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Background: Measuring changes in dopamine (DA) levels in humans using radioligand-displacement studies and positron emission tomography (PET) has provided important empirical findings in disease and normal neurophysiology. These studies are based on the assumption that DA exerts a competitive inhibition on radioligand binding. To test this, we used PET and a Scatchard approach to investigate whether the decrease in [11C]raclopride binding following amphetamine results from competitive or noncompetitive interactions with DA.Methods: Scatchard analyses of [11C]raclopride/PET data were used to quantify changes in apparent D2-receptor density (Bmax) and radioligand apparent affinity (K′D) at baseline and after amphetamine pretreatment (2 mg/kg; intravenous) in cats.Results: Amphetamine induced a 46% decrease in [11C]raclopride binding in the striatum of five cats. Scatchard analyses revealed that this decrease in binding was due to a 28% decrease in Bmax and a concomitant 35% increase in K′D.Conclusions: Competition with DA is an insufficient explanation for the decrease in [11C]raclopride binding observed after amphetamine. Noncompetitive interactions, likely representing D2-receptor internalization, also play an important role in this phenomenon. This finding may have important implications for the interpretation of amphetamine–raclopride PET studies in schizophrenia because dysregulation of the agonist-induced internalization of D2 receptors was recently suggested in this disorder. [Copyright &y& Elsevier]

Background: Dopamine D3 receptors are involved in the pathophysiology of several neuropsychiatric conditions. [11C]-(+)-PHNO is a radiolabeled D2 and D3 agonist, suitable for imaging the agonist binding sites (denoted D2HIGH and D3) of these receptors with positron emission tomography (PET). PET studies in nonhuman primates documented that, in vivo, [11C]-(+)-PHNO displays a relative selectivity for D3 compared with D2HIGH receptor sites and that the [11C]-(+)-PHNO signal is enriched in D3 contribution compared with conventional ligands such as [11C] raclopride. Methods: To define the D3 contribution () to [11C]-(+)-PHNO binding potential (BPND) in healthy humans, 52 PET scans were obtained in 19 healthy volunteers at baseline and following oral administration of various doses of the selective D3 receptor antagonist, GSK598809. Results: The impact of GSK598809 on [11C]-(+)-PHNO was regionally selective. In dorsal regions of the striatum, GSK598809 did not significantly affect [11C]-(+)-PHNO BPND ( ≈ 0%). Conversely, in the substantia nigra, GSK598809 dose-dependently reduced [11C]-(+)-PHNO binding to nonspecific level ( ≈ 100%). In ventral striatum (VST), globus pallidus and thalamus (THA), [11C]-(+)-PHNO BPND was attributable to a combination of D2HIGH and D3 receptor sites, with of 26%, 67% and 46%, respectively. D3 receptor binding potential () was highest in globus pallidus (1.90) and substantial nigra (1.39), with lower levels in VST (.77) and THA (.18) and negligible levels in dorsal striatum. Conclusions: This study elucidated the pharmacologic nature of the [11C]-(+)-PHNO signal in healthy subjects and provided the first quantification of D3 receptor availability with PET in the living human brain. [Copyright &y& Elsevier]

Background: The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated LA and LG. Only LA is associated with high levels of in vitro 5-HTT expression, whereas LG is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([11C]DASB) positron emission tomography. Methods: The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. Results: The LA/LA was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. Conclusions: The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy LA/LA carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the LA/LA genotype into in vivo brains of healthy human subjects. [Copyright &y& Elsevier]

Background: The high-affinity states of dopamine D2-receptors (D2high) are postulated to be functionally responsible for signal transduction. At present, no useful in vivo method exists to selectively measure D2high in humans, as current D2 radioligands for positron emission tomography (PET) are either not D2-selective or do not differentiate between D2 high- and low-affinity states. Methods: The D2-agonist (+)-PHNO [(+)4-propyl-9-hydroxynaphthoxazine] was labeled with carbon-11 and studied with PET. Eight [11C]-(+)-PHNO scans were acquired in four healthy volunteers. Results: We observed greatest [11C]-(+)-PHNO accumulation in caudate, putamen, and globus pallidus [binding potentials (BPs): 3.00 ± .4, 3.10 ± .2, and 4.17 ± 1.2]. Small but detectable binding was identified in the substantia nigra/ventral tegmental area. Preliminary test-retest data in two subjects suggests BP-estimates to be reliable. Pre-treatment with haloperidol reduced BPs in regions showing specific binding with no detectable changes in cerebellum. Parallel imaging with [11C]-raclopride showed substantial differences in the globus pallidus. Conclusions: [11C]-(+)-PHNO proved to be a D2/3-receptor agonist-radioligand with good brain uptake and favorable kinetics for PET in humans. [11C]-(+)-PHNO delineated D2/3-receptor rich brain regions with high signal-to-noise ratio. This is the first demonstration of a viable agonist-radioligand for D2 receptors in humans and opens the door for investigating D2high in health and disease. [Copyright &y& Elsevier]

Recurrence of depressive symptoms after tryptophan depletion (TD) in selective serotonin reuptake inhibitor (SSRI)-treated depression is an important, unexplained phenomenon. With [18F] MPPF positron emission tomography (PET), serotonin (5-hydroxytryptamine, 5-HT) 1A receptor binding potential (5-HT1ABP) was measured after TD in various brain regions in citalopram-treated depression. This 5-HT1ABP measurement is sensitive to changes in extracellular 5-HT in animal models.Eight remitted patients with major depressive disorder received [18F] MPPF PET scans twice: once after TD and once after sham depletion. Behavioral measures were evaluated with the Hamilton Depression Rating Scale and visual analog scales.No effect on regional 5-HT1ABP was observed after TD, despite an 86% decrease in total plasma tryptophan and transient depressive relapse in six of eight patients.Large-magnitude changes in extracellular 5-HT are not crucial for the mood effects observed in SSRI-treated subjects after TD. Therefore, greater consideration must be given to other mechanisms that involve vulnerability to small perturbations in extracellular 5-HT, such as impairment of signal transduction. [Copyright &y& Elsevier]

Background: Reductions in fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid anandamide, may play a role in drinking behavior and risk for alcohol use disorder. We tested the hypotheses that lower brain FAAH levels in heavy-drinking youth are related to increased alcohol intake, hazardous drinking, and differential response to alcohol., Methods: FAAH levels in the striatum, prefrontal cortex, and whole brain were determined using positron emission tomography imaging of [ 11 C]CURB in heavy-drinking youth (N = 31; 19-25 years of age). C385A FAAH genotype (rs324420) was determined. Behavioral (n = 29) and cardiovascular (n = 22) responses to alcohol were measured during a controlled intravenous alcohol infusion., Results: Lower [ 11 C]CURB binding was not significantly related to frequency of use but was positively associated with hazardous drinking and reduced sensitivity to the negative effects of alcohol. During alcohol infusion, lower [ 11 C]CURB binding related to greater self-reported stimulation and urges and lower sedation (p < .05). Lower heart rate variability was related to both greater alcohol-induced stimulation and lower [ 11 C]CURB binding (p < .05). Family history of alcohol use disorder (n = 14) did not relate to [ 11 C]CURB binding., Conclusions: In line with preclinical studies, lower FAAH in the brain was related to a dampened response to the negative, impairing effects of alcohol, increased drinking urges, and alcohol-induced arousal. Lower FAAH might alter positive or negative effects of alcohol and increase urges to drink, thereby contributing to the addiction process. Determining whether FAAH influences motivation to drink through increased positive/arousing effects of alcohol or greater tolerance should be investigated., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)