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Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT 1 and MT 2 ). The melatonergic system is an emerging therapeutic target for new pharmacological interventions in the treatment of sleep and mood disorders; thus, imaging tools to further investigate its role in the brain are highly sought-after. We aimed to develop selective radiotracers for in vivo imaging of both MT 1 and MT 2 by positron emission tomography (PET). We identified four previously reported MT ligands with picomolar affinities to the target based on different scaffolds which were also amenable for radiolabeling with either carbon-11 or fluorine-18. [ 11 C]UCM765, [ 11 C]UCM1014, [ 18 F]3-fluoroagomelatine ([ 18 F]3FAGM), and [ 18 F]fluoroacetamidoagomelatine ([ 18 F]FAAGM) have been synthesized in high radiochemical purity and evaluated in wild-type rats. All four tracers showed moderate to high brain permeability in rats with maximum standardized uptake values (SUV max of 2.53, 1.75, 3.25, and 4.47, respectively) achieved 1-2 min after tracer administration, followed by a rapid washout from the brain. Several melatonin ligands failed to block the binding of any of the PET tracer candidates, while in some cases, homologous blocking surprisingly resulted in increased brain retention. Two 18 F-labeled agomelatine derivatives were brought forward to PET scans in non-human primates and autoradiography on human brain tissues. No specific binding has been detected in blocking studies. To further investigate pharmacokinetic properties of the putative tracers, microsomal stability, plasma protein binding, log D , and membrane bidirectional permeability assays have been conducted. Based on the results, we conclude that the fast first pass metabolism by the enzymes in liver microsomes is the likely reason of the failure of our PET tracer candidates. Nevertheless, we showed that PET imaging can serve as a valuable tool to investigate the brain permeability of new therapeutic compounds targeting the melatonergic system.

Objective: Only a minority of drug and alcohol users develops a substance use disorder. Previous studies suggest that this differential vulnerability commonly reflects a developmental trajectory characterized by diverse externalizing behaviors. In this study, we examined the relation between child and adolescent externalizing behaviors and adolescent substance use in a prospectively followed Canadian birth cohort, accounting for the temporal sequence of a wide variety of contributing factors., Methods: Two hundred and forty-two adolescents followed since birth (date range: 1996 to 2012) were assessed on externalizing behavior (age 17 months to 16 years), alcohol and cannabis use at age 16, age of alcohol use onset, family history of substance use problems, family functioning (age 11 to 15), sensation seeking (age 16), prenatal substance exposure, socioeconomic status (age 1 to 9), and sex., Results: Age of alcohol use onset was predicted by a family history of substance use problems, externalizing traits from ages 6 to 10 and 11 to 16, sensation seeking at age 16, prenatal alcohol and tobacco exposure and family functioning at ages 11 to 15. High frequencies of alcohol and cannabis use at age 16 were both predicted by externalizing traits from ages 11 to 16, a family history of substance use problems and sensation seeking after controlling for other individual, environmental and familial variables. The association between familial substance use problems and substance use during adolescence was partially mediated by externalizing traits from age 11 to 16., Conclusions: The present findings provide prospective evidence for a developmental risk pathway for adolescent substance use, potentially identifying those who could benefit from early interventions.

Background: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood., Methods: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.0 mg/kg, i.p.) on locomotor activity and binding of the mGlu5 ligand [3H]ABP688. In a parallel study, in 19 stimulant-drug-naïve healthy human volunteers (14 female) we administered 3 doses of dextroamphetamine (0.3 mg/kg, p.o.) or placebo, followed by a fourth dose 2 weeks later. We measured [11C]ABP688 binding using positron emission tomography before and after the induction phase. We assessed psychomotor and behavioural sensitization using speech rate, eye blink rate and self-report. We measured the localization of mGlu5 relative to synaptic markers in mouse striatum using immunofluorescence., Results: We observed amphetamine-induced psychomotor sensitization in mice and humans. We did not see group differences in mGlu5 availability following 3 pre-challenge amphetamine doses, but group differences did develop in mice administered 5 doses. In mice and humans, individual differences in mGlu5 binding after repeated amphetamine administration were negatively correlated with the extent of behavioural sensitization. In drug-naïve mice, mGlu5 was expressed at 67% of excitatory synapses on dendrites of striatal medium spiny neur., Limitations: Correlational results should be interpreted as suggestive because of the limited sample size. We did not assess sex differences., Conclusion: Together, these results suggest that changes in mGlu5 availability are not part of the earliest neural adaptations in stimulant-induced behavioural sensitization, but low mGlu5 binding might identify a higher propensity for sensitization., Competing Interests: M. Leyton is an associate editor of JPN. He was not involved in reviewing or the decision to accept this paper for publication., (© 2021 Joule Inc. or its licensors.)

The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [ 11 C]ABP688 binding potential (BP ND ) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [ 11 C]ABP688 BP ND values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [ 11 C]ABP688 BP ND values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.

The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control, and altered sensitivity to rewards and punishments (i.e., externalizing features). To test these associations in humans, we measured type-2/3 dopamine receptor (DA 2/3 R) availability in youth at high vs. low risk for substance use disorders (SUDs). In this study, N = 58 youth (18.5 ± 0.6 years) were recruited from cohorts that have been followed since birth. Participants with either high (high EXT; N = 27; 16 F/11 M) or low pre-existing externalizing traits (low EXT; N = 31; 20 F/11 M) underwent a 90-min positron emission tomography [ 18 F]fallypride scan, and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile scale (SURPS), and Sensitivity to Punishment (SP) and Sensitivity to Reward (SR) questionnaire. We found that high vs. low EXT trait participants reported elevated substance use, BIS-11, SR, and SURPS impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [ 18 F]fallypride binding potential (BP ND ) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in midbrain dopamine cell body regions, but, across all participants, low midbrain BP ND values were associated with low SP scores. Together, the results suggest that altered DA 2/3 R availability in terminal extra-striatal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity (i.e., an internalizing feature).

When a cue no longer predicts a threat, a diminished ability to extinguish or reverse this association is thought to increase risk for stress-related disorders. Despite the clear clinical relevance, the mediating neurochemical mechanisms of threat reversal have received relatively little study. One neurotransmitter implicated in rodent research of changing associations with threat is dopamine. To study whether dopamine is involved in threat reversal in humans, we used high-resolution positron emission tomography (PET) coupled with 18 F-fallypride. Twelve healthy volunteers (6 F/6 M) underwent three PET scans: (i) at baseline, (ii) following threat conditioning (the response to a cue associated with electric wrist shock), and (iii) following threat reversal (the response to the same cue now associated with safety). We observed moderate evidence of reduced dopamine D2/3 receptor availability, consistent with greater dopamine release, in the bilateral anterior hippocampus following threat reversal, in response to a safety cue that was previously associated with threat, as compared to both baseline and during exposure to the same cue prior to threat reversal. These findings offer the first preliminary evidence that the response to a previously threatening cue that has since become associated with safety involves dopaminergic neurotransmission within the hippocampus in healthy humans.

We report an efficient protocol for the radiosynthesis of diastereomerically pure (E)-[ 11 C]ABP688, a positron emission tomography (PET) tracer for metabotropic glutamate type 5 (mGlu5) receptor imaging. The protocol reliably provides sterile and pyrogen-free formulation of (E)-[ 11 C]ABP688 suitable for preclinical and clinical PET imaging with >99% diastereomeric excess (d.e.), >99% overall radiochemical purity (RCP), 14.9 ± 4.3% decay-corrected radiochemical yield (RCY), and 148.86 ± 79.8 GBq/μmol molar activity in 40 minutes from the end of bombardment., (© 2019 John Wiley & Sons, Ltd.)

Purpose: The purpose of this study was to assess, in a large sample of healthy young adults, sex differences in the binding potential of [ 11 C]ABP688, a positron emission tomography (PET) tracer selective for the metabotropic glutamate type 5 (mGlu5) receptor., Methods: High resolution [ 11 C]ABP688 PET scans were acquired in 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). Mean binding potential (BP ND  = f ND * (B avail / K D )) values were calculated in the prefrontal cortex, striatum, and limbic regions using the simplified reference tissue model with cerebellar grey matter as the reference region., Results: [ 11 C]ABP688 BP ND was significantly higher in men compared to women in the prefrontal cortex (p < 0.01), striatum (p < 0.001), and hippocampus (p < 0.05). Whole-brain BP ND was 17% higher in men. BP ND was not related to menstrual phase in women., Conclusions: Binding availability of mGlu5 receptors as measured by PET [ 11 C]ABP688 is higher in healthy men than women. This likely represents a source of variability in [ 11 C]ABP688 studies and could have relevance for sex differences in cognitive-behavioral functions and neuropsychiatric disorders.

Purpose: To determine how the low-affinity (Z)-isomer of the radiotracer [ 11 C]ABP688 affects binding potential values in vivo in humans., Methods: High-resolution [ 11 C]ABP688 PET scans were acquired on 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). The relative contents of (E)- and (Z)-isomers were determined prior to injection using analytical high-performance liquid chromatography [r t (E) = 10 min, r t (Z) = 8.5 min]. Mean binding potential [BP ND  = f ND * (B avail /K D )] values were calculated in the striatum, limbic regions, and prefrontal cortex using the simplified reference tissue model with cerebellar grey matter as reference., Results: Mean ± SD (E)-isomer content in [ 11 C]ABP688 production was 92 ± 3.8% (range 78-97%). Percent (E)-isomer was positively correlated with BP ND in the striatum (ρ = 0.28, p = 0.015) and limbic regions (ρ = 0.25, p = 0.036). In multiple regression analysis, sex (β = 0.39, p = 0.001) and (E)-isomer content (β = 0.23, p = 0.040) were significant predictors of BP ND ., Conclusions: Even modest levels of (Z)-[ 11 C]ABP688 can reduce estimates of tracer binding in vivo. Future studies should use production methods that enrich levels of (E)-[ 11 C]ABP688, report tracer isomer ratios, and account for this factor in their analyses.

Using resting-state functional MRI (rsfMRI) data of younger and older healthy volunteers and patients with Parkinson's disease (PD) with and without mild cognitive impairment (MCI) and applying two different analytic approaches, we investigated the effects of age, pathology, and cognition on brain connectivity. When comparing rsfMRI connectivity strength of PD patients and older healthy volunteers, reduction between multiple brain regions in PD patients with MCI (PD-MCI) compared with PD patients without MCI (PD-non-MCI) was observed. This group difference was not affected by the number and location of clusters but was reduced when age was included as a covariate. Next, we applied a graph-theory method with a cost-threshold approach to the rsfMRI data from patients with PD with and without MCI as well as groups of younger and older healthy volunteers. We observed decreased hub function (measured by degree and betweenness centrality) mainly in the medial prefrontal cortex (mPFC) in older healthy volunteers compared with younger healthy volunteers. We also found increased hub function in the posterior medial structure (precuneus and the cingulate cortex) in PD-non-MCI patients compared with older healthy volunteers and PD-MCI patients. Hub function in these posterior medial structures was positively correlated with cognitive function in all PD patients. Together these data suggest that overlapping patterns of hub modifications could mediate the effect of age as a risk factor for cognitive decline in PD, including age-related reduction of hub function in the mPFC, and recruitment availability of the posterior medial structure, possibly to compensate for impaired basal ganglia function.

Objective: Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC +/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC +/- mutation carriers without mirror movements might exhibit some of these features., Methods: The participants (n = 52) included 13 DCC +/- mutation carriers with mirror movements, 7 DCC +/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity., Results: Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC +/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity., Interpretation: Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

[ 11 C]ABP688 is a positron emission tomography (PET) radioligand that binds selectively to metabotropic glutamate type 5 receptors (mGluR5). The use of this tracer has identified receptor binding changes in clinical populations, and has been informative in drug occupancy studies. However, previous studies have found significant increases in [ 11 C]ABP688 binding in the later scan of same-day comparisons, and estimates of test-retest reliability under consistent scanning conditions are not available. The objective of this study was to assess the variability of [ 11 C]ABP688 binding in healthy people in scans performed at the same time of day. Two [ 11 C]ABP688 scans were acquired in eight healthy volunteers (6 women, 2 men) using a high-resolution research tomograph (HRRT). Scans were acquired 3 weeks apart with start times between 10:00am and 1:30pm. Mean mGluR5 binding potential (BP ND ) values were calculated across cortical, striatal and limbic brain regions. Participants reported on subjective mood state after each scan and blood samples were drawn for cortisol analysis. No significant change in BP ND between scans was observed. Variability in BP ND values of 11-21% was observed across regions, with the greatest change in the hippocampus and amygdala. Reliability was low to moderate. BP ND was not statistically related to scan start time, subjective anxiety, serum cortisol levels, or menstrual phase in women. Overall, [ 11 C]ABP688 BP ND estimates show moderate variability in healthy people. Reliability is fair in cortical and striatal regions, and lower in limbic regions. Future research using this ligand should account for this in study design and analysis., (© 2018 Wiley Periodicals, Inc.)

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc -haploinsufficient mice. The human volunteers were 20 DCC +/- mutation carriers, 16 DCC +/+ relatives, and 20 DCC +/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc +/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC +/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [ DCC +/+ : p = 0.0005, r ( effect size ) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex ( DCC +/+ : p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores ( DCC +/+ : p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume ( DCC +/+ : p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc +/- mice, and these were seen during adolescence ( p = 0.0058, d = 1.09) and adulthood ( p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders. SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC , enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC -haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders., (Copyright © 2018 the authors 0270-6474/18/384655-11$15.00/0.)

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[ 11 C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[ 11 C]methyl-L-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.

Recent studies suggest that dopaminergic tone influences resting state activity in multiple brain networks. Although dopamine receptors and transporters have been identified in the posteromedial and parietal cortices, which are linked to functional networks such as the default mode network (DMN), the relationship between dopamine receptor distribution in these posterior regions and resting-state connectivity has yet to be explored. Here, we used a multi-modal neuroimaging strategy, combining resting-state functional magnetic resonance imaging (rsfMRI) and [18 F]-fallypride high-resolution positron emission tomography (PET), to examine the association between within-network functional connectivity and the dopamine D2/3 receptor distribution in the posterior portion of the brain in 13 healthy adults. Our results indicate that the posterior distribution of D2/3 receptors coincides primarily with the posterior portion of the DMN. Furthermore, in the posterior portion of the brain, the level of [18 F]-fallypride binding in the posteromedial cortex correlated positively with the functional connectivity strength of the DMN and sensorimotor network, and negatively with the functional connectivity strength of the dorsal attention network, the salience network, and a network that included the anterior part of the temporo-parietal junction. On the basis of these findings, we propose that posterior brain dopamine influences the configuration of the posterior DMN and several other functional brain networks. The posterior distribution of D2/3 receptors binding (hot colour spectrum) coincides with the functional connectivity of the posterior portion of the default mode network (green colour spectrum). The mean BP ND in a posteromedial cortex and the mean ICA-Z score in the precuneus showed significant positive correlation., (© 2017 Wiley Periodicals, Inc.)

Bright light can affect mood states and social behaviours. Here, we tested potential interacting effects of light and dopamine on facial emotion recognition. Participants were 32 women with subsyndromal seasonal affective disorder tested in either a bright (3000 lux) or dim light (10 lux) environment. Each participant completed two test days, one following the ingestion of a phenylalanine/tyrosine-deficient mixture and one with a nutritionally balanced control mixture, both administered double blind in a randomised order. Approximately four hours post-ingestion participants completed a self-report measure of mood followed by a facial emotion recognition task. All testing took place between November and March when seasonal symptoms would be present. Following acute phenylalanine/tyrosine depletion (APTD), compared to the nutritionally balanced control mixture, participants in the dim light condition were more accurate at recognising sad faces, less likely to misclassify them, and faster at responding to them, effects that were independent of changes in mood. Effects of APTD on responses to sad faces in the bright light group were less consistent. There were no APTD effects on responses to other emotions, with one exception: a significant light × mixture interaction was seen for the reaction time to fear, but the pattern of effect was not predicted a priori or seen on other measures. Together, the results suggest that the processing of sad emotional stimuli might be greater when dopamine transmission is low. Bright light exposure, used for the treatment of both seasonal and non-seasonal mood disorders, might produce some of its benefits by preventing this effect.

Alterations in catecholamine signaling and cortical morphology have both been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, possible links between the two remain unstudied. Here, we report exploratory analyses of cortical thickness and its relation to striatal dopamine transmission in treatment-naïve adults with ADHD and matched healthy controls. All participants had one magnetic resonance imaging (MRI) and two [ 11 C]raclopride positron emission tomography scans. Associations between frontal cortical thickness and the magnitude of d -amphetamine-induced [ 11 C]raclopride binding changes were observed that were divergent in the two groups. In the healthy controls, a thicker cortex was associated with less dopamine release; in the ADHD participants the converse was seen. The same divergence was seen for baseline D2/3 receptor availability. In healthy volunteers, lower D2/3 receptor availability was associated with a thicker cortex, while in the ADHD group lower baseline D2/3 receptor availability was associated with a thinner cortex. Individual differences in cortical thickness in these regions correlated with ADHD symptom severity. Together, these findings add to the evidence of associations between dopamine transmission and cortical morphology, and suggest that these relationships are altered in treatment-naïve adults with ADHD.

It has been proposed that the acquisition of drug seeking is related to the development of conditioned dopamine responses in the ventral striatum. As drug use continues and becomes habit-like, conditioned responses have been shown to shift to the dorsal striatum. Here, using the PET [ 11 C]raclopride method and highly personalized cocaine cues, we report the first evidence in humans of the dorsal dopamine response prior to the onset of addiction.

Background: Novelty-seeking (NS) and impulsive personality traits have been proposed to reflect an interplay between fronto-cortical and limbic systems, including the limbic striatum (LS). Although neuroimaging studies have provided some evidence for this, most are comprised of small samples and many report surprisingly large effects given the challenges of trying to relate a snapshot of brain function or structure to an entity as complex as personality. The current work tested a priori hypotheses about associations between striatal dopamine (DA) release, cortical thickness (CT), and NS in a large sample of healthy adults., Methods: Fifty-two healthy adults (45M/7F; age: 23.8±4.93) underwent two positron emission tomography scans with [11C]raclopride (specific for striatal DA D2/3 receptors) with or without amphetamine (0.3 mg/kg, p.o.). Structural magnetic resonance image scans were acquired, as were Tridimensional Personality Questionnaire data. Amphetamine-induced changes in [11C]raclopride binding potential values (ΔBPND) were examined in the limbic, sensorimotor (SMS) and associative (AST) striatum. CT measures, adjusted for whole brain volume, were extracted from the dorsolateral sensorimotor and ventromedial/limbic cortices., Results: BPND values were lower in the amphetamine vs. no-drug sessions, with the largest effect in the LS. When comparing low vs. high LS ΔBPND groups (median split), higher NS2 (impulsiveness) scores were found in the high ΔBPND group. Partial correlations (age and gender as covariates) yielded a negative relation between ASTS ΔBPND and sensorimotor CT; trends for inverse associations existed between ΔBPND values in other striatal regions and frontal CT. In other words, the greater the amphetamine-induced striatal DA response, the thinner the frontal cortex., Conclusions: These data expand upon previously reported associations between striatal DA release in the LS and both NS related impulsiveness and CT in the largest sample reported to date. The findings add to the plausibility of these associations while suggesting that the effects are likely weaker than has been previously proposed.

Background: Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown., Methods: We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence., Results: Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BPND values were significantly correlated with changes in BPND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BPND and self-reported craving., Limitations: Limitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release., Conclusion: In people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms.

Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent d-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to d-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean ± s.d. = 22.1 ± 3.4 years) [(11)C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated d-amphetamine (3 × 0.3 mg kg(-1), by mouth; n = 8) or placebo (3 × lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the d-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P ⩽ 0.05). Following the d-amphetamine regimen, the stress-induced cortisol responses were augmented (P < 0.04), and voxel-based analyses showed larger stress-induced decreases in [(11)C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [(11)C]raclopride binding, primarily in the sensorimotor striatum (P < 0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.

Background: Despite more than 60 years of research in the role of serotonin (5-HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development., Methods: Studies were identified using common databases (e.g., PubMed, Google Scholar) and reference lists., Results: Despite the widely supported view that the 5-HT system matures in early life, different 5-HT receptors, proteins and enzymes have different developmental patterns, and development is brain region-specific. A disruption in 5-HT homeostasis during development may lead to structural and functional changes in brain circuits that modulate emotional stress responses, including subcortical limbic and (pre)frontal areas. This may result in a predisposition to psychopathology. DNA methylation might be one of the underlying physiologic mechanisms., Limitations: There is a need for prospective studies. The impact of stressors during adolescence on the 5-HT system is understudied. Questions regarding efficacy of drugs acting on 5-HT still remain., Conclusion: A multidisciplinary and longitudinal approach in designing studies on the role of 5-HT in psychopathology might help to bring us closer to the understanding of the role of 5-HT in psychopathology.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In this study, positron emission tomography with the tracer alpha-[(11) C]methyl-l-tryptophan ((11) C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional (11) C-AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized (11) C-AMT trapping in pre-frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized (11) C-AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized (11) C-AMT trapping in the brainstem and pre-frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre-existing 5-HT alterations pre-disposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms., (© 2014 International Society for Neurochemistry.)

Cocaine self-administration decreases type 5 metabotropic glutamate receptor (mGluR5) tissue concentrations in laboratory rats during early abstinence. These changes are thought to influence the drug's reinforcing properties and the ability of drug-related cues to induce relapse. Here, our goal was to measure brain regional mGluR5 availability in recently abstinent cocaine dependent humans. Participants meeting DSM-IV diagnostic criteria for current cocaine dependence (n=9) were recruited from the general population. mGluR5 availability (binding potential, non-displaceable; BPND) was measured with high-resolution positron emission tomography (PET HRRT) and [(11)C]ABP688. Compared to age- and sex-matched healthy controls (n=9), cocaine dependent subjects showed significantly lower BPND values in the ventral (bilateral: -28.2%, p=0.011), associative (right: -21.4%, p=0.043), and sensorimotor striatum (bilateral: -21.7%, p=0.045), amygdala (left: -26%, p=0.046) and insula (right: -23.3%, p=0.041). Among the cocaine users, receptor availabilities were related to abstinence (range: 2 to 14days). The longer the duration of abstinence, the lower the BPND values in the sensorimotor striatum (r=-0.71, p=0.034), left amygdala (r=-0.73, p=0.026) and right insula (r=-0.67, p=0.046). Compared to healthy controls, BPND values were significantly reduced in those who tested negative for cocaine on the PET test session in the ventral (p=0.018) and sensorimotor striatum (p=0.017), left amygdala (p=0.008), and right insula (p=0.029), but not in those who tested positive. Together, these results provide evidence of time-related mGluR5 alterations in striatal and limbic regions in humans during early cocaine abstinence., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Spatial patterns of functional connectivity derived from resting brain activity may be used to elucidate the topological properties of brain networks. Such networks are amenable to study using graph theory, which shows that they possess small world properties and can be used to differentiate healthy subjects and patient populations. Of particular interest is the possibility that some of these differences are related to alterations in the dopamine system. To investigate the role of dopamine in the topological organization of brain networks at rest, we tested the effects of reducing dopamine synthesis in 13 healthy subjects undergoing functional magnetic resonance imaging. All subjects were scanned twice, in a resting state, following ingestion of one of two amino acid drinks in a randomized, double-blind manner. One drink was a nutritionally balanced amino acid mixture, and the other was tyrosine and phenylalanine deficient. Functional connectivity between 90 cortical and subcortical regions was estimated for each individual subject under each dopaminergic condition. The lowered dopamine state caused the following network changes: reduced global and local efficiency of the whole brain network, reduced regional efficiency in limbic areas, reduced modularity of brain networks, and greater connection between the normally anti-correlated task-positive and default-mode networks. We conclude that dopamine plays a role in maintaining the efficient small-world properties and high modularity of functional brain networks, and in segregating the task-positive and default-mode networks. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Not everyone who tries addictive drugs develops a substance use disorder. One of the best predictors of risk is a family history (FH) of substance use problems. In part, this might reflect perturbed mesolimbic dopamine responses., Methods: We measured amphetamine-induced changes in [(11)C]raclopride binding in 1) high-risk young adults with a multigenerational FH of substance use disorders (n = 16); 2) stimulant drug-naïve healthy control subjects with no known risk factors for addiction (n = 17); and 3) subjects matched to the high-risk group on personal drug use but without a FH of substance use problems (n = 15)., Results: Compared with either control group, the high-risk young adults with a multigenerational FH of substance use disorders exhibited smaller [(11)C]raclopride responses, particularly within the right ventral striatum. Past drug use predicted the dopamine response also, but including it as a covariate increased the group differences., Conclusions: Together, the results suggest that young people at familial high risk for substance use disorders have decreased dopamine responses to an amphetamine challenge, an effect that predates the onset of addiction., (© 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.)

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.

Rationale: Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood., Objective: This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women., Methods: In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n = 13) and nonuser controls (n = 17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task., Results: The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n = 7), relative to controls (n = 9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users., Limitation: The group sizes were small, when males and females were considered separately., Conclusions: Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.

Background: The neurobiology of risk for alcohol use disorders (AUDs) remains poorly understood. Individual differences in vulnerability, though, have been indicated by subjective responses to alcohol ingestion and personality traits., Methods: To investigate the relationship between these features and striatal dopamine (DA) responses to alcohol, we studied 26 healthy young social drinkers (21.3 ± 3.0 years old; 10.7 ± 8.8 drinks/wk) at varying risk for alcoholism. Each participant received 2 positron emission tomography [(11) C]raclopride scans after administration of either placebo or oral alcohol (1 ml/kg body weight of 94% alcohol, 0.75 g/kg) in a randomized and counterbalanced design., Results: Subjects with high-risk subjective responses to alcohol had more family members with AUDs, greater alcohol use problems, and, in response to the alcohol challenge, significant decreases in [(11) C]raclopride binding indicative of increased extracellular DA. In contrast, low-risk subjects exhibited increases in [(11) C]raclopride binding in response to alcohol. The results were similar when risk groups were based on personality traits, although statistically less robust., Conclusions: Changes in striatal DA in response to alcohol ingestion may be a neurobiological marker of vulnerability to AUDs., (Copyright © 2013 by the Research Society on Alcoholism.)

Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans., Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [(18)F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BP ND ) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BP ND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans., Results: The psychological stressor significantly decreased [(18)F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress-induced decrease in [(18)F]fallypride binding in the dmPFC, the greater the stress-induced increases in heart rate., Conclusions: The present study provides evidence of stress-induced dopamine release in the mPFC in humans, in vivo., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Despite evidence that bright light can improve mood, the neurobiology remains poorly understood. Some evidence implicates the catecholamines. In the present study, we measured the effects of transiently decreasing dopamine (DA) synthesis on mood and motivational states in healthy women with mild seasonal mood changes who were tested in either bright or dim light., Methods: On 2 test days, participants slept overnight in a light-controlled room. On the morning of each session, half of the participants awoke to gradual increases of bright light, up to 3000 lux, and half to dim light (10 lux). For all participants, DA was reduced on 1 of the test days using the acute phenylalanine/tyrosine depletion (APTD) method; on the other day, they ingested a nutritionally balanced control mixture (BAL). Beginning 4 hours postingestion, participants completed subjective mood questionnaires, psychological tests and a progressive ratio breakpoint task during which they worked for successive units of $5., Results: Thirty-two women participated in our study. The APTD lowered mood, agreeableness, energy and the willingness to work for monetary reward. The effects on energy and motivation were independent of light, while the effects on mood and agreeableness were seen in the dim condition only, being prevented by bright light., Limitations: Acute phenylalanine/tyrosine depletion might affect systems other than DA. The sample size was small., Conclusion: These results suggest that increased DA function may be responsible for some of the beneficial effects of light, while adding to the evidence that the neurobiology of mood and motivational states can be dissociated.

The meso-striatal dopamine system influences responses to rewards and the motivation to seek them out. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex. Here we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy young people. Participants were 24 (17 male, 7 female; age 23.0 ± 6.2 years) stimulant drug-naive subjects who underwent PET [(11)C]raclopride scans with 0.3 mg/kg d-amphetamine orally and placebo, and an anatomical MRI scan for measuring cortical thickness. As expected, d-amphetamine produced significant reductions in [(11)C]raclopride binding potential in the striatum as a percentage of the value in the placebo condition. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. The association was strongest in the anterior part of the right lateral prefrontal cortex and bilateral supplementary motor area. A thicker cortex was correlated with a smaller dopamine response. Together, this work demonstrates in humans an association between cortical thickness and the striatal dopamine response to drugs of abuse. Although prefrontal regulation of striatal function has been well studied, it was unclear whether the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is.

Drug-related cues are potent triggers for relapse in people with cocaine dependence. Dopamine (DA) release within a limbic network of striatum, amygdala and hippocampus has been implicated in animal studies, but in humans it has only been possible to measure effects in the striatum. The objective here was to measure drug cue-induced DA release in the amygdala and hippocampus using high-resolution PET with [(18)F]fallypride. Twelve cocaine-dependent volunteers (mean age: 39.6 ± 8.0 years; years of cocaine use: 15.9 ± 7.4) underwent two [(18)F]fallypride high-resolution research tomography-PET scans, one with exposure to neutral cues and one with cocaine cues. [(18)F]Fallypride non-displaceable-binding potential (BPND) values were derived for five regions of interest (ROI; amygdala, hippocampus, ventral limbic striatum, associative striatum, and sensorimotor striatum). Subjective responses to the cues were measured with visual analog scales and grouped using principal component analysis. Drug cue exposure significantly decreased BPND values in all five ROI in subjects who had a high-, but not low-, craving response (limbic striatum: p=0.019, associative striatum: p=0.008, sensorimotor striatum: p=0.004, amygdala: p=0.040, and right hippocampus: p=0.025). Individual differences in the cue-induced craving response predicted the magnitude of [(18)F]fallypride responses within the striatum (ventral limbic: r=0.581, p=0.048; associative: r=0.589, p=0.044; sensorimotor: r=0.675, p=0.016). To our knowledge this study provides the first evidence of drug cue-induced DA release in the amygdala and hippocampus in humans. The preferential induction of DA release among high-craving responders suggests that these aspects of the limbic reward network might contribute to drug-seeking behavior.

The serotonin system originates from a small number of neurons (a few hundred thousand of the 100 billion in man) located in the midbrain raphe nuclei, that project widely throughout the central nervous system to influence a large array of inter-related biological functions, not least of which are circuits involved in mood and emotion. The serotonin hypothesis of depression has postulated that a reduction in serotonin leads to increased predisposition to depression. Indeed, it has become evident from therapeutic strategies that affect serotonin activity, that alterations in serotonin may not only predispose to depression, but also to aggressive behaviour, impulsivity, obsessive-compulsive behaviour and suicide. Many potential mechanisms known to alter the genes that regulate the serotonin system, including developmental epigenetic modifications, are presented, as additional evidence implicating the serotonin system. This second issue of two special issues of Philosophical Transactions B presents a series of reviews, perspectives and new findings that argue that the serotonin hypothesis remains an important idea that continues to guide research into the aetiology and treatment of depression.

The serotonin (5-HT) hypothesis of depression dates from the 1960s. It originally postulated that a deficit in brain serotonin, corrected by antidepressant drugs, was the origin of the illness. Nowadays, it is generally accepted that recurring mood disorders are brain diseases resulting from the combination, to various degrees, of genetic and other biological as well as environmental factors, evolving through the lifespan. All areas of neuroscience, from genes to behaviour, molecules to mind, and experimental to clinical, are actively engaged in attempts at elucidating the pathophysiology of depression and the mechanisms underlying the efficacy of antidepressant treatments. This first of two special issues of Philosophical Transactions B seeks to provide an overview of current developments in the field, with an emphasis on cellular and molecular mechanisms, and how their unravelling opens new perspectives for future research.

Objective: The current study examined whether age after menopause impacted the effect of estradiol (E2) on mood after a psychosocial stress manipulation., Background: Previous studies have shown that E2 improves mood in women around the menopause transition but does not improve mood for older postmenopausal women. We have previously shown that E2 treatment in nondepressed women resulted in increased negative mood after psychosocial stress., Design: Participants were 22 postmenopausal women placed on either oral placebo or 17β-estradiol (1 mg/day for 1 month, then 2 mg/day for 2 months)., Method: At the end of the 3-month treatment phase, the participants performed the Trier Social Stress Test followed by mood ratings. To examine the effects of age on the estrogen-stress interaction, we performed a median split on age and created four groups of participants: younger-placebo (mean age: 55.5 years), younger-E2 (mean age: 55.5 years), older-placebo (mean age: 73.0 years), and older-E2 (mean age: 76.8 years)., Results: : The results showed that both older and younger E2-treated participants exhibited a significant and similar increase in negative mood after psychosocial stress compared with placebo-treated women., Conclusions: These results suggest that E2 may play a significant role in modulating emotional reactivity to stressful events and that this effect persists in older women. Furthermore, responsivity to E2 effects on emotional processing appears to be intact even years after menopause in contrast with other cognitive and behavioral effects of E2, which may be limited to the early postmenopausal years.

Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[((11))C]methyl-L-tryptophan ((11)C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized (11)C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH(2)). In all, 46 healthy controls had PET (11)C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH(2) gene and its 5' upstream region. Several TPH(2) SNPs were associated with lower normalized blood-to-brain clearance of (11)C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5' upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC.

During simple sensorimotor decision making, neurons in the parietal cortex extract evidence from sensory information provided by visual areas until a decision is reached. Contextual information can bias parietal activity during the task and change the decision-making parameters. One type of contextual information is the availability of reward for correct decisions. We tested the hypothesis that the frontal lobes and basal ganglia use contextual information to bias decision making to maximize reward. Human volunteers underwent functional MRI while making decisions about the motion of dots on a computer monitor. On rewarded trials, subjects responded more slowly by increasing the threshold to decision. Rewarded trials were associated with activation in the ventral striatum and prefrontal cortex in the period preceding coherent dot motion, and the degree of activation predicted the increased decision threshold. Decreasing dopamine transmission, using a tyrosine-depleting amino acid mixture, abolished the reward-related corticostriatal activation and eliminated the correlation between striatal activity and decision threshold. These observations provide direct evidence that some reward-related functional MRI signals in the striatum are the result of dopamine neuron activity and demonstrate that mesolimbic dopamine transmission can influence perceptual and decision-making neural processes engaged to maximize reward harvest.

Alcohol-use disorders are thought to be heterogeneous in etiology, pathophysiology and response to treatment. One hypothesized contributor to this variability is the common A118G polymorphism of the µ-opioid receptor gene, OPRM1. This article critically evaluates the evidence that the A118G substitution affects subjective, behavioral and neurobiological responses to alcohol and the opioid receptor antagonist, naltrexone. Although screening of patients in a clinical setting remains premature, results suggest the A118G substitution may influence one etiological pathway to alcoholism, for which naltrexone pharmacotherapy is more effective.

There is an increasing evidence that prenatal and early postnatal stressors have life long impacts on physical and mental health problems. Animal studies have shown that this could include enduring changes to brain serotonin neurotransmission. In the present study, we tested whether perinatal adversity in humans has a long-term impact on brain serotonin neurotransmission in adulthood. Twenty-six healthy males, recruited from a 27-year longitudinal study, underwent a positron emission tomography scan with the tracer alpha-[¹¹C]methyl-L-tryptophan (¹¹C-AMT), as an index of serotonin synthesis capacity. The trapping constant is taken as a proxy for the regional 5-HT synthesis. Birth complications, especially a delivery where the fetus showed signs of physiological distress, predicted lower ¹¹C-AMT trapping in the hippocampus and medial orbitofrontal cortex. Lower ¹¹C-AMT trapping in the medial orbitofrontal cortex was also predicted by maternal smoking and lower birth weight. There were no effects of childhood or recent adversity. This is the first human study reporting associations between perinatal adversity and adult ¹¹C-AMT trapping in the hippocampus and medial orbitofrontal cortex. The associations suggest that limbic serotonin pathways may be particularly vulnerable to environmental challenges during the period when they undergo the most prominent neurodevelopmental changes. In combination with other risk factors, perinatal stressors may contribute to increased vulnerability for psychiatric disorders in which serotonin plays a major role., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Dopamine neurotransmission influences approach toward rewards and reward-related cues. The best cited interpretation of this effect proposes that dopamine mediates the pleasure that commonly accompanies reward. This hypothesis has received support in some animal models and a few studies in humans. However, direct assessments of the effect of transiently increasing dopamine neurotransmission have been largely limited to the use of psychostimulant drugs, which elevate brain levels of multiple neurotransmitters in addition to dopamine. In the present study we tested the effect of more selectively elevating dopamine neurotransmission, as produced by administration of the immediate dopamine precursor, L-DOPA (0, 100/25, 200/50 mg, Sinemet), in healthy human volunteers. Neither dose altered positive mood. The results suggest that dopamine neurotransmission does not directly influence positive mood in humans.

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

Background: Low serotonin transmission is thought to increase susceptibility to a wide range of substance use disorders and impulsive traits., Aims: To investigate the effects of lowered serotonin on cocaine-induced (1.0 mg/kg cocaine, self-administered intranasally) dopamine responses and drug craving., Method: In non-dependent cocaine users, serotonin transmission was reduced using the acute tryptophan depletion method. Striatal dopamine responses were measured using positron emission tomography with [(11)C]raclopride., Results: Acute tryptophan depletion increased drug craving and striatal dopamine responses to cocaine. These acute tryptophan depletion-induced increases did not occur in the absence of cocaine., Conclusions: The results suggest that low serotonin transmission can increase dopaminergic and appetitive responses to cocaine. These findings might identify a mechanism by which individuals with low serotonin are at elevated risk for both substance use disorders and comorbid conditions.

The neurobiology of tobacco use is poorly understood, possibly in part because the relevant mechanisms might differ depending on past nicotine exposure and degree of addiction. In the present study we investigated whether these factors might affect the role of dopamine (DA). Using the acute phenylalanine/tyrosine depletion method (APTD), DA synthesis was transiently decreased in three groups of abstinent smokers (n=47): (1) early low-frequency smokers, who had smoked a maximum of five cigarettes per day for less than one year, (2) stable low-frequency smokers smoking at the same level as early low-frequency smokers for at least 3 years, and (3) stable high-frequency smokers, who smoked a minimum of 10 or more cigarettes per day for at least 5 years. Motivation to obtain tobacco was measured using a progressive ratio breakpoint schedule for nicotine-containing and de-nicotinized cigarettes. Compared with a nutritionally balanced control mixture, APTD decreased the self-administration of nicotine-containing cigarettes, and this occurred in all three groups of smokers. The results suggest that DA influenced the willingness to sustain effort for nicotine reward, and this was seen in participants at all three levels of cigarette addiction. In the transition from sporadic to addicted use, the role of DA in the motivation to seek drug may change less than previously proposed.

Context: The hypothesis of a serotonin (5-hydroxytryptamine [5-HT]) dysfunction in obsessive-compulsive disorder (OCD) stems largely from the clinical efficacy of 5-HT reuptake inhibitors. Serotonergic abnormalities in the unmedicated symptomatic state, however, remain to be fully characterized., Objective: To investigate brain regional 5-HT synthesis, as indexed by positron emission tomography and the α-[(11)C]methyl-L-tryptophan trapping constant (K*), in treatment-free adults meeting criteria for OCD., Design: Between-group comparison., Setting: Department of Psychiatry and Montreal Neurological Institute, McGill University, and Department of Psychology, McGill University Health Centre, Quebec, Canada., Participants: Twenty-one medication-free patients with OCD (15 men with a mean [SD] age of 33.2 [9.3] years and 6 women with a mean [SD] age of 35.8 [7.1] years) and 21 healthy controls matched for age and sex (15 men with a mean [SD] age of 32.9 [10.1] years and 6 women with a mean [SD] age of 36.5.5 [8.6] years). Main Outcome Measure The α-[(11)C]methyl-L-tryptophan brain trapping constant K*, which was analyzed with Statistical Parametric Mapping (SPM8) and with proportional normalization (extent threshold of 100 voxels with a peak threshold of P ≤ .005)., Results: Compared with healthy controls, the patients with OCD exhibited significantly greater α-[(11)C]methyl-L-tryptophan trapping in the right hippocampus and left temporal gyrus (Brodmann area 20). In the larger subsample of all men, these same differences were also evident, as well as higher K* values in the caudate nucleus. Individual differences in symptom severity correlated positively with K* values sampled from the caudate and temporal lobe of the patients with OCD, respectively. There were no regions where the patients exhibited abnormally low K* values. Volumetric analyses found no morphometric alterations that would account for the group differences., Conclusion: The results support previous reports of greater striatal and temporal lobe activity in patients with OCD than in healthy controls and suggest that these disturbances include a serotonergic component. Previously reported glucose metabolic disturbances in OCD involving the orbitofrontal and cingulate cortices, in comparison, might reflect postsynaptic changes in the serotonergic system.

Background: Few pharmacological treatments for alcohol dependence are available. Moreover, the best supported treatment, naltrexone hydrochloride, appears to work for only some., Methods: To investigate potential predictors of these differential responses, 40 social drinkers (20 women) were administered 6 days of treatment with naltrexone vs. placebo in a double-blind, counterbalanced, crossover design. At the end of each treatment period, participants received a single dose of their preferred alcoholic beverage followed by the opportunity to work for additional alcohol units using a progressive ratio (PR) breakpoint paradigm. All subjects but one were genotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1)., Results: Naltrexone decreased the ethanol-induced 'euphoria' to a priming dose of alcohol in two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholic beverages on the PR task regardless of gender or genotype., Conclusions: The results add to the evidence that naltrexone decreases positive subjective effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkers might decrease alcohol use., (Copyright © 2011 by the Research Society on Alcoholism.)

In healthy never-depressed individuals, acute tryptophan depletion (ATD) may selectively decrease the accurate recognition of fearful facial expressions. Here we investigated the perception of facial emotions after ATD in more detail. We also investigated whether bright light, which can reverse ATD's mood-lowering effect, can also reverse its effect on the perception of facial emotions. On two separate test days, spent in a room that was either bright (n = 14) or dim (n = 16), healthy never-depressed women completed a facial emotion perception task six hours after ingesting tryptophan-deficient and balanced amino acid mixtures. Treatments were administered double blind and in randomized order using a crossover design. In dim light ATD decreased recognition accuracy of anger, disgust, and surprise. The labeling of fear and sadness was not affected. In bright light no effects of ATD were seen. Bright light was identified as a potential confounding factor in task performance. The effects of ATD on facial emotion perception may be less emotion-specific than thought previously, and occurred in a direction opposite to what might be expected based on theories of mood-congruent bias.

Rationale: Baseline performance has been reported to predict dopamine (DA) effects on working memory, following an inverted-U pattern. This pattern may hold true for other executive functions that are DA-sensitive., Objectives: The objective of this study is to investigate the effect of D: -amphetamine, an indirect DA agonist, on two other putatively DA-sensitive executive functions, inhibition and motor planning, as a function of baseline performance., Methods: Participants with no prior stimulant exposure participated in a double-blind crossover study of a single dose of 0.3 mg/kg, p.o. of D: -amphetamine and placebo. Participants were divided into high and low groups, based on their performance on the antisaccade and predictive saccade tasks on the baseline day. Executive functions, mood states, heart rate and blood pressure were assessed before (T0) and after drug administration, at 1.5 (T1), 2.5 (T2) and 3.5 h (T3) post-drug., Results: Antisaccade errors decreased with D: -amphetamine irrespective of baseline performance (p = 0.025). For antisaccade latency, participants who generated short-latency antisaccades at baseline had longer latencies on D: -amphetamine than placebo, while those with long-latency antisaccades at baseline had shorter latencies on D: -amphetamine than placebo (drug x group, p = 0.04). D: -amphetamine did not affect motor planning. Ratings of mood improved on D: -amphetamine (p < 0.001). Magnitude of D: -amphetamine-induced changes in elation was related to baseline reaction time variability., Conclusions: D: -amphetamine reduced antisaccade error rates in healthy controls, replicating and extending findings with DA agonists in clinical populations. D: -amphetamine had baseline-dependent effects on antisaccade latency, consistent with an inverted-U relationship between performance and DA activity.

Objective: Recent studies have shown that women experience an acceleration of cognitive problems after menopause and that estrogen treatment can improve or at least maintain current levels of cognitive functioning in postmenopausal women. However, we have previously shown that the negative emotional effects of psychosocial stress are magnified in normal postmenopausal women after estrogen treatment. This study examined whether estradiol (E2) administration can modify cognitive performance after exposure to psychological stress and monoamine depletion., Methods: Participants consisted of 22 postmenopausal women placed on either oral placebo or 17beta-E2 (1 mg/d for 1 mo, then 2 mg/d for 2 mo). At the end of the 3-month treatment phase, participants underwent three depletion challenges in which they ingested one of three amino acid mixtures: deficient in tryptophan, deficient in phenylalanine/tyrosine, or balanced. Five hours later, participants performed the Trier Social Stress Test (TSST), followed by mood and anxiety ratings and cognitive testing. Cognitive measures included tests of attention, psychomotor function, and verbal episodic memory., Results: E2-treated compared with placebo-treated participants exhibited significant worsening of cognitive performance on tasks measuring attentional performance and psychomotor speed. Similar trends for impairment were seen in measures of long-term episodic memory compared with placebo-treated postmenopausal women. E2-treated participants also showed a significant increase in negative mood and anxiety compared with placebo-treated women after, but not before, the TSST, although the worsening of both cognitive and behavioral functioning was not correlated. These effects were independent of tryptophan or tyrosine/phenylalanine depletion and were not manifested before the TSST or at baseline., Conclusions: These data suggest that the relationship between estrogen administration and cognitive/behavioral performance in postmenopausal women may be more complex than initially appreciated and that the effects of psychosocial stress may influence whether hormone effects are beneficial.

Background: Adults exhibiting severe impulsive and aggressive behaviors have multiple indices of low serotonin (5-HT) neurotransmission. It remains unclear though whether low 5-HT mediates the behavior or instead reflects a pre-existing vulnerability trait., Methodology/principal Findings: In the present study, positron emission tomography with the tracer alpha-[(11)C]methyl-L-tryptophan ((11)C-AMT) was used to compare 5-HT synthesis capacity in two groups of adult males from a 21-year longitudinal study (mean age +/- SD: 27.1+/-0.7): individuals with a history of childhood-limited high physical aggression (C-LHPA; N = 8) and individuals with normal (low) patterns of physical aggression (LPA; N = 18). The C-LHPA males had significantly lower trapping of (11)C-AMT bilaterally in the orbitofrontal cortex and self-reported more impulsiveness. Despite this, in adulthood there were no group differences in plasma tryptophan levels, genotyping, aggression, emotional intelligence, working memory, computerized measures of impulsivity, psychosocial functioning/adjustment, and personal and family history of mood and substance abuse disorders., Conclusions/significance: These results force a re-examination of the low 5-HT hypothesis as central in the biology of violence. They suggest that low 5-HT does not mediate current behavior and should be considered a vulnerability factor for impulsive-aggressive behavior that may or may not be expressed depending on other biological factors, experience, and environmental support during development.