Mesocorticolimbic function in cocaine polydrug users: A multimodal study of drug cue reactivity and cognitive regulation.

Addictions are thought to be fostered by the emergence of poorly regulated mesocorticolimbic responses to drug-related cues. The development and persistence of these responses might be promoted by altered glutamate transmission, including changes to type 5 metabotropic glutamate receptors (mGluR5s). Unknown, however, is when these changes arise and whether the mGluR5 and mesocorticolimbic alterations are related. To investigate, non-dependent cocaine polydrug users and cocaine-naïve healthy controls underwent a positron emission tomography scan (15 cocaine users and 14 healthy controls) with [11 C]ABP688, and a functional magnetic resonance imaging scan (15/group) while watching videos depicting activities with and without cocaine use. For some drug videos, participants were instructed to use a cognitive strategy to lower craving. Both groups exhibited drug cue-induced mesocorticolimbic activations and these were larger in the cocaine polydrug users than healthy controls during the session's second half. During the cognitive regulation trials, the cocaine users' corticostriatal responses were reduced. [11 C]ABP688 binding was unaltered in cocaine users, relative to healthy controls, but post hoc analyses found reductions in those with 75 or more lifetime cocaine use sessions. Finally, among cocaine users (n = 12), individual differences in prefrontal [11 C]ABP688 binding were associated with midbrain and limbic region activations during the regulation trials. Together, these preliminary findings raise the possibility that (i) recreational polydrug cocaine users show biased brain processes towards cocaine-related cues and (ii) repeated cocaine use can lower cortical mGluR5 levels, diminishing the ability to regulate drug cue responses. These alterations might promote susceptibility to addiction and identify early intervention targets.

Recognition of masked and unmasked facial expressions in males and females and relations with mental wellness.

Background: While the effects of mask wearing/facial occlusion are known to impair facial expression recognition, little is known about the role of mental wellness on facial expression recognition, as well as the influence of sex on misattribution errors (i.e., confusions between emotions). In this large study, we aimed to address the relation between facial expression recognition and loneliness, perceived stress, anxiety, and depression symptoms in male and female adults. Methods: We assessed the influence of mask-wearing on facial expression recognition [i.e., accuracy and response time (RT)] via an online study in N = 469 adult males and females across Canada. Results: Expectedly, recognition was impaired under masked conditions (i.e., lower accuracy, longer RTs, more misattribution errors). Females were faster and more accurate than males, with less misattribution errors. A novel finding was that people with higher perceived stress were less accurate at identifying masked fearful faces. Perceived stress influenced the relation between sex and RT to masked happy faces; males with high stress scores were slower to recognize masked happy faces, the opposite was true for females. Finally, this study was among the first to show that higher loneliness predicted shorter RT to unmasked faces. Impact: Our results show that facial expression recognition is impaired by mask-wearing, and that sex and mental health features are important predictors of performance. Such insight could be detrimental in certain sectors of the population (e.g., health care or education), and inform policies being adopted in future pandemics.

Associating Internalizing and Externalizing Symptom Features With the Personality Inventory for DSM-5 Brief Form (PID-5-BF) in a Large Community Sample.

The Personality Inventory for DSM-5-Brief Form (PID-5-BF) is a relatively novel measure assessing maladaptive personality traits. We examined whether PID-5-BF traits are associated with non-personality measures of wellbeing in N = 661 Canadian adults in the community. Depression, anxiety, and perceived stress measures were obtained, as were indices of alcohol and cannabis use. Symptoms of depression and perceived stress were associated with all PID-5-BF dimensions, except for antagonism. Anxiety symptoms were associated with negative affectivity (NA) and, to a lesser extent, psychoticism. A younger age and female sex were related to higher depression and stress scores. In contrast to the models assessing depressive, anxiety and stress symptoms, in which NA was the strongest contributor, no significant contribution of internalizing traits (i.e., PID-5-BF NA) on substance use outcomes was found when externalizing traits were included in the models. Specifically, binge drinking and cannabis use were associated with higher disinhibition scores and lower psychoticism scores. Regression models were substantially weaker for substance use than for the mood and stress symptoms. Younger individuals used more cannabis and males engaged in more binge drinking. These findings largely confirm PID-5-BF's construct validity, and indicate that various indices of wellbeing (not necessarily personality-associated measures) are associated with personality traits, as measured with the brief from of PID-5-BF.

Integrating multimodal and multiscale connectivity blueprints of the human cerebral cortex in health and disease.

The brain is composed of disparate neural populations that communicate and interact with one another. Although fiber bundles, similarities in molecular architecture, and synchronized neural activity all reflect how brain regions potentially interact with one another, a comprehensive study of how all these interregional relationships jointly reflect brain structure and function remains missing. Here, we systematically integrate 7 multimodal, multiscale types of interregional similarity ("connectivity modes") derived from gene expression, neurotransmitter receptor density, cellular morphology, glucose metabolism, haemodynamic activity, and electrophysiology in humans. We first show that for all connectivity modes, feature similarity decreases with distance and increases when regions are structurally connected. Next, we show that connectivity modes exhibit unique and diverse connection patterns, hub profiles, spatial gradients, and modular organization. Throughout, we observe a consistent primacy of molecular connectivity modes-namely correlated gene expression and receptor similarity-that map onto multiple phenomena, including the rich club and patterns of abnormal cortical thickness across 13 neurological, psychiatric, and neurodevelopmental disorders. Finally, to construct a single multimodal wiring map of the human cortex, we fuse all 7 connectivity modes and show that the fused network maps onto major organizational features of the cortex including structural connectivity, intrinsic functional networks, and cytoarchitectonic classes. Altogether, this work contributes to the integrative study of interregional relationships in the human cerebral cortex.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

A three-factor model of common early onset psychiatric disorders: temperament, adversity, and dopamine.

Commonly comorbid early onset psychiatric disorders might reflect the varying expression of overlapping risk factors. The mediating processes remain poorly understood, but three factors show some promise: adolescent externalizing traits, early life adversity, and midbrain dopamine autoreceptors. To investigate whether these features acquire greater predictive power when combined, a longitudinal study was conducted in youth who have been followed since birth. Cohort members were invited to participate based on externalizing scores between 11 to 16 years of age. At age 18 (age 18.5 ± 0.6 y.o.), 52 entry criteria meeting volunteers had a 90-min positron emission tomography scan with [18F]fallypride, completed the Childhood Trauma Questionnaire, and were assessed with the Structured Clinical Interview for DSM-5. The three-factor model identified those with a lifetime history of DSM-5 disorders with an overall accuracy of 90.4% (p = 2.4 × 10-5) and explained 91.5% of the area under the receiver operating characteristic curve [95% CI: .824, 1.000]. Targeting externalizing disorders specifically did not yield a more powerful model than targeting all disorders (p = 0.54). The model remained significant when including data from participants who developed their first disorders during a three-year follow-up period (p = 3.5 × 10-5). Together, these results raise the possibility that a combination of temperamental traits, childhood adversity, and poorly regulated dopamine transmission increases risk for diverse, commonly comorbid, early onset psychiatric problems, predicting this susceptibility prospectively.

Cocaine cue-induced mesocorticolimbic activation in cocaine users: Effects of personality traits, lifetime drug use, and acute stimulant ingestion.

Stimulant drug-paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine-related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d-amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue-induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue-induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS-11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d-amphetamine did not augment the cue-induced activations, but, in cocaine users, drug cue-induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems.

Externalizing Risk Pathways for Adolescent Substance Use and Its Developmental Onset: A Canadian Birth Cohort Study: Trajectoires de comportements extériorisés et le risque pour l'initiation et l'usage de substances des adolescents : Une étude de cohorte de naissance canadienne.

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.

The burden of loneliness: Implications of the social determinants of health during COVID-19.

This study sought to examine if mental health issues, namely depression and anxiety symptoms, and loneliness were experienced differently according to various demographic groups during the COVID-19 pandemic (i.e., a societal stressor). An online survey, comprising demographic questions and questionnaires on depression, anxiety and loneliness symptoms, was distributed in Canada during the height of social distancing restrictions during the COVID-19 pandemic. Respondents (N=661) from lower income households experienced greater anxiety, depression and loneliness. Specifically, loneliness was greater in those with an annual income <$50,000/yr versus higher income brackets. Younger females (18-29yr) displayed greater anxiety, depressive symptoms and loneliness than their male counterparts; this difference did not exist among the other age groups (30-64yr, >65yr). Moreover, loneliness scores increased with increasing depression and anxiety symptom severity category. The relationship between loneliness and depression symptoms was moderated by gender, such that females experienced higher depressive symptoms when encountering greater loneliness. These data identify younger females, individuals with lower income, and those living alone as experiencing greater loneliness and mental health challenges during the height of the pandemic in Canada. We highlight the strong relationship between loneliness, depression and anxiety, and emphasize increased vulnerability among certain cohorts.

mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use.

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 [11C]ABP688 binding potential (BPND) 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 [11C]ABP688 BPND 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, [11C]ABP688 BPND 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.

Extra-striatal D2/3 receptor availability in youth at risk for addiction.

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 (DA2/3R) 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 [18F]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 [18F]fallypride binding potential (BPND) 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 BPND values were associated with low SP scores. Together, the results suggest that altered DA2/3R 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).

Effect of (Z)-isomer content on [11C]ABP688 binding potential in humans.

PURPOSE: To determine how the low-affinity (Z)-isomer of the radiotracer [11C]ABP688 affects binding potential values in vivo in humans. METHODS: High-resolution [11C]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 [rt(E) = 10 min, rt(Z) = 8.5 min]. Mean binding potential [BPND = fND * (Bavail/KD)] 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 [11C]ABP688 production was 92 ± 3.8% (range 78-97%). Percent (E)-isomer was positively correlated with BPND in the striatum (ρ = 0.28, p = 0.015) and limbic regions (ρ = 0.25, p = 0.036). In multiple regression analysis, sex (ß = 0.39, p = 0.001) and (E)-isomer content (ß = 0.23, p = 0.040) were significant predictors of BPND. CONCLUSIONS: Even modest levels of (Z)-[11C]ABP688 can reduce estimates of tracer binding in vivo. Future studies should use production methods that enrich levels of (E)-[11C]ABP688, report tracer isomer ratios, and account for this factor in their analyses.

Sex differences in [11C]ABP688 binding: a positron emission tomography study of mGlu5 receptors.

PURPOSE: The purpose of this study was to assess, in a large sample of healthy young adults, sex differences in the binding potential of [11C]ABP688, a positron emission tomography (PET) tracer selective for the metabotropic glutamate type 5 (mGlu5) receptor. METHODS: High resolution [11C]ABP688 PET scans were acquired in 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). Mean binding potential (BPND = fND * (Bavail / KD)) 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: [11C]ABP688 BPND 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 BPND was 17% higher in men. BPND was not related to menstrual phase in women. CONCLUSIONS: Binding availability of mGlu5 receptors as measured by PET [11C]ABP688 is higher in healthy men than women. This likely represents a source of variability in [11C]ABP688 studies and could have relevance for sex differences in cognitive-behavioral functions and neuropsychiatric disorders.

Neural function in DCC mutation carriers with and without mirror movements.

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.

Test-retest variability of [11 C]ABP688 estimates of metabotropic glutamate receptor subtype 5 availability in humans.

[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 (BPND ) 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 BPND between scans was observed. Variability in BPND values of 11-21% was observed across regions, with the greatest change in the hippocampus and amygdala. Reliability was low to moderate. BPND was not statistically related to scan start time, subjective anxiety, serum cortisol levels, or menstrual phase in women. Overall, [11 C]ABP688 BPND 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.

Cocaine Cue-Induced Dopamine Release in Recreational Cocaine Users.

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 [11C]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.

Is there a relation between novelty seeking, striatal dopamine release and frontal cortical thickness?

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.

Cocaine cue-induced dopamine release in the human prefrontal cortex.

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.

Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes.

The extent to which we learn from positive and negative outcomes of decisions is modulated by the neurotransmitter dopamine. Dopamine neurons burst fire in response to unexpected rewards and pause following negative outcomes. This dual signaling mechanism is hypothesized to drive both approach and avoidance behavior. Here we test a prediction deriving from a computational reinforcement learning model, in which approach is mediated via activation of the direct cortico-striatal pathway due to striatal D1 receptor stimulation, while avoidance occurs via disinhibition of indirect pathway striatal neurons secondary to a reduction of D2 receptor stimulation. Using positron emission tomography with two separate radioligands, we demonstrate that individual differences in human approach and avoidance learning are predicted by variability in striatal D1 and D2 receptor binding, respectively. Moreover, transient dopamine precursor depletion improved learning from negative outcomes. These findings support a bidirectional modulatory role for striatal dopamine in reward and avoidance learning via segregated D1 and D2 cortico-striatal pathways.

Cocaine cue-induced dopamine release in amygdala and hippocampus: a high-resolution PET [¹8F]fallypride study in cocaine dependent participants.

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.