Impulsive behavior is thought to reflect a trait-like characteristic that can have broad consequences for an individual’s success and well-being, but its neurobiological basis remains elusive. Although striatal dopamine D2-like receptors have been linked with impulsive behavior and behavioral inhibition in rodents, a role for D2-like receptor function in frontostriatal circuits mediating inhibitory control in humans has not been shown. We investigated this role in a study of healthy research participants who underwent positron emission tomography with the D2/D3 dopamine-receptor ligand [18F]fallypride, and blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) while they performed the Stop-signal Task, a test of response inhibition. Striatal dopamine D2/D3-receptor availability was negatively correlated with speed of response inhibition (stop-signal reaction time), and positively correlated with inhibition-related fMRI activation in frontostriatal neural circuitry. Correlations involving D2/D3 receptor availability were strongest in the dorsal regions (caudate and putamen) of the striatum, consistent with findings of animal studies relating dopamine receptors and response inhibition. The results suggest that striatal D2-like receptor function in humans plays a major role in the neural circuitry that mediates behavioral control, an ability that is essential for adaptive responding and is compromised in a variety of common neuropsychiatric disorders.
The Barratt Impulsiveness Scale Version 11 (BIS-11; Patton, Stanford & Barratt, 1995) is a gold-standard measure that has been influential in shaping current theories of impulse control, and has played a key role in studies of impulsivity and its biological, psychological, and behavioral correlates. Psychometric research on the structure of the BIS-11, however, has been scant. We therefore applied exploratory and confirmatory factor analyses to data collected using the BIS-11 in a community sample (N = 691). Our goal was to test four theories of the BIS-11 structure: (a) a unidimensional model; (b) a six correlated first-order factor model, (c) a three second-order factor model, and (d) a bifactor model. Among the problems identified were: (a) low or near-zero correlations of some items with others; (b) highly redundant content of numerous item pairs; (c) items with salient cross-loadings in multidimensional solutions; and ultimately; (d) poor fit to confirmatory models. We conclude that use of the BIS-11 total score as reflecting individual differences on a common dimension of impulsivity presents challenges in interpretation. Also, the theory that the BIS-11 measures three subdomains of impulsivity (attention, motor, and non-planning) was not empirically supported. A two-factor model is offered as an alternative multidimensional structural representation.
The cannabinoid CB 1 receptor is one of the most abundant G protein-coupled receptors in the brain and is a promising target of therapeutic drug development. Success of drug development for neuropsychiatric indications is significantly enhanced with the ability to directly measure spatial and temporal binding of compounds to receptors in central compartments. We assessed the utility of a new positron emission tomography (PET) radioligand to image CB 1 receptors in monkey brain. showed that the majority (489%) of brain uptake in regions with high receptor densities was specific and reversibly bound to CB 1 receptors in the high binding regions. [ 11 C]MePPEP was rapidly removed from arterial plasma. Regional brain uptake could be quantified as distribution volume relative to the concentration of parent radiotracer in plasma. The P-glycoprotein (P-gp) inhibitor DCPQ ((R)-4- [(1a,6,10b)-1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-[(5-quinolinyloxy)methyl]-1-piperazineethanol) did not significantly increase brain uptake of [ 11 C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood-brain barrier.[ 11 C]MePPEP is a radioligand with high brain uptake, high specific signal to CB 1 receptors, and adequately fast washout from brain that allows quantification with 11 C (half-life ¼ 20 min). These promising results in monkey justify studying this radioligand in human subjects.
Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D-amphetamine-induced and alpha-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [(18)F]fallypride binding in striatal and extrastriatal areas. Subjects underwent [18F]fallypride PET studies at baseline and following oral D-amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BP(ND)) of [18F]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BP(ND) was computed and correlated with change in cognition and mood. Test-retest variability of [18F]fallypride was low in both striatal and extrastriatal regions. D-Amphetamine significantly decreased BP(ND) by 8-14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BP(ND) and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [18F]fallypride BP(ND) in both striatum and extrastriatal regions. These findings indicate that [18F]fallypride is useful for measuring amphetamine-induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans.
2-fluoromethyl analogs of (3-[(2-methyl-1,3-thiazol-4yl)ethynyl]pyridine) were synthesized as potential ligands for metabotropic glutamate subtype-5 receptors (mGluR5s). One of these, namely, 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile (3), was found to have exceptionally high affinity (IC50 = 36 pM) and potency in a phosphoinositol hydrolysis assay (IC50 = 0.714 pM) for mGluR5. Compound 3 was labeled with fluorine-18 (t1/2 = 109.7 min) in high radiochemical yield (87%) by treatment of its synthesized bromomethyl analog (17) with [18F]fluoride ion and its radioligand behavior was assessed with positron emission tomography (PET). Following intravenous injection of [18F]3 into rhesus monkey, radioactivity was avidly taken up into brain with high uptake in mGluR5 receptor-rich regions such as striata. [18F]3 was stable in monkey plasma and human whole blood in vitro and in monkey and human brain homogenates. In monkey in vivo, a single polar radiometabolite of [18F]3 appeared rapidly in plasma. [18F]3 merits further evaluation as a PET radioligand for mGluR5 in human subjects.
Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BP ND )) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n = 10) or one that received equal-time health education training (n = 9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [ 18 F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BP ND . At baseline, striatal D2/D3 BP ND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BP ND , whereas those in the education group did not. There were no changes in D2/D3 BP ND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.
We developed a radioligand, 3-fluoro-5-(2-(2-18 F-(fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile ( 18 F-SP203), for metabotropic glutamate subtype 5 (mGluR5) receptors that showed both promising (high specific binding) and problematic (defluorination) imaging characteristics in animals. The purposes of this initial evaluation in human subjects were to determine whether 18 F-SP203 is defluorinated in vivo (as measured by uptake of radioactivity in the skull) and to determine whether the uptake in the brain can be quantified as distribution volume relative to concentrations of 18 F-SP203 in plasma. Methods: Seven healthy subjects were injected with 18 F-SP203 (323 6 87 MBq) and scanned over 5 h, with rest periods outside the camera. The concentrations of 18 F-SP203, separated from radiometabolites, were measured in arterial plasma. Results: The skull was difficult to visualize on PET images in the initial 2 h, because of high radioactivity in the brain. Although radioactivity in the skull and adjacent cortex showed some cross-contamination, the concentration of radioactivity in the skull was less than half of that in the adjacent cortex during the initial 2 h. Modeling of regional brain and plasma data showed that a 2-tissue-compartment model was superior to a 1-tissuecompartment model, consistent with measurable amounts of both receptor-specific and nonspecific binding. The concentrations of activity in the brain measured with PET were consistently greater than the modeled values at late but not early time points and may well have been caused by the slow accumulation of radiometabolites in the brain. To determine an adequate time for more accurate measurement of distribution volume, we selected a scan duration (i.e., 2 h) associated with maximal or near-maximal identifiability. Distribution volume was well identified (;2%) by only 2 h (and even just 1) of image acquisition. Conclusion: This initial evaluation of 18 F-SP203 in healthy human subjects showed that defluorination is relatively small and that brain uptake can be robustly calculated as distribution volume. The values of distribution volume were well identified and had relatively small variation in this group of 7 subjects. These results suggest that 18 F-SP203 will have good sensitivity to measure mGluR5 receptors for both within-subject studies (e.g., receptor occupancy) and between-subject studies (e.g., patients vs. healthy subjects).
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