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1.
Brain Sci ; 13(10)2023 Sep 27.
Article in English | MEDLINE | ID: mdl-37891745

ABSTRACT

BACKGROUND: Endocannabinoids and related N-acylethanolamines (NAEs) are bioactive lipids with important physiological functions and putative roles in mental health and addictions. Although chronic cannabis use is associated with endocannabinoid system changes, the status of circulating endocannabinoids and related NAEs in people with cannabis use disorder (CUD) is uncertain. METHODS: Eleven individuals with CUD and 54 healthy non-cannabis using control participants (HC) provided plasma for measurement by high-performance liquid chromatography-mass spectrometry of endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and related NAE fatty acids (N-docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA)). Participants were genotyped for the functional gene variant of FAAH (rs324420, C385A) which may affect concentrations of AEA as well as other NAEs (OEA, DHEA). RESULTS: In overnight abstinent CUD, AEA, OEA and DHEA concentrations were significantly higher (31-40%; p < 0.05) and concentrations of the endocannabinoid 2-AG were marginally elevated (55%, p = 0.13) relative to HC. There were no significant correlations between endocannabinoids/NAE concentrations and cannabis analytes, self-reported cannabis use frequency or withdrawal symptoms. DHEA concentration was inversely related with marijuana craving (r = -0.86; p = 0.001). Genotype had no significant effect on plasma endocannabinoids/NAE concentrations. CONCLUSIONS: Our preliminary findings, requiring replication, might suggest that activity of the endocannabinoid system is elevated in chronic cannabis users. It is unclear whether this elevation is a compensatory response or a predating state. Studies examining endocannabinoids and NAEs during prolonged abstinence as well as the potential role of DHEA in craving are warranted.

2.
Neuropsychopharmacology ; 46(12): 2112-2120, 2021 11.
Article in English | MEDLINE | ID: mdl-34349232

ABSTRACT

Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [11C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n = 17; 6.59 ± 4.14 days of abstinence) and healthy controls (n = 18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [11C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk's Λ = .58, F(6,28) =3.33, p = 0.013, η2p = 0.42), however there were no region-specific differences. Binding values demonstrate -12.3% and -16.1% lower [11C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [11C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r = 0.66, p = 0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.


Subject(s)
Alcoholism , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Alcohol Drinking , Alcoholism/diagnostic imaging , Brain/diagnostic imaging , Brain/metabolism , Humans , Oxazines , Positron-Emission Tomography , Protein Binding , Receptors, Dopamine D2/genetics , Receptors, Dopamine D3/genetics
3.
Sci Rep ; 11(1): 11667, 2021 06 03.
Article in English | MEDLINE | ID: mdl-34083612

ABSTRACT

Stimuli previously paired with drugs of dependence can produce cravings that are associated with increased dopamine (DA) levels in limbic and striatal brain areas. Positron Emission Tomography (PET) imaging with [11C]-(+)-PHNO allows for a sensitive measurement of changes in DA levels. The purpose of the present study was to investigate changes in DA levels, measured with PET imaging with [11C]-(+)-PHNO, in regions of interest in smokers who had maintained abstinence for 7-10 days. Participants (N = 10) underwent two PET scans on separate days, during which they viewed either smoking-related or neutral images, in counterbalanced order. Craving was measured with the 12-item Tobacco Craving Questionnaire (TCQ) and the Questionnaire on Smoking Urges-Brief (QSU-B). Compared to neutral cues, smoking cues did not increase craving. There were no changes in [11C]-(+)-PHNO binding in the cue condition compared to the neutral condition for most regions of interest (ventral pallidum, globus pallidus, limbic striatum, associative striatum, sensorimotor striatum). However, binding potential in the substantia nigra was greater in the smoking-cue condition, indicating decreased synaptic dopamine. There is a potential change of DA level occurring in midbrain following the presentation of smoking-related cues. However, this preliminary finding would need to be validated with a larger sample.


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Carbon Radioisotopes , Positron-Emission Tomography/methods , Radiopharmaceuticals , Smokers , Adult , Biomarkers , Craving , Dopamine/metabolism , Female , Humans , Male , Middle Aged , Tobacco Smoking , Tobacco Use Disorder/diagnostic imaging , Tobacco Use Disorder/metabolism , Young Adult
4.
Br J Pharmacol ; 177(15): 3464-3472, 2020 08.
Article in English | MEDLINE | ID: mdl-32293706

ABSTRACT

BACKGROUND AND PURPOSE: BF2.649 (pitolisant, Wakix®) is a novel histamine H3 receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H3 receptors by BF2.649 using PET brain imaging with the H3 receptor antagonist radioligand [11 C]GSK189254. EXPERIMENTAL APPROACH: Six healthy adult participants were scanned with [11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 h after oral administration of placebo or after pitolisant hydrochloride (40 mg). [11 C]GSK189254 regional total distribution volumes were estimated in nine brain regions of interest with the two tissue-compartment model with arterial input function using a common VND across the regions. Brain receptor occupancies were calculated with the Lassen plot. KEY RESULTS: Pitolisant, at the dose administered, provided high (84 ± 7%; mean ± SD) occupancy of H3 receptors. The drug was well-tolerated, and participants experienced few adverse events. CONCLUSION AND IMPLICATIONS: The administration of pitolisant (40 mg) produces a high occupancy of H3 receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H3 receptors.


Subject(s)
Histamine , Receptors, Histamine H3 , Adult , Histamine Agonists , Humans , Piperidines , Positron-Emission Tomography
5.
Neuropsychopharmacology ; 45(8): 1289-1296, 2020 07.
Article in English | MEDLINE | ID: mdl-31910433

ABSTRACT

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3-7 days (n = 14) and 2-4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30-67%). No significant differences in FAAH or FAAH substrates were noted after 2-4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = -0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.


Subject(s)
Alcoholism , Alcoholism/diagnostic imaging , Amidohydrolases/metabolism , Brain/diagnostic imaging , Brain/metabolism , Carbon Radioisotopes , Endocannabinoids , Humans , Pilot Projects , Positron-Emission Tomography
6.
Neuropsychopharmacology ; 45(5): 745-752, 2020 04.
Article in English | MEDLINE | ID: mdl-31775159

ABSTRACT

The endocannabinoid and dopaminergic systems have independently been implicated in substance use disorder and obesity. We investigated a potential interaction between genetically inherited variation in fatty acid amide hydrolase (FAAH, C385A), which metabolizes the cannabis-like endocannabinoid anandamide, and dopaminergic system, measured by dopamine receptor levels and mRNA. Binding of the dopamine D3 preferring probe [C-11]-(+)-PHNO was measured with positron emission tomography (PET) in 79 human subjects genotyped for the FAAH C385A polymorphism (36/79 AC + AA). Autoradiography with [H-3]-(+)-PHNO and in situ hybridization with a D3-specific S-35 riboprobe were carried out in 30 knock-in mice with the FAAH C385A polymorphism (20/30 AC + AA). We found that the FAAH genetic variant C385A was associated with significantly higher (+)-PHNO binding in both humans and in knock-in mice, and this effect was restricted to D3 selective brain regions (limbic striatum, globus pallidus, and ventral pallidum (9-14%; p < 0.04) in humans and Islands of Calleja (28%; p = 0.036) in mice). In situ hybridization with a D3-specific S-35 riboprobe in FAAH knock-in C385A mice confirmed significantly increased D3 receptor mRNA across examined regions (7-44%; p < 0.02). The association of reduced FAAH function with higher dopamine D3 receptors in human and mouse brain provide a mechanistic link between two brain systems that have been implicated in addiction-risk. This may explain the greater vulnerability for addiction and obesity in individuals with C385A genetic variant and by extension, suggest that a D3 antagonism strategy in substance use disorders should consider FAAH C385A polymorphism.


Subject(s)
Amidohydrolases/metabolism , Brain/metabolism , Receptors, Dopamine D3/genetics , Receptors, Dopamine D3/metabolism , Substance-Related Disorders/enzymology , Adult , Aged , Animals , Autoradiography , Female , Gene Knock-In Techniques , Humans , Male , Mice , Middle Aged , Mutation, Missense , Polymorphism, Single Nucleotide , Positron-Emission Tomography , RNA, Messenger/metabolism , Substance-Related Disorders/genetics , Young Adult
7.
Neuropsychopharmacology ; 44(7): 1284-1290, 2019 06.
Article in English | MEDLINE | ID: mdl-30659274

ABSTRACT

There has been considerable interest in the development of dopamine D3 receptor (DRD3) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD3 partial agonists. Here we investigate for the first time in healthy controls, the in vivo occupancy of a novel D3 partial agonist (BP1.4979) at the DRD3 and DRD2. Participants received either a single dose (1, 3, 10 or 30 mg) or a subchronic regimen (5-7 days, q.d. or b.i.d) of BP1.4979, with the last dose given at 1, 12 or 24 h prior to scanning with [11C]-(+)-PHNO. Single and subchronic administration of BP1.4979 dose-dependently occupied the DRD3 and DRD2, and this occupancy was preferential for the DRD3, notably at longer time points after administration of BP1.4979. Also consistent with preference for the DRD3, prolactin levels were minimally increased, and no subjective effects of BP1.4979 were reported. Serum levels of BP1.4979 were higher than its active metabolite, BP1.6239, while no notable increases in the inactive metabolite, BP1.6197, were found. These findings indicate the range of doses that can be used to occupy selectively the DRD3 over the DRD2 with BP1.4979 and speak to the use of in vivo imaging approaches in dose finding studies.


Subject(s)
Brain/drug effects , Brain/metabolism , Dopamine Agonists/pharmacokinetics , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/agonists , Receptors, Dopamine D3/metabolism , Adult , Dopamine Agonists/administration & dosage , Dose-Response Relationship, Drug , Drug Partial Agonism , Female , Humans , Male , Oxazines , Positron-Emission Tomography
8.
Int J Neuropsychopharmacol ; 21(6): 503-512, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29346545

ABSTRACT

Background: Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, affects multiple aspects of nicotine dependence. Fast nicotine metabolizers tend to smoke more, experience more withdrawal and craving, and have lower cessation rates compared with slow metabolizers. The nicotine metabolite ratio predicts treatment response, and differences in brain activation between fast metabolizers and slow metabolizers have been reported in fMRI studies. As reinforcing/rewarding effects of tobacco are associated with dopamine transmission, the purpose of the present study was to study the dopaminergic system in human smokers based on their nicotine metabolite ratio. Methods: The first aim of the study was to explore if there were differences in D2 and D3 receptor binding between fast metabolizers and slow metabolizers during abstinence. The second aim was to explore smoking-induced dopamine release in both groups. Participants underwent 2 [11C]-(+)-PHNO PET scans: one scan during abstinence and the other after smoking a tobacco cigarette. Subjective measures were recorded and blood was drawn for measurement of nicotine and cotinine levels. Results: During abstinence, slow metabolizers (n = 13) had lower [11C]-(+)-PHNO binding potential than fast metabolizers (n = 15) restricted to the D2 regions of the associative striatum and sensorimotor striatum. After smoking a cigarette, [11C]-(+)-PHNO binding potential was decreased in the limbic striatum and ventral pallidum, suggestive of increases in dopamine, but there were no nicotine metabolite ratio differences. Conclusions: Further studies are required to delineate if differences in [11C]-(+)-PHNO binding between slow metabolizers and fast metabolizers at abstinence baseline are preexisting traits or induced by prolonged tobacco use.


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Nicotine/metabolism , Oxazines/metabolism , Tobacco Use Disorder/diagnostic imaging , Tobacco Use Disorder/metabolism , Adult , Carbon Isotopes , Cotinine/metabolism , Female , Humans , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/metabolism , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Substance Withdrawal Syndrome/diagnostic imaging , Substance Withdrawal Syndrome/metabolism , Tobacco Smoking/metabolism
9.
Synapse ; 71(7)2017 07.
Article in English | MEDLINE | ID: mdl-28233334

ABSTRACT

Interest in a role for norepinephrine (NE) in substance use disorders has increased over recent years. In particular, its interaction with dopamine (DA) is of importance. In this study, positron emission tomography (PET) was used to explore the impact of prazosin (an alpha 1 NE antagonist) on DA levels. Healthy volunteers were administered prazosin for approximately 4 weeks at the daily dose of 15 mg to reach steady state. Participants were scanned with PET imaging and the [11 C]-(+)-PHNO tracer at baseline (before prazosin), at steady state, and after a wash out period. Prazosin administration was associated with an increase of [11 C]-(+)-PHNO binding potential in the dorsal caudate relative to baseline, which corresponds to a decrease in DA levels. This study is the first to demonstrate interactions between DA and NE in healthy humans.


Subject(s)
Adrenergic alpha-1 Receptor Antagonists/pharmacology , Brain/drug effects , Brain/metabolism , Dopamine/metabolism , Prazosin/pharmacology , Adult , Brain/diagnostic imaging , Brain Mapping , Female , Humans , Male , Middle Aged , Oxazines , Pilot Projects , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, Adrenergic, alpha-1/metabolism , Young Adult
10.
Psychoneuroendocrinology ; 76: 192-196, 2017 02.
Article in English | MEDLINE | ID: mdl-27951520

ABSTRACT

Corticotropin-releasing hormone (CRH) is a key component of the neuroendocrine response to stress. In animal models, CRH has been shown to modulate dopamine release, and this interaction is believed to contribute to stress-induced relapse in neuropsychiatric disorders. Here we investigated whether CRH administration induces dopamine release in humans, using positron emission tomography (PET). Eight healthy volunteers (5 female, 22-48 years old) completed two PET scans with the dopamine D2/3 receptor radioligand [11C]-(+)-PHNO: once after saline injection, and once after injection of corticorelin (synthetic human CRH). We also assessed subjective reports and measured plasma levels of endocrine hormones (adrenocorticotropic hormone and cortisol). Relative to saline, corticorelin administration decreased binding of the D2/3 PET probe [11C]-(+)-PHNO, suggesting dopamine release. Endocrine stress markers were also elevated, in line with activation of the hypothalamic-pituitary-adrenal axis, but we detected no changes in subjective ratings. Preliminary results from this proof-of-concept study suggests that CRH challenge in combination with [11C]-(+)-PHNO PET may serve as an assay of dopamine release, presenting a potential platform for evaluating CRH/dopamine interactions in neuropsychiatric disorders and CRH antagonists as potential treatment avenues.


Subject(s)
Corticotropin-Releasing Hormone/pharmacology , Dopamine/metabolism , Globus Pallidus/metabolism , Mesencephalon/metabolism , Neostriatum/metabolism , Adult , Corticotropin-Releasing Hormone/administration & dosage , Dopamine Agonists/metabolism , Female , Globus Pallidus/diagnostic imaging , Healthy Volunteers , Humans , Male , Mesencephalon/diagnostic imaging , Middle Aged , Neostriatum/diagnostic imaging , Oxazines/metabolism , Positron-Emission Tomography , Young Adult
11.
Biol Psychiatry ; 80(9): 691-701, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27345297

ABSTRACT

BACKGROUND: One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. METHODS: Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine, and hair levels of cannabinoids and metabolites were determined. RESULTS: In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects (overall Cohen's d = 0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. CONCLUSIONS: Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.


Subject(s)
Amidohydrolases/metabolism , Brain/diagnostic imaging , Brain/metabolism , Marijuana Abuse/diagnostic imaging , Marijuana Abuse/metabolism , Positron-Emission Tomography/methods , Adult , Amygdala/diagnostic imaging , Amygdala/metabolism , Cannabinoids/blood , Cannabinoids/urine , Cannabis/metabolism , Carbon Radioisotopes , Dronabinol/blood , Dronabinol/urine , Female , Humans , Impulsive Behavior/drug effects , Male , Marijuana Abuse/enzymology
12.
Neuropsychopharmacology ; 41(2): 529-37, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26089182

ABSTRACT

There is considerable interest in blocking the dopamine D3 receptor (DRD3) versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.


Subject(s)
Brain/drug effects , Brain/metabolism , Buspirone/pharmacology , Dopamine Agents/pharmacology , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Administration, Oral , Adult , Brain/diagnostic imaging , Buspirone/adverse effects , Buspirone/blood , Carbon Radioisotopes , Dizziness/chemically induced , Dizziness/metabolism , Dopamine Agents/adverse effects , Dopamine Agents/blood , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Oxazines , Positron-Emission Tomography , Prolactin/blood , Single-Blind Method , Sleep Stages/drug effects , Sleep Stages/physiology , Young Adult
13.
J Cereb Blood Flow Metab ; 35(11): 1827-35, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26082009

ABSTRACT

Positron emission tomography with [(11)C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test-retest reliability of [(11)C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test-retest [(11)C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n=2 each). The composite parameter λk3 (an index of FAAH activity, λ=K1/k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [(11)C]CURB injection. Oral administration of PF-04457845 reduced [(11)C]CURB binding to a homogeneous level at all three doses, with λk3 values decreased by ⩾91%. Excellent reproducibility and good reliability (test-retest variability=9%; intraclass correlation coefficient=0.79) were observed across all regions of interest investigated. Our findings suggest that λk3/[(11)C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.


Subject(s)
Amidohydrolases/antagonists & inhibitors , Biphenyl Compounds , Brain/diagnostic imaging , Brain/enzymology , Carbamates , Enzyme Inhibitors/pharmacology , Pyridazines/pharmacology , Radiopharmaceuticals , Urea/analogs & derivatives , Adult , Binding, Competitive/drug effects , Biphenyl Compounds/pharmacokinetics , Brain/drug effects , Carbamates/pharmacokinetics , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Female , Healthy Volunteers , Humans , Image Processing, Computer-Assisted , Kinetics , Male , Middle Aged , Positron-Emission Tomography , Pyridazines/administration & dosage , Radiopharmaceuticals/pharmacokinetics , Reproducibility of Results , Urea/administration & dosage , Urea/pharmacology , Young Adult
14.
J Cereb Blood Flow Metab ; 35(8): 1237-40, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26036940

ABSTRACT

The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [(11)C]CURB ([(11)C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n=24) completed one [(11)C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [(11)C]CURB binding (λk3) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [(11)C]CURB measurement.


Subject(s)
Alleles , Amidohydrolases , Anxiety Disorders , Polymorphism, Single Nucleotide , Positron-Emission Tomography , Radiopharmaceuticals , Adult , Amidohydrolases/genetics , Amidohydrolases/metabolism , Anxiety Disorders/diagnostic imaging , Anxiety Disorders/genetics , Anxiety Disorders/metabolism , Female , Humans , Male , Middle Aged , Radiography , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/pharmacokinetics
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