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1.  I Want to Help You, But I Am Not Sure Why: Gaze-Cuing Induces Altruistic Giving 
Detecting subtle indicators of trustworthiness is highly adaptive for moving effectively amongst social partners. One powerful signal is gaze direction, which individuals can use to inform (or deceive) by looking toward (or away from) important objects or events in the environment. Here, across 5 experiments, we investigate whether implicit learning about gaze cues can influence subsequent economic transactions; we also examine some of the underlying mechanisms. In the 1st experiment, we demonstrate that people invest more money with individuals whose gaze information has previously been helpful, possibly reflecting enhanced trust appraisals. However, in 2 further experiments, we show that other mechanisms driving this behavior include obligations to fairness or (painful) altruism, since people also make more generous offers and allocations of money to individuals with reliable gaze cues in adapted 1-shot ultimatum games and 1-shot dictator games. In 2 final experiments, we show that the introduction of perceptual noise while following gaze can disrupt these effects, but only when the social partners are unfamiliar. Nonconscious detection of reliable gaze cues can prompt altruism toward others, probably reflecting the interplay of systems that encode identity and control gaze-evoked attention, integrating the reinforcement value of gaze cues.
PMCID: PMC3970851  PMID: 23937180
gaze; joint attention; altruism
2.  Systemic Administration of 8-OH-DPAT and Eticlopride, but not SCH23390, Alters Loss-Chasing Behavior in the Rat 
Neuropsychopharmacology  2013;38(6):1094-1104.
Gambling to recover losses is a common gaming behavior. In a clinical context, however, this phenomenon mediates the relationship between diminished control over gambling and the adverse socioeconomic consequences of gambling problems. Modeling loss-chasing through analogous behaviors in rats could facilitate its pharmacological investigation as a potential therapeutic target. Here, rats were trained to make operant responses that produced both food rewards, and unpredictably, imminent time-out periods in which rewards would be unavailable. At these decision points, rats were offered choices between waiting for these time-out periods to elapse before resuming responding for rewards (‘quit' responses), or selecting risky options with a 0.5 probability of avoiding the time-outs altogether and a 0.5 probability of time-out periods twice as long as signaled originally (‘chase' responses). Chasing behavior, and the latencies to chase or quit, during sequences of unfavorable outcomes were tested following systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT, the D2 receptor antagonist, eticlopride, and the D1 receptor antagonist, SCH23390. 8-OH-DPAT and eticlopride significantly reduced the proportion of chase responses, and the mean number of consecutive chase responses, in a dose-dependent manner. 8-OH-DPAT also increased latencies to chase. Increasing doses of eticlopride first speeded, then slowed, latencies to quit while SCH23390 had no significant effects on any measure. Research is needed to identify the precise cognitive mechanisms mediating these kinds of risky choices in rats. However, our data provide the first experimental demonstration that 5-HT1A and D2, but not D1, receptor activity influence a behavioral analog of loss-chasing in rats.
PMCID: PMC3629409  PMID: 23303072
5-HT1A receptors; addiction & substance abuse; behavioral science; D2 receptors; gambling; loss-chasing; neurotransmitters; psychiatry & behavioral sciences; gambling; loss-chasing; dopamine; serotonin; 5-HT1A receptors; D2 receptors
3.  White matter alterations in antipsychotic- and mood stabilizer-naïve individuals with bipolar II/NOS disorder☆ 
NeuroImage : Clinical  2013;3:271-278.
Structural magnetic resonance imaging (MRI) studies using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) have been inconsistent in demonstrating impairments in gray matter (GM) and white matter (WM) structures in bipolar disorder (BD). This may be a consequence of significant confounding effects of medication, illness history and selection of controls in existing studies. Study of bipolar II or not-otherwise-specified (BD II/NOS) disorder provides a solution to these confounds and a bridge to unipolar cases across the affective spectrum.
Thirty-eight euthymic, antipsychotic- and mood stabilizer-naïve young adults (mean age = 20.9 years) with BD II/NOS and 37 age-, cognitive ability- and gender-matched healthy controls (HCs) underwent MRI. Voxel-wise and regional gray matter volume comparisons were conducted using voxel-based morphometry (VBM). Tract-based spatial statistics (TBSS) were used to assess whole-brain WM, as indexed using fractional anisotropy (FA), mean diffusivity (MD), parallel and perpendicular diffusion values. No between-group differences were observed for whole-brain VBM comparisons. By contrast, in comparison to HCs, participants with BD II/NOS had significant widespread reductions in FA and increased MD and perpendicular diffusion values in virtually all the major cortical white matter tracts.
These data suggest pathophysiological involvement of WM microstructures – but not GM macrostructures – in high functioning BD II/NOS patients at an early age and before significant clinical adversity has been recorded. We propose that white matter development is a valid candidate target for understanding genetic and environmental antecedents to bipolar disorder and mood disorder more generally.
•Antipsychotic- and mood stabilizer-naïve bipolar II/NOS participants underwent MRI.•Data analysis included tract-based spatial statistics and voxel-based morphometry.•Bipolar II/NOS participants had widespread reductions in fractional anisotropy.•We report alterations in white – but not gray – matter structures in bipolar II/NOS.
PMCID: PMC3814955  PMID: 24273712
Bipolar II disorder; Bipolar disorder NOS; Diffusion tensor imaging; Voxel-based morphometry; Mood stabilizers; Antipsychotics
4.  Dopamine Modulates Risk-Taking as a Function of Baseline Sensation-Seeking Trait 
The Journal of Neuroscience  2013;33(32):12982-12986.
Trait sensation-seeking, defined as a need for varied, complex, and intense sensations, represents a relatively underexplored hedonic drive in human behavioral neuroscience research. It is related to increased risk for a range of behaviors including substance use, gambling, and risky sexual practice. Individual differences in self-reported sensation-seeking have been linked to brain dopamine function, particularly at D2-like receptors, but so far no causal evidence exists for a role of dopamine in sensation-seeking behavior in humans. Here, we investigated the effects of the selective D2/D3 agonist cabergoline on performance of a probabilistic risky choice task in healthy humans using a sensitive within-subject, placebo-controlled design. Cabergoline significantly influenced the way participants combined different explicit signals regarding probability and loss when choosing between response options associated with uncertain outcomes. Importantly, these effects were strongly dependent on baseline sensation-seeking score. Overall, cabergoline increased sensitivity of choice to information about probability of winning; while decreasing discrimination according to magnitude of potential losses associated with different options. The largest effects of the drug were observed in participants with lower sensation-seeking scores. These findings provide evidence that risk-taking behavior in humans can be directly manipulated by a dopaminergic drug, but that the effectiveness of such a manipulation depends on baseline differences in sensation-seeking trait. This emphasizes the importance of considering individual differences when investigating manipulation of risky decision-making, and may have relevance for the development of pharmacotherapies for disorders involving excessive risk-taking in humans, such as pathological gambling.
PMCID: PMC3735881  PMID: 23926253
5.  Reduced Subjective Response to Acute Ethanol Administration Among Young Men with a Broad Bipolar Phenotype 
Neuropsychopharmacology  2012;37(8):1808-1815.
Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals at-risk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8 g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo-controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects (‘feel high': F=14.2, p=0.001; ‘feel effects': F=8.1, p=0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD.
PMCID: PMC3376329  PMID: 22491350
alcohol abuse/dependence; bipolar disorder; adolescence; hypomania; mood; ethanol; alcohol and alcoholism; mood/anxiety/stress disorders; depression; unipolar/bipolar; psychopharmacology; adolescence; hypomania; mood; ethanol; bipolar disorder; alcohol use disorders
6.  Dopamine Modulates Reward Expectancy During Performance of a Slot Machine Task in Rats: Evidence for a ‘Near-miss' Effect 
Neuropsychopharmacology  2011;36(5):913-925.
Cognitive accounts of gambling suggest that the experience of almost winning—so-called ‘near-misses'—encourage continued play and accelerate the development of pathological gambling (PG) in vulnerable individuals. One explanation for this effect is that near-misses signal imminent winning outcomes and heighten reward expectancy, galvanizing further play. Determining the neurochemical processes underlying the drive to gamble could facilitate the development of more effective treatments for PG. With this aim in mind, we evaluated rats' performance on a novel model of slot machine play, a form of gambling in which near-miss events are particularly salient. Subjects responded to a series of three flashing lights, loosely analogous to the wheels of a slot machine, causing the lights to set to ‘on' or ‘off'. A winning outcome was signaled if all three lights were illuminated. At the end of each trial, rats chose between responding on the ‘collect' lever, resulting in reward on win trials, but a time penalty on loss trials, or starting a new trial. Rats showed a marked preference for the collect lever when both two and three lights were illuminated, indicating heightened reward expectancy following near-misses similar to wins. Erroneous collect responses were increased by amphetamine and the D2 receptor agonist quinpirole, but not by the D1 receptor agonist SKF 81297 or receptor subtype selective antagonists. These data suggest that dopamine modulates reward expectancy following the experience of almost winning during slot machine play, via activity at D2 receptors, and this may result in an enhancement of the near-miss effect and facilitate further gambling.
PMCID: PMC3077261  PMID: 21209612
amphetamine; D2 receptor; extinction; gambling; quinpirole; reinstatement; dopamine; psychopharmacology; animal models; psychostimulants; gambling; extinction; reinstatement; amphetamine; quinpirole
7.  The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans 
Neuropsychopharmacology  2010;36(1):114-132.
Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive appraisal of reinforcers when selecting between actions, potentially accounting for its influence upon the processing salient aversive outcomes and social choice.
PMCID: PMC3055502  PMID: 20881944
dopamine; serotonin; psychiatry and behavioral sciences; value; choice; social; dopamine; serotonin; psychiatry and behavioral sciences; cognition; decision making; value; choice; social; risk
8.  Serotonin and Dopamine Play Complementary Roles in Gambling to Recover Losses 
Neuropsychopharmacology  2010;36(2):402-410.
Continued gambling to recover losses—‘loss chasing'—is a prominent feature of social and pathological gambling. However, little is known about the neuromodulators that influence this behavior. In three separate experiments, we investigated the role of serotonin activity, D2/D3 receptor activity, and beta-adrenoceptor activity on the loss chasing of age and IQ-matched healthy adults randomized to treatment or an appropriate control/placebo. In Experiment 1, participants consumed amino-acid drinks that did or did not contain the serotonin precursor, tryptophan. In Experiment 2, participants received a single 176 μg dose of the D2/D3 receptor agonist, pramipexole, or placebo. In Experiment 3, participants received a single 80 mg dose of the beta-adrenoceptor blocker, propranolol, or placebo. Following treatment, participants completed a computerized loss-chasing game. Mood and heart rate were measured at baseline and following treatment. Tryptophan depletion significantly reduced the number of decisions made to chase losses, and the number of consecutive decisions to chase, in the absence of marked changes in mood. By contrast, pramipexole significantly increased the value of losses chased and diminished the value of losses surrendered. Propranolol markedly reduced heart rate, but produced no significant changes in loss-chasing behavior. Loss chasing can be thought of as an aversively motivated escape behavior controlled, in part, by the marginal value of continued gambling relative to the value of already accumulated losses. Serotonin and dopamine appear to play dissociable roles in the tendency of individuals to gamble to recover, or to seek to ‘escape' from, previous losses. Serotonergic activity seems to promote the availability of loss chasing as a behavioral option, whereas D2/D3 receptor activity produces complex changes in the value of losses judged worth chasing. Sympathetic arousal, at least as mediated by beta-adrenoceptors, does not play a major role in laboratory-based loss-chasing choices.
PMCID: PMC3055672  PMID: 20980990
serotonin; dopamine; loss chasing; gambling; persistence; value; addiction and substance abuse; behavioral science; dopamine; serotonin; gambling; loss chasing; persistence; value
9.  Serotonin and Social Norms 
Psychological Science  2014;25(7):1303-1313.
How do people sustain resources for the benefit of individuals and communities and avoid the tragedy of the commons, in which shared resources become exhausted? In the present study, we examined the role of serotonin activity and social norms in the management of depletable resources. Healthy adults, alongside social partners, completed a multiplayer resource-dilemma game in which they repeatedly harvested from a partially replenishable monetary resource. Dietary tryptophan depletion, leading to reduced serotonin activity, was associated with aggressive harvesting strategies and disrupted use of the social norms given by distributions of other players’ harvests. Tryptophan-depleted participants more frequently exhausted the resource completely and also accumulated fewer rewards than participants who were not tryptophan depleted. Our findings show that rank-based social comparisons are crucial to the management of depletable resources, and that serotonin mediates responses to social norms.
PMCID: PMC4230382  PMID: 24815611
social behavior; social influences; neurotransmitters
10.  Neuropsychological function in ecstasy users: a study controlling for polydrug use 
Psychopharmacology  2005;189(4):505-516.
A number of studies have compared ecstasy users to control groups on various measures of neuropsychological function in order to determine whether ecstasy use results in lasting cognitive deficits. However, few of those studies controlled adequately for non-ecstasy illicit drug use.
The aim of this study was to investigate neuropsychological function in chronic ecstasy users while controlling for polydrug use.
Neuropsychological function was assessed in four groups—30 current 3,4-methylenedioxymethamphetamine (MDMA) users with a little history of illicit drug use other than ecstasy and cannabis, 30 polydrug controls, 30 drug-naïve controls and 20 ex-MDMA users—using a battery of well-validated, computerized neuropsychological tests. The battery focused on memory, executive function, impulsivity and risk-taking.
Few differences were apparent between the groups, and on no measure were the current MDMA users impaired significantly relative to the polydrug controls. However, within the current MDMA users, questionnaire-measured impulsivity correlated with performance on a number of tests—a relationship that was not apparent in the controls.
These data highlight the complexity in understanding the current ecstasy literature and suggest that some individuals may be particularly vulnerable to cognitive impairment following chronic use. Although no differences were identified between the current MDMA users and the controls, trait impulsiveness was significantly correlated with impairment on a number of neuropsychological outcome measures in the MDMA users, but not in the controls. These data suggest that impulsive individuals may be those most at risk for the development of cognitive impairment following chronic ecstasy use.
PMCID: PMC2653936  PMID: 16163532
3,4-Methylenedioxymethamphetamine (MDMA); Ecstasy; Neuropsychology; Polydrug use; Executive function; Memory; Decision-making; Risk-taking; Impulsivity
11.  The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls 
Psychopharmacology  2006;188(2):213-227.
3, 4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a popular drug of abuse known to result in depletions of the serotonin (5-HT) system. A number of studies have reported that ecstasy users differ from controls on a variety of measures of cognitive function. However, the literature is not consistent and many negative findings were also reported. One reason for such inconsistency might be interindividual variance in vulnerability to the deleterious effects of ecstasy due to a number of factors, both genetic and environmental.
To investigate the hypothesis that carriers of the s allele at the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), which was associated with reduced serotonergic neurotransmission relative to the l allele, would be most vulnerable to the effects of ecstasy on cognitive function.
We assessed memory, decision-making, and executive function in ecstasy users and controls, stratifying by genotype at the 5-HTTLPR.
We observed that the 5-HTTLPR genotype groups differed on a number of measures in both the ecstasy users and the controls. While performing a risky decision-making task, ss and ls controls attended to differences in the probability of winning chosen gambles to a greater extent than the ll controls. However, this difference was dramatically attenuated in the ss ecstasy users. Furthermore, independent of ecstasy use, volunteers of the ss genotype outperformed the ll genotype on a visual planning task.
The results are consistent with the hypothesis that cognitive impairment in ecstasy users may depend on genetic variation at the 5-HTTLPR.
PMCID: PMC2585286  PMID: 16941121
Ecstasy (MDMA); Decision-making; Serotonin transporter-linked polymorphic region (5-HTTLPR); Neuropsychology; Memory; Executive function
12.  Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study 
Brain imaging and behavior  2007;1(3-4):43-57.
To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs—suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.
PMCID: PMC2367252  PMID: 18458752
fMRI; Smoking; Tobacco; Cue reactivity; Ventral striatum; Nucleus accumbens

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