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The relationship between alcohol and pain is complex. Associations between pain and alcohol use disorder (AUD) vary by race, but the underlying biological basis is not understood. We examined the association of the kappa opioid receptor (KOR) with responses to the cold-pressor test (CPT), before and after treatment with the opioid antagonist naltrexone, among individuals with AUD who self-identified as Black or White.Thirty-seven individuals (12 Black, 24 White, and 1 Multiracial) with AUD participated in two CPTs, separated by 1 week during which they received naltrexone 100 mg daily. During each CPT, pain reporting threshold (PRT), average pain increase rate (APIR), relative pain recovery (RPR), and alcohol craving were recorded. KOR availability was measured using [Black participants reported higher PRT and APIR than White participants during the CPT before, but not after, naltrexone treatment. Among Black participants, KOR availability was positively associated with PRT and APIR before, but not after naltrexone. Greater KOR availability was associated with faster RPR for White, but not Black, participants. The CPT induced more alcohol craving in Black than White participants, particularly in individuals with low KOR availability, an effect that was not attenuated by naltrexone.KOR involvement and naltrexone effects on responses to the CPT were different between Black and White participants. These preliminary findings suggest that further exploration of the differences in the opioid system and pain among Black and White individuals with AUD and their relationship with naltrexone's effects is warranted.

We recently introduced voxel-level images of drug occupancy from PET via our “Lassen plot filter.” Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an “EC50 image” from human data to evaluate this hypothesis. Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50. As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision. Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials.

Background Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans. Methods We assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the [11C]-(+)-PHNO and [18F]FPEB radioligands to quantify regional dopamine D2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. Results We found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D2/3 and, importantly, midbrain D3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. Conclusions These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals.

Background Results from neuroimaging studies suggest that disruptions in flexible decision-making functions in substance-dependent individuals are a consequence of drug-induced neural adaptations. In addicted populations, however, the causal relationship between biobehavioral phenotypes of susceptibility and addiction consequence is difficult to dissociate. Indeed, evidence from animals suggests that poor decision making due to preexisting biological factors can independently enhance the risk for developing addiction-like behaviors. Neuroimaging studies in animals provide a unique translational approach for the identification of the neurobiological mechanisms that mediate susceptibility to addiction. Methods We used positron emission tomography in rats to quantify regional dopamine D2/3 receptors and metabotropic glutamate receptor 5 (mGluR5) and assessed decision making using a probabilistic reversal learning task. Susceptibility to self-administer cocaine was then quantified for 21 days followed by tests of motivation and relapse-like behaviors. Results We found that deficits specifically in reward-guided choice behavior on the probabilistic reversal learning task predicted greater escalation of cocaine self-administration behavior and greater motivation for cocaine and, critically, were associated with higher midbrain D3 receptor availability. Additionally, individual differences in midbrain D3 receptor availability independently predicted the rate of escalation in cocaine-taking behaviors. No differences in mGluR5 availability, responses during tests of extinction, or cue-induced reinstatement were observed between the groups. Conclusions These findings indicate that our identified D3-mediated decision-making phenotype can be used as a behavioral biomarker for assessment of cocaine use susceptibility in human populations.

Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [

Introduction Tobacco smoking is a major public health burden. The mesocortical dopamine system—including the dorsolateral prefrontal cortex (dlPFC)—plays an important role in cognitive function. Dysregulated dopamine signaling in dlPFC is associated with cognitive deficits such as impairments in attention, learning, working memory, and inhibitory control. We recently showed that dlPFC dopamine D2/3-type receptor (D2R) availability was significantly lower in people who smoke than in healthy-controls and that dlPFC amphetamine-induced dopamine release was lower in females who smoke relative to males who smoke and female healthy-controls. However, we did not examine whether the smoking-related dopamine deficits were related to cognitive deficits. Aims and Methods The goal of this study was to relate dopamine metrics to cognitive performance in people who smoke and healthy-controls. In total 24 (12 female) people who smoke cigarettes and 25 sex- and age-matched healthy-controls participated in two same-day [11C]FLB457 positron emission tomography (PET) scans before and after amphetamine administration. Two outcome measures were calculated—D2R availability (non-displaceable binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND). Cognition (verbal learning and memory) was assessed with a computerized test from the CogState battery (International Shopping List). Results People who smoke had significantly worse immediate (p = .04) and delayed (p = .03) recall than healthy-controls. Multiple linear regression revealed that for people who smoke only, lower D2R availability was associated with worse immediate (p = .04) and delayed (p < .001) recall. %ΔBPND was not significantly related to task performance. Conclusion This study demonstrated that lower dlPFC D2R availability in people who smoke is associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. Implications This is the first study to directly relate dopamine metrics in the prefrontal cortex to cognitive function in people who smoke cigarettes compared to healthy-controls. The current work included a well-characterized subject sample with regards to demographic and smoking variables, as well as a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature by relating dopamine metrics to cognition in people who smoke, providing a better understanding of brain-behavior relationships.

There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [To develop the harmonization technique (Experiment 1), the Iida brain phantom was filled with F-18 solution and scanned on the two scanners in question (HRRT, HR+, Siemens/CTI). Phantom images were used to determine the optimal isotropic Gaussian filter to harmonize HRRT and HR+ images. To evaluate the harmonization on human images (Experiment 2), inter-scanner variability was calculated using [Experiment 1 identified the optimal filter as a Gaussian with a 4.5 mm FWHM. Experiment 2 resulted in 13.9% PD for unfiltered HRRT and 3.71% for HRRT filtered with 4.5 mm. Experiment 3 yielded 5.24% PDThe PD results show that the variability of harmonized HRRT is less than the T/RT variability of the HR+. The harmonization technique makes it possible for BP

BACKGROUND: Naltrexone is a nonselective opioid receptor antagonist used as a treatment for alcohol use disorder. However, only modest clinical effects have been observed, possibly because of limited knowledge about the biological variables affecting the efficacy of naltrexone. We investigated the potential role of the kappa opioid receptor (KOR) in the therapeutic effect of naltrexone. METHODS: A total of 48 non-treatment-seeking heavy drinkers (16 women) who met DSM-IV criteria for alcohol dependence participated in two alcohol drinking paradigms (ADPs) separated by a week of open-label naltrexone (100 mg daily). Craving, assessed with the Alcohol Urge Questionnaire and the Yale Craving Scale, and drinking behavior were recorded in each ADP. Prior to naltrexone initiation, KOR availability was determined in the amygdala, hippocampus, pallidum, striatum, cingulate cortex, and prefrontal cortex using positron emission tomography with [11C]LY2795050. RESULTS: Participants reported lower levels of craving (Yale Craving Scale: -11 ± 1, p < .0001; Alcohol Urge Questionnaire: -6 ± 0.6, p < .0001) and consumed fewer drinks (-3.7 ± 4, p < .0001) during the second ADP following naltrexone therapy. The observed reduction in drinking was negatively associated with baseline KOR availability in the striatum (p = .005), pallidum (p = .023), and cingulate cortex (p = .018). Voxelwise analysis identified clusters in the bilateral insula, prefrontal, and cingulate cortex associated with the reduction in drinking (p < .0001). In addition, KOR availability in all evaluated brain regions was associated with craving measured in both ADPs. CONCLUSIONS: The KOR is implicated in drinking and craving following naltrexone therapy in alcohol use disorder. ispartof: BIOLOGICAL PSYCHIATRY vol:86 issue:11 pages:864-871 ispartof: location:United States status: published

BACKGROUND: Dopaminergic mechanisms that may underlie cannabis’ reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D(2/3) receptor antagonist [(11)C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample. METHODS: PET emission data were acquired from regular cannabis users (n=14; 7M/7F; 19-32 years old) over 90 minutes immediately after [(11)C]raclopride administration (584±95 MBq) as bolus followed by constant infusion (K(bol)=105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 minutes after scan start. Plasma concentrations of Δ(9)-THC and metabolites and ratings of subjective “high” were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [(11)C]raclopride binding, linearized-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region). RESULTS: Cannabis smoking increased plasma Δ(9)-THC levels (peak: 0-10 minutes) and subjective high (peak: 0-30 minutes). Significant clusters (>16 voxels) modeled by transient reductions in [(11)C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans. CONCLUSIONS: These preliminary data support the sensitivity of [(11)C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.

We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence ofFive healthy subjects were scanned with the nonselective GABAa tracer,As expected, the ECOur results argue for (a) confidence in the ability of the EC

Introduction Tobacco smoking is a major public health burden. The first-line pharmacological treatment for tobacco smoking is nicotine replacement therapy (eg, the nicotine patch (NIC)). Nicotine acts on nicotinic-acetylcholine receptors on dopamine terminals to release dopamine in the ventral and dorsal striatum encoding reward and habit formation, respectively. Aims and Methods To better understand treatment efficacy, a naturalistic experimental design combined with a kinetic model designed to characterize smoking-induced dopamine release in vivo was used. Thirty-five tobacco smokers (16 female) wore a NIC (21 mg, daily) for 1-week and a placebo patch (PBO) for 1-week in a randomized, counter-balanced order. Following 1-week under NIC and then overnight abstinence, smokers participated in a 90-minute [11C]raclopride positron emission tomography scan and smoked a cigarette while in the scanner. Identical procedures were followed for the PBO scan. A time-varying kinetic model was used at the voxel level to model transient dopamine release peaking instantaneously at the start of the stimulus and decaying exponentially. Magnitude and spatial extent of dopamine release were estimated. Smokers were subcategorized by nicotine dependence level and nicotine metabolism rate. Results Dopamine release magnitude was enhanced by NIC in ventral striatum and diminished by NIC in dorsal striatum. More-dependent smokers activated more voxels than the less-dependent smokers under both conditions. Under PBO, fast metabolizers activated more voxels in ventral striatum and fewer voxels in dorsal striatum compared to slow metabolizers. Conclusions These findings demonstrate that the model captured a pattern of transient dopamine responses to cigarette smoking which may be different across smoker subgroup categorizations. Implications This is the first study to show that NIC alters highly localized patterns of cigarette smoking-induced dopamine release and that levels of nicotine dependence and nicotine clearance rate contribute to these alterations. This current work included a homogeneous subject sample with regards to demographic and smoking variables, as well as a highly sensitive model capable of detecting significant acute dopamine transients. The findings of this study add support to the recent identification of biomarkers for predicting the effect of nicotine replacement therapies on dopamine function which could help refine clinical practice for smoking cessation.

Background: [(11)C]-Erlotinib is a radiolabeled analogue of a tyrosine kinase inhibitor used to treat non-small cell lung cancer (NSCLC) which expresses specific kinase domain mutations of the epidermal growth factor receptor (EGFR). In this study, 10 subjects with NSCLC and assorted EGFR mutation status underwent a dynamic, multi-bed positron emission tomography (PET) scan using [(11)C]-erlotinib. Data were analyzed using a variety of quantitative techniques common in PET (graphical methods, kinetic models, and uptake value-based endpoints). Our primary goal was to determine the most reliable imaging endpoint given the need for maintaining minimal patient burden and recognizing the advantage of simple calculations in future trials. Results: Standard uptake values (a semi-quantitative endpoint) were well correlated with both binding potential and volume of distribution (fully quantitative endpoints). Normalized tracer uptake was found to stabilize approximately 60 minutes post tracer injection. Conclusions: The kinetic properties of [(11)C]-erlotinib varied greatly across subjects. Our novel scanning protocol produced an important dataset which highlights the great heterogeneity of NSCLC and its apparent impact on [(11)C]-erlotinib kinetics. A lack of correlation between EGFR mutational status and quantitative endpoints appears to be due to disease heterogeneity and low tracer uptake. The most reliable fits of the dynamic data were based on the one-tissue compartmental model which were well correlated with mean SUV. Due to this correlation and good stability at late-time, SUV seems sufficiently well-suited to quantitative imaging of NSCLC lesions in the whole body with [(11)C]-erlotinib.

Efforts to build the next generation of brain PET scanners are underway. It is expected that a new scanner (NS) will offer an order-of-magnitude improvement in sensitivity to counts compared to the current state-of-the-art, Siemens HRRT. Our goal was to explore the use of the anticipated increased sensitivity in combination with the linear-parametric neurotransmitter PET (lp-ntPET) model to improve detection and classification of transient dopamine (DA) signals. We simulated striatal [11C]raclopride PET data to be acquired on a future NS which will offer ten times the sensitivity of the HRRT. The simulated PET curves included the effects of DA signals that varied in start-times, peak-times, and amplitudes. We assessed the detection sensitivity of lp-ntPET to various shapes of DA signal. We evaluated classification thresholds for their ability to separate ‘early’- versus ‘late’-peaking, and ‘low’- versus ‘high’-amplitude events in a 4D phantom. To further refine the characterization of DA signals, we developed a weighted k-nearest neighbors (wkNN) algorithm to incorporate information from the neighborhood around each voxel to reclassify it, with a level of certainty. Our findings indicate that the NS would expand the range of detectable neurotransmitter events to 72%, compared to the HRRT (31%). Application of wkNN augmented the detection sensitivity to DA signals in simulated NS data to 92%. This work demonstrates that the ultra-high sensitivity expected from a new generation of brain PET scanner, combined with a novel classification algorithm, will make it possible to accurately detect and classify short-lived DA signals in the brain based on their amplitude and timing.

For radioligands without a reference region, the Lassen plot can be used to estimate receptor occupancy by an exogenous drug ([Formula: see text]). However, the Lassen plot is not well-suited for spatial variation in [Formula: see text]. To overcome this limitation, we introduce a Lassen plot filter, i.e. a Lassen plot applied to local neighborhoods in PET images. Image data were simulated with regional variation in [Formula: see text], [Formula: see text], both, or neither and analyzed using the change in binding potential ([Formula: see text]), the conventional Lassen plot, and the Lassen plot filter at the region of interest (ROI) and voxel level. All methods were also applied to a human [11C]flumazenil occupancy study using PF-06372865. This combination of a non-selective radioligand and selective drug should lead to varying [Formula: see text]provided the distribution of subtypes varies spatially. In contrast with [Formula: see text] and the conventional Lassen plot, ROI-level and voxel-level Lassen plot filter estimates remained unbiased in the presence of regional variation in [Formula: see text] or [Formula: see text]. In the [11C]flumazenil data-set, [Formula: see text] was shown to vary regionally in accordance with the distribution of binding sites for [11C]flumazenil and PF-06372865. We demonstrate that a local-neighborhood Lassen plot filter provides robust and unbiased estimates of [Formula: see text] and [Formula: see text] without the need for any user intervention.

Sex differences are present in psychiatric disorders associated with disrupted dopamine function, and thus, sex differences in dopamine neurobiology may underlie these clinical disparities. In this chapter, we review sex differences in the dopaminergic system with a focus on substance use disorders, especially tobacco smoking, as our exemplar disorder. This chapter is organized into five sections describing sex differences in the dopaminergic system: (1) neurobiology, (2) role of sex hormones, (3) genetic underpinnings, (4) cognitive function, and (5) influence on addiction. In each section, we provide an overview of the topic area, summarize sex differences identified to date, highlight addiction research, especially clinical neuroimaging studies, and suggest avenues for future research.

BACKGROUND: Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships between drug-induced alterations, cocaine taking and maladaptive decision-making processes, however, are difficult to establish in humans. METHODS: We assessed decision making in adult, male rats using a probabilistic reversal learning (PRL) task and used positron emission tomography with the [(11)C]-(+)-PHNO and [(18)F]FPEB radioligands to quantify regional dopamine D(2/3) receptors and metabotropic glutamate 5 (mGlu(5)) receptor availability, respectively, before and after 21 d of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. RESULTS: We found that self-administration of cocaine, but not saline, disrupted behavior in the PRL task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D(2/3) and, importantly, midbrain D(3) receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. CONCLUSIONS: These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals.

BACKGROUND: Results from neuroimaging studies suggest that disruptions in flexible decision-making functions in substance-dependent individuals are a consequence of drug-induced neural adaptations. In addicted populations, however, the causal relationship between biobehavioral phenotypes of susceptibility and addiction consequence are difficult to dissociate. Indeed, evidence from animals suggest that poor decision making due to pre-existing biological factors can independently enhance the risk for developing addiction-like behaviors. Neuroimaging studies in animals provide a unique translational approach for the identification of the neurobiological mechanisms that mediate susceptibility to addiction. METHODS: Here, we used positron emission tomography in rats to quantify regional dopamine D(2/3) receptors and metabotropic glutamate receptor 5 (mGluR5) and assessed decision making using a probabilistic reversal learning (PRL). Susceptibility to self-administer cocaine was then quantified for 21 days followed by tests of motivation and relapse-like behaviors. RESULTS: We found that deficits specifically in reward-guided choice behavior on the PRL predicted greater escalation of cocaine self-administration behavior, greater motivation for cocaine, and, critically, was associated with higher midbrain D(3) receptor availability. Additionally, individual differences in midbrain D(3) receptor availability independently predicted the rate of escalation in cocaine-taking behaviors. No differences in mGlu5 receptor availability, responses during tests of extinction or cue-induced reinstatement were observed between the groups. CONCLUSIONS: These findings indicate that our identified D(3)-mediated decision-making phenotype can be used as a behavioral biomarker for the assessment of cocaine use susceptibility in human populations.

The efficacy of naltrexone to treat alcohol use disorder (AUD) is modest. A better understanding of the neurobiology underlying naltrexone effects could optimize treatments. We evaluated the occupancy of the kappa opioid receptor (KOR) by naltrexone measured with [11C]-LY2795050 positron emission tomography (PET) as a predictor of response to naltrexone. Response to naltrexone was defined as the difference in craving and the difference between the number of drinks consumed during an alcohol drinking paradigm (ADP) before and after 1 week of supervised 100 mg daily oral naltrexone. Forty-four (14 F) nontreatment seeking heavy drinkers meeting criteria for AUD were enrolled. Participants drank 47 ± 16 drinks per week and were balanced in family history of alcoholism (FH, 26 positive). High KOR occupancy (92 ± 1%) was achieved. Occupancy was negatively associated with number of years drinking (YOD) in FH positive, but not FH negative, participants (t3,42 = 4.00, p = 0.0003). Higher KOR occupancy by naltrexone was associated with higher alcohol craving during the ADP (F1,81 = 4.88, p = 0.030). The reduction in drinking after naltrexone was negatively associated with KOR occupancy, with significant effects of FH status (t1,43 = −2.08, p = 0.044). A logistic regression model including KOR occupancy, YOD, and FH variables achieved an 84% prediction accuracy for ≥50% reduction in drinking. These results confirm that naltrexone binds at the KOR site and suggest that KOR occupancy by naltrexone may be related to clinical response. Based on our results, we propose that differential affinities for the mu and KOR could explain why lower doses of naltrexone can have greater clinical efficacy.

Sex differences are present in psychiatric disorders associated with disrupted dopamine function, and thus, sex differences in dopamine neurobiology may underlie these clinical disparities. In this chapter, we review sex differences in the dopaminergic system with a focus on substance use disorders, especially tobacco smoking, as our exemplar disorder. This chapter is organized into five sections describing sex differences in the dopaminergic system: (1) neurobiology, (2) role of sex hormones, (3) genetic underpinnings, (4) cognitive function, and (5) influence on addiction. In each section, we provide an overview of the topic area, summarize sex differences identified to date, highlight addiction research, especially clinical neuroimaging studies, and suggest avenues for future research.

Background and purpose Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype-selective PAMs. Experimental approach In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits. In vivo receptor occupancy (RO) was conducted, prior to confirmation of in vivo α2/3 and α1 pharmacology through quantitative EEG (qEEG) beta frequency and zolpidem drug discrimination in rats respectively. PF-06372865 was then progressed to Phase 1 clinical trials. Key results PF-06372865 exhibited functional selectivity for those receptors containing α2/3/5 subunits, with significant positive allosteric modulation (90-140%) but negligible activity (≤20%) at GABAA receptors containing α1 subunits. PF-06372865 exhibited concentration-dependent occupancy of GABAA receptors in preclinical species. There was an occupancy-dependent increase in qEEG beta frequency and no generalization to a GABAA α1 cue in the drug-discrimination assay, clearly demonstrating the lack of modulation at the GABAA receptors containing an α1 subtype. In a Phase 1 single ascending dose study in healthy volunteers, evaluation of the pharmacodynamics of PF-06372865 demonstrated a robust increase in saccadic peak velocity (a marker of α2/3 pharmacology), increases in beta frequency qEEG and a slight saturating increase in body sway. Conclusions and implications PF-06372865 has a unique clinical pharmacology profile and a highly predictive translational data package from preclinical species to the clinical setting.

The mesocorticolimbic dopamine (DA) circuit, comprising the mesolimbic and mesocortical DA pathways, plays a crucial role in reward, cognitive control, and motivation. The positron emission tomography (PET) radiotracer, [C-11]raclopride, has been used widely to image DA receptors and DA changes in the mesolimbic pathway before and after pharmacological and behavioral challenges. In certain circumstances, properties of traditional kinetic models—used to analyze dynamic PET data—are not well-suited to describing the effects of stimulus-induced DA release. To combat model shortcomings, the authors have advanced a suite of models that characterizes PET data in the presence of time-varying DA release. We review select [C-11]raclopride studies of the striatum during cigarette smoking to illustrate the advantages of such models. DA receptors occur in lower density in the cortex than the striatum. This, as well as higher relative background signal, poses a serious challenge to quantitative PET of DA changes in the mesocortical system. Novel high affinity radioligands [F-18]fallypride and [C-11]FLB457 have been used to image mesocortical DA transmission. Models with time-varying terms may also hold the key to optimizing sensitivity to changes in mesocortical DA. As an illustration, we compare recent PET studies of the effect of stress on cortical DA release. Finally, we consider some challenges and strategies for further optimization of sensitivity of PET to stimulus-induced DA changes throughout the whole brain. Electronic supplementary material The online version of this article (10.1007/s11682-017-9779-7) contains supplementary material, which is available to authorized users.

Guanfacine, a noradrenergic alpha2a agonist, reduced tobacco smoking in a 4-week trial and in animal models has been shown to reduce cortical dopamine release, which is critically involved in the reinforcing effect of tobacco smoking. We measured amphetamine-induced extrastriatal dopamine release before and after treatment with guanfacine with [11C]FLB457, a dopamine D2/D3 receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [11C]FLB457 PET scans on the same day, one before and one at 2.5–3 h after amphetamine (0.4–0.5 mg/kg, PO). A subset (n=12) then underwent guanfacine treatment (3 mg/day for 3 weeks) and the set of scans were repeated. [11C]FLB457-binding potential (BPND) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BPND after vs before amphetamine (Δ BPND) is an indirect measure of DA release and was compared between the untreated and guanfacine-treated conditions. Guanfacine treatment attenuated amphetamine-induced DA release; however, the change was due to a global 8% decrease in baseline BPND from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [11C]FLB457 BPND in tobacco smokers, suggesting an increase in dopaminergic tone. Guanfacine-induced normalization of dopamine signaling may be an important mesocortical mechanism contributing to its ability to aid in tobacco smoking cessation.

Converging lines of evidence suggest that men generally smoke for nicotine-related reinforcement, whereas women smoke for non-nicotine factors. Women have more difficulty quitting smoking and are less responsive to nicotine replacement therapies than men, underscoring the importance of examining sex differences in the neurochemical mechanisms underlying nicotine-motivated behavior. We review the recent imaging literature on sex differences in the nicotinic acetylcholine receptor system and in the dopaminergic system in response to nicotine administration and tobacco smoking. We offer an explanation to unify imaging findings related to the dopamine system. We then propose a course of action for future medication development for tobacco smoking addiction.