

RationalePoor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex.ObjectivesIn the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys.Materials and methodsAdult male Long-Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations.ResultsIn accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance.ConclusionsOur results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding i

Genome-wide gene expression studies may provide substantial insight into gene activities and biological pathways differing between tissues and individuals. We investigated such gene expression variation by analyzing expression profiles in brain tissues derived from eight different brain regions and from blood in 12 monkeys from a biomedically important non-human primate model, the vervet (Chlorocebus aethiops sabaeus). We characterized brain regional differences in gene expression, focusing on transcripts for which inter-individual variation of expression in brain correlates well with variation in blood from the same individuals. Using stringent criteria, we identified 29 transcripts whose expression is measurable, stable, replicable, variable between individuals, relevant to brain function and heritable. Polymorphisms identified in probe regions could, in a minority of transcripts, confound the interpretation of the observed inter-individual variation. The high heritability of levels of these transcripts in a large vervet pedigree validated our approach of focusing on transcripts that showed higher inter-individual compared with intra-individual variation. These selected transcripts are candidate expression Quantitative Trait Loci, differentially regulating transcript levels in the brain among individuals. Given the high degree of conservation of tissue expression profiles between vervets and humans, our findings may facilitate the understanding of regional and individual transcriptional variation and its genetic mechanisms in humans. The approach employed here-utilizing higher quality tissue and more precise dissection of brain regions than is usually possible in humans-may therefore provide a powerful means to investigate variation in gene expression relevant to complex brain related traits, including human neuropsychiatric diseases.