Mu-opioid Receptor Availability Research Articles

Aberrant type 2 dopamine receptor availability in violent offenders with psychopathy

Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n=11) and healthy matched controls (n=17) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.

Changes in hypothalamic mu-opioid receptor expression following acute olanzapine treatment in female rats: Implications for feeding behavior

Advances have been made in recent years in using opioid receptor antagonists as an adjunct therapy to psychotropic medication to reduce debilitating weight gain and metabolic adverse effects associated with in particular second generation antipsychotics. However, it is unknown whether second generation antipsychotics produce a change in opioid receptor expression in the brain. The present study investigated early changes in opioid receptor expression in the female rat hypothalamus, a master controller of hunger and metabolic regulation, after acute treatment with olanzapine, a commonly used second generation antipsychotic. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the three opioid receptors; kappa, mu and delta, were determined at mRNA and protein level, respectively, in the five hypothalamic areas: paraventricular nucleus, arcuate nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamus. After 48 h of olanzapine treatment at clinically relevant plasma concentration weight gain and food intake changes, and increased plasma glucose were observed in female rats. Olanzapine treatment also led to a significant increase in mu opioid receptor availability in the arcuate nucleus, which contains both satiety and hunger controlling neurons. No other areas showed any opioid receptor expressional changes with olanzapine treatment on neither at mRNA nor protein level. Technical difficulties made it impossible to analyze mRNA levels in the lateral hypothalamus and overall binding of delta opioid receptors. Thus, the present study provided insights in to how olanzapine at clinically relevant plasma levels already at an early stage modulated the opioid system in the hypothalamus.

Reward processing in schizophrenia and its relation to Mu opioid receptor availability and negative symptoms: A [11C]-carfentanil PET and fMRI study

BackgroundReward processing deficits are a core feature of schizophrenia and are thought to underlie negative symptoms. Pre-clinical evidence suggests that opioid neurotransmission is linked to reward processing. However, the contribution of Mu Opioid Receptor (MOR) signalling to the reward processing abnormalities in schizophrenia is unknown. Here, we examined the association between MOR availability and the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging. Method37 subjects (18 with Schizophrenia with moderate severity negative symptoms and 19 age and sex-matched healthy controls) underwent a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. Participants also had a [11C]-carfentanil PET scan to measure MOR availability. ResultsReward anticipation was associated with increased neural activation in a widespread network of brain regions including the striatum. Patients with schizophrenia had both significantly lower MOR availability in the striatum as well as striatal hypoactivation during reward anticipation. However, there was no association between MOR availability and striatal neural activity during reward anticipation in either patient or controls (Pearson's Correlation, controls df = 17, r = 0.321, p = 0.18, patients df = 16, r = 0.295, p = 0.24). There was no association between anticipation-related neural activation and negative symptoms (r = –0.120, p = 0.14) or anhedonia severity (social r = –0.365, p = 0.14 physical r = –0.120, p = 0.63). ConclusionsOur data suggest reduced MOR availability in schizophrenia might not underlie striatal hypoactivation during reward anticipation in patients with established illness. Therefore, other mechanisms, such as dopamine dysfunction, warrant further investigation as treatment targets for this aspect of the disorder.

11C]carfentanil PET imaging for studying the peripheral opioid system in vivo: effect of photoperiod on mu-opioid receptor availability in brown adipose tissue

PurposePhotoperiod determines the metabolic activity of brown adipose tissue (BAT) and affects the food intake and body mass of mammals. Sympathetic innervation of the BAT controls thermogenesis and facilitates physiological adaption to seasonal changes, but the exact mechanism remains elusive. Previous studies have shown that central opioid signaling regulates BAT thermogenesis, and that the expression of the brain mu-opioid receptor (MOR) varies seasonally. Therefore, it is important to know whether MOR expression in BAT shows seasonal variation.MethodsWe determined the effect of photoperiod on BAT MOR availability using [11C]carfentanil positron emission tomography (PET). Adult rats (n = 9) were repeatedly imaged under various photoperiods in order to simulate seasonal changes.ResultsLong photoperiod was associated with low MOR expression in BAT (β = − 0.04, 95% confidence interval: − 0.07, − 0.01), but not in muscles. We confirmed the expression of MOR in BAT and muscle using immunofluorescence staining.ConclusionPhotoperiod affects MOR availability in BAT. Sympathetic innervation of BAT may influence thermogenesis via the peripheral MOR system. The present study supports the utility of [11C]carfentanil PET to study the peripheral MOR system.

Genetics of adult attachment and the endogenous opioid system

Since the pioneering work by Panksepp et al, the neurobiological bases of attachment behavior have been closely linked with opioid neurotransmission. Candidate gene studies of adult individuals have shown that variation in the mu-opioid receptor gene (OPRM1) influences attachment behavior. Early maternal care and the A/A genotype of the A118G polymorphism interact in modulating levels of fearful attachment. Compared to their counterparts carrying the A/A genotype, individuals expressing the minor 118G allele show lower levels of avoidant attachment and experience more pleasure in social situations. Brain imaging research has strengthened the biological plausibility of candidate gene studies. The avoidance dimension of attachment correlates negatively with mu-opioid receptor availability in the thalamus and anterior cingulate cortex, as well as the frontal cortex, amygdala, and insula. Overall, findings from human studies combined with those from animal models suggest that research on the genetic bases of attachment should include the endogenous opioid system among the investigated variables.

\u03bc-opioid receptor availability is associated with sex drive in human males

The endogenous mu-opioid receptor (MOR) system modulates a multitude of social and reward-related functions, and exogenous opiates also influence sex drive in humans and animals. Sex drive shows substantial variation across humans, and it is possible that individual differences in MOR availability underlie interindividual of variation in human sex drive. We measured healthy male subjects’ (n = 52) brain’s MOR availability with positron emission tomography (PET) using an agonist radioligand, [11C]carfentanil, that has high affinity for MORs. Sex drive was measured using self-reports of engaging in sexual behaviour (sex with partner and masturbating). Bayesian hierarchical regression analysis revealed that sex drive was positively associated with MOR availability in cortical and subcortical areas, notably in caudate nucleus, hippocampus, and cingulate cortices. These results were replicated in full-volume GLM analysis. These widespread effects are in line with high spatial autocorrelation in MOR expression in human brain. Complementary voxel-based morphometry analysis (n = 108) of anatomical MR images provided limited evidence for positive association between sex drive and cortical density in the midcingulate cortex. We conclude that endogenous MOR tone is associated with individual differences in sex drive in human males.

The impact of advanced age and sex on Mu Opioid Receptor signaling in the midbrain periaqueductal gray: implications on analgesia

Chronic pain is under-managed in individuals over 65 years of age due to a dearth of knowledge regarding the impact of age on opioid efficacy in the elderly. We have previously shown that advanced age and sex alter morphine modulation of persistent inflammatory pain (induced by intraplantar administration of Complete Freund's adjuvant (CFA)), such that morphine potency is highest in adult male rats (2mos), with EC50 values 2-fold higher in aged males (18mos) and females regardless of age. Age-induced reductions in morphine potency were accompanied by reduced mu opioid receptor (MOR) expression in the ventrolateral periaqueductal gray (vlPAG), a CNS region critical in pain modulation. The present studies further explore the impact of age on opioid signaling within the PAG. MOR affinity, availability, and G-protein activation were assessed using radioligand binding assays and GTPγS assays in vlPAG tissue from adult and aged, male and female rats collected 72h following CFA administration. Regulation of opioid induced G-protein signaling was assessed using RNAscope to analyze mRNA expression of Regulator of G-Protein Signaling (RGS) proteins RGS4 and RGS9-2. We find that aged males and females (adult and aged) exhibit reduced vlPAG MOR binding potential and reduced G-protein activation efficiency compared to adult males, suggesting age- and sex- differences in MOR machinery drive reduced opioid potency. RNAscope revealed increased expression of RGS4 and RGS9-2 in the vlPAG of aged animals compared to adults, indicating that MOR signaling is subject to greater negative regulation in the aged vlPAG. The observed age-related reductions in vlPAG MOR agonist binding and opioid induced G-protein activation, along with the observed increase in vlPAG RGS expression have significant implications in pain management in the aged population. Our novel findings elucidate several mechanisms mediating reduced morphine potency in aged animals, and identify potential targets to improve pain management in the elderly. R01DA041529-04.

Adult Attachment System Links With Brain Mu Opioid Receptor Availability In Vivo

BackgroundSecure attachment is important in maintaining an individual’s health and well-being. Attachment disturbances increase the risk for developing psychiatric disorders such as affective disorders. Yet, the neurobiological correlates of human attachment are poorly understood at the neurotransmitter level. We investigated whether adult attachment style is linked to functioning of the opioid and serotonergic systems in the human brain. MethodsWe used positron emission tomography with radioligands [11C]carfentanil and [11C]MADAM to quantify mu opioid receptor (n = 39) and serotonin transporter (n = 37) availability in volunteers with no current psychiatric disorders. Attachment style was determined according to the Dynamic-Maturational Model of Attachment and Adaptation with the structured Adult Attachment Interview. ResultsSecure attachment was associated with higher mu opioid receptor availability in the hippocampus, amygdala, thalamus, and prefrontal cortex when compared with insecure (i.e., avoidant or ambivalent groups combined) attachment. In contrast, attachment style was not associated with serotonin transporter availability. ConclusionsOur results provide preliminary in vivo evidence that the opioid system may be involved in the neurocircuits associated with individual differences in adult attachment behavior. The results suggest that variation in mu opioid receptor availability may be linked with the individuals’ social relationships and psychosocial well-being and thus contributes to risk for psychiatric morbidity.

Lowered endogenous mu-opioid receptor availability in subclinical depression and anxiety.

Major depressive disorder is associated with lowered mood, anxiety, anhedonia, sleep problems, and cognitive impairments. Many of these functions are regulated by μ-opioid receptor (MOR) system. Preclinical, in vivo, and post-mortem studies have however yielded inconclusive results regarding the role of the MOR in depression and anxiety. Moreover, it is not known whether alterations in MOR are already present in subclinical depression and anxiety. In a large-scale retrospective cross-sectional study we pooled data from 135 (113 males and 22 females) healthy subjects whose brain’s MOR availability was measured with positron emission tomography (PET) using an agonist radioligand [11C]carfentanil that has high affinity for MORs. Depressive and anxious symptomology was addressed with BDI-II and STAI-X questionnaires, respectively. Both anxiety and depression scores in the subclinical range were negatively associated with MOR availability in cortical and subcortical areas, notably in amygdala, hippocampus, ventral striatum, and orbitofrontal and cingulate cortices. We conclude that dysregulated MOR availability is involved in altered mood and pathophysiology of depression and anxiety disorders.

O5.5. THE NEUROBIOLOGY OF NEGATIVE SYMPTOMS IN SCHIZOPHRENIA: MULTI-MODAL PET AND FMRI FINDINGS

BackgroundThe neurobiological mechanisms underlying anhedonia and other negative symptoms in schizophrenia are unknown. Understanding this would help identify treatments for these symptoms. Pre-clinical and human evidence shows the mu-opioid receptor plays a key role in reward processing and anhedonia. However, the contribution of Mu Opioid Receptor (MOR) signalling to negative symptoms and the reward processing abnormalities in schizophrenia is unknown. Here, we investigated for the first time in vivo in patients whether MOR availability is altered in schizophrenia and if this is associated with the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging.MethodsForty volunteers (n=20 patients with schizophrenia and 20 age and sex-matched healthy controls) received an [11C]-carfentanil PET scan to measure MOR availability, a structural MRI scan and a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. All the patients met criteria for persistent negative symptoms. Our primary ROI for the PET analysis was the striatum. In addition, we analysed MOR availability in brain regions in the hedonic network (the striatum, insula and anterior cingulate cortex). The fMRI analysis focused on brain regions in this hedonic network as these have previously associated with MOR mediated reward processing in humans and preclinical studies. Brain volumes of regions of interest (ROIs) were also extracted.ResultsThe analysis showed significantly lower MOR availability in the striatum of patients with schizophrenia relative to controls (patients vs. controls (mean binding potential (BPND) ± SEM): 1.54 ± 0.06 vs. 1.7 ± 0.05, Cohen’s d= 0.7, t=-2.2, df (37), p<0.05). There was also a significant effect of both group (F (5, 222) = 334.5, p<0.05) and ROI (F (1, 222) = 5.65, p<0.05) on BPND measures in the hedonic brain network. The group* ROI interaction was not significant (F (5, 222) = 0.2167, p>0.05). There were no significant differences in the volume of the striatum or other brain regions between groups (patients vs controls: mean ± SEM (mm3) 13019 ± 302 vs 12937 ± 327 respectively, p = 0.86).Reward anticipation in controls was associated with increased neural activation in a widespread network of brain regions including the ventral striatum and insula. The activation in the ventral striatum was significantly lower in patients compared to healthy controls. MOR availability was positively correlated with neural activation in the insula during reward anticipation in controls (spearman’s rho=0.6, p=0.006) but not in patients (spearman’s rho=0.13, p=0.57). In contrast, MOR availability in the striatum was not associated with neural activation in the striatum.DiscussionThese data show for the first time in vivo that mu-opioid receptor availability is lower in schizophrenia across the hedonic brain network. Moreover, patients with schizophrenia show altered coupling between mu-opioid signalling in the insula and brain activation during reward anticipation. These findings identify the mu-opioid receptor as a potential therapeutic target for reward dysfunction in schizophrenia.

Reduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging

Negative symptoms, such as amotivation and anhedonia, are a major cause of functional impairment in schizophrenia. There are currently no licensed treatments for negative symptoms, highlighting the need to understand the molecular mechanisms underlying them. Mu-opioid receptors (MOR) in the striatum play a key role in hedonic processing and reward function and are reduced post-mortem in schizophrenia. However, it is unknown if mu-opioid receptor availability is altered in-vivo or related to negative symptoms in schizophrenia. Using [11 C]-carfentanil positron emission tomography (PET) scans in 19 schizophrenia patients and 20 age-matched healthy controls, here we show a significantly lower MOR availability in patients with schizophrenia in the striatum (Cohen’s d = 0.7), and the hedonic network. In addition, we report a marked global increase in inter-regional covariance of MOR availability in schizophrenia, largely due to increased cortical-subcortical covariance.

Positron Emission Tomography: Updates on Imaging of Addiction.

Positron Emission Tomography: Updates on Imaging of Addiction.

(221) μ-Opioid Receptor Binding Potential is Higher among Non-Hispanic Black Compared to Non-Hispanic White Adults

Ethnic group differences in pain perception and prevalence have been well documented. These disparities persist despite controlling for other factors (e.g., sex, socioeconomic status), suggesting differences in endogenous pain modulation. One potential mechanism underlying this disparity might be differences in mu-opioid receptor (MOPR) function, given that MOPRs critically contribute to pain modulation. Previous work demonstrated racial differences in the association between the MOPR gene (OPRM1) and pain perception; however, no study has reported whether differences in MOPR physiology support these genetic findings. The present study sought to address this knowledge gap by examining differences between 24 Black and 26 age-, sex-, education-matched White healthy participants in mu-selective agonist binding (i.e., [ 11 C]-Carfentanil) during a 90-minute dynamic high resolution research tomograph PET imaging session. Participants underwent two counterbalanced scans following application of: 1) 10% capsaicin cream to induce pain and 2) a control cream. Only data from the control scan are presented. Participants also completed a battery of quantitative sensory testing to quantify pain sensitivity outside of the scanner. PET volumes of interest (VOIs) analysis (40 VOIs) demonstrated significant differences between Black and White participant groups in [ 11 C]-Carfentanil binding potential in left dorsolateral prefrontal cortex (dlPFC) and right ventral striatum (vS) VOIs after Bonferroni correction [dlPFC: t48=3.6, p p .001). Results suggest that Black individuals might have greater MOPR availability due to lower MOPR occupancy by endogenous opioids than White peers, with higher binding potential (i.e., lower endogenous opioid binding) associated with greater pain sensitivity across the sample. If replicated, findings have implications for physiological differences underlying ethnicity-related pain disparities, highlighting the need for tailored treatments in historically underserved populations.

Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects.

Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [11C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300-360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.

Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol-dependent individuals

Addiction has been proposed as a ‘reward deficient’ state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.

Binge eating disorder and morbid obesity are associated with lowered mu-opioid receptor availability in the brain

Both morbid obesity and binge eating disorder (BED) have previously been linked with aberrant brain opioid function. Behaviorally these two conditions are however different suggesting also differences in neurotransmitter function. Here we directly compared mu-opioid receptor (MOR) availability between morbidly obese and BED subjects. Seven BED and nineteen morbidly obese (non-BED) patients, and thirty matched control subjects underwent positron emission tomography (PET) with MOR-specific ligand [11C]carfentanil. Both subjects with morbid obesity and BED had widespread reduction in [11C]carfentanil binding compared to control subjects. However, there was no significant difference in brain MOR binding between subjects with morbid obesity and BED. Thus, our results indicate that there is common brain opioid abnormality in behaviorally different eating disorders involving obesity.

Tobacco Smoking and Brain Endogenous Opioid Release: More Than Nicotine Alone.

The effects of smoking denicotinized (denic) and average nicotine (avnic) tobacco cigarettes were studied on brain mu opioid receptor binding by positron emission tomography with 11C carfentanil. The results indicated the importance of physiological and psychological effects induced by denic smoking. Regional mu opioid binding potential (nondisplaceable binding potential, BPND) was measured in 20 adult male overnight abstinent chronic tobacco smokers. The denic sessions were conducted about 8:00 am followed by avnic sessions about 2 hours later. Venous plasma nicotine levels and scores of craving to smoke were assessed before and after each smoking session. Fagerstrom scores of nicotine dependence were determined. Pearson's and Spearman's correlation tests were used to examine associations between BPND and other smoking parameters. Surprisingly, the very low plasma nicotine peak levels after denic smoking (mean ± SD: 3.3 ± 1.8 ng/mL) were significantly correlated with BPND after denic and avnic smoking. Equally surprising no association was found between nicotine levels after avnic smoking and BPND. Delta craving scores and Fagerstrom scores were correlated with both BPND after denic and avnic in several brain regions. Very small amounts of nicotine, psychological and behavioral effects of denic smoking appear to have important actions on the endogenous mu opioid system. Associations between very low venous plasma nicotine levels after denic smoking and regional brain mu opioid receptor availability are a surprising "placebo" effect. Delta craving and Fagerstrom scores were correlated with BPND in several brain regions including amygdala, hippocampus, insula, nucleus accumbens, putamen, and ventral striatum. This study is limited by modest Power (mean 1 - β = 0.6) for all correlation analyses.

Reaching out for Sensitive Evaluation of the Mu Opioid Receptor in Vivo: Positron Emission Tomography Imaging of the Agonist [11C]AH7921.

Imaging of the mu opioid receptor (MOR) availability with positron emission tomography (PET) is a pertinent challenge in Neuroscience. Both, regulation of receptor expression and occupancy by endogeneous opioids play into cognitive and behavioral phenotypes of healthy function and disease. Receptor expression in the active and inactive states can be measured using high affinity radioagonist and radioantagonist PET tracers, respectively. Occupancy assessment requires radioligands showing competitive and reversible binding with moderate affinity to the MOR, which may lead to physical extinction of the receptor specific signal in vivo. We investigated a moderately potent, selective MOR agonist in rat to test if a radiotracer design paradigm tailored to competition with endogeneous opioids leads to viable imaging results. The benzamide 3,4-dichlorobenzenecarboxylic acid (dimethylamino)cyclohexyl)methyl amide (AH-7921, 1) was synthesized and characterized in rat brain using autoradiography and positron emission tomography. Compound 1 was found to activate with low nanomolar potency the MOR and to a lesser extent KOR as a full agonist. Concentration dependent binding studies with agonist and antagonist radioligands were conducted to assess competition behavior and obtain inhibition constants. Kinetic analysis of 3,4-dichlorobenzene[11C]carboxylic acid (dimethylamino)cyclohexyl)methyl amide binding in rat brain resulted in low but reproducible binding potential in the thalamus (0.8 ± 0.1). A radioactive metabolite was detected in brain (17%, after 15 min). Nonetheless, we conclude that quantitative imaging of MOR availability is possible when using a moderate affinity radiotracer.

Dopamine and Opioid Neurotransmission in Behavioral Addictions: A Comparative PET Study in Pathological Gambling and Binge Eating.

Although behavioral addictions share many clinical features with drug addictions, they show strikingly large variation in their behavioral phenotypes (such as in uncontrollable gambling or eating). Neurotransmitter function in behavioral addictions is poorly understood, but has important implications in understanding its relationship with substance use disorders and underlying mechanisms of therapeutic efficacy. Here, we compare opioid and dopamine function between two behavioral addiction phenotypes: pathological gambling (PG) and binge eating disorder (BED). Thirty-nine participants (15 PG, 7 BED, and 17 controls) were scanned with [11C]carfentanil and [18F]fluorodopa positron emission tomography using a high-resolution scanner. Binding potentials relative to non-displaceable binding (BPND) for [11C]carfentanil and influx rate constant (Ki) values for [18F]fluorodopa were analyzed with region-of-interest and whole-brain voxel-by-voxel analyses. BED subjects showed widespread reductions in [11C]carfentanil BPND in multiple subcortical and cortical brain regions and in striatal [18F]fluorodopa Ki compared with controls. In PG patients, [11C]carfentanil BPND was reduced in the anterior cingulate with no differences in [18F]fluorodopa Ki compared with controls. In the nucleus accumbens, a key region involved in reward processing, [11C]Carfentanil BPND was 30-34% lower and [18F]fluorodopa Ki was 20% lower in BED compared with PG and controls (p<0.002). BED and PG are thus dissociable as a function of dopaminergic and opioidergic neurotransmission. Compared with PG, BED patients show widespread losses of mu-opioid receptor availability together with presynaptic dopaminergic defects. These findings highlight the heterogeneity underlying the subtypes of addiction and indicate differential mechanisms in the expression of pathological behaviors and responses to treatment.

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers.

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [11C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [11C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [11C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [11C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.