-
Synapse (New York, N.Y.) Jan 2023The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and... (Meta-Analysis)
Meta-Analysis
The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and dopamine transporter (DAT) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to November 2020) and EMBASE (from inception to November 2020) for articles published in English using the keywords "dopamine receptor," "dopamine transporter," "obesity," and "neuroimaging." Body mass index (BMI) and the corresponding binding potential (BP ) were extracted from figures in each study using Engauge Digitizer, version 12.1, and plotted for radiopharmaceuticals and regions of interest (ROIs). Five studies involving 119 subjects with DR and five studies including 421 subjects with DAT were eligible for inclusion in this study. In overweight or obese subjects with BMI of 25 kg/m or higher, DR availability from C-Racloprie was negatively associated with BMI. However, DR availability from C-PHNO was positively associated with BMI. DAT ratio was calculated after dividing DAT availabilities of overweight/obese BMI with mean DAT availabilities of normal BMI. The association between DAT ratio and BMI was not significant regardless of radiopharmaceuticals. In conclusion, dopamine plays a main role in the reward system with regard to obesity. Overweight and obese subjects had negative association between DR availability from C-Raclopride and BMI. However, the association of DR availability with BMI was dependent on radiopharmaceuticals. DAT availability did not show the significant relationship with BMI regardless of radiopharmaceuticals.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Radiopharmaceuticals; Overweight; Obesity; Receptors, Dopamine D2
PubMed: 36099576
DOI: 10.1002/syn.22254 -
Brain, Behavior, and Immunity Nov 2022Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain... (Randomized Controlled Trial)
Randomized Controlled Trial
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 [C]raclopride positron emission tomography three times-at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [C]raclopride binding potential (ΔBP) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment.
Topics: Central Nervous System Stimulants; Corpus Striatum; Dopamine; Humans; Inflammation; Lipopolysaccharides; Methylphenidate; Positron-Emission Tomography; Raclopride; Smokers
PubMed: 36058419
DOI: 10.1016/j.bbi.2022.08.016 -
Addiction Biology Sep 2022Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For...
Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group). Specifically, all monkeys self-administered cocaine (0.1 mg/kg per injection) 5 days per week in the morning. In the afternoon, six monkeys consumed 2.0 g/kg ethanol over 1 h to model binge drinking and six monkeys drank an ethanol-free solution. Assessment of D2R availability using positron emission tomography (PET) and [ C]raclopride occurred when monkeys were drug-naïve and again when monkeys had self-administered approximately 400-mg/kg cocaine. D R function was assessed at the same time points by determining the potency of the D R-preferring agonist quinpirole to elicit yawns. Chronic cocaine self-administration decreased D2R availability in subregions of the basal ganglia in control monkeys, but not those that also drank ethanol. In contrast, D R sensitivity increased significantly after chronic cocaine self-administration in ethanol-drinking monkeys but not controls. These results suggest that co-use of ethanol substantially changes the effects of chronic cocaine self-administration on dopamine receptors, specifically implicating D R as a target for medications in these individuals.
Topics: Animals; Brain; Cocaine; Dose-Response Relationship, Drug; Ethanol; Humans; Macaca mulatta; Male; Receptors, Dopamine D2; Receptors, Dopamine D3; Self Administration; Substance-Related Disorders
PubMed: 36001440
DOI: 10.1111/adb.13219 -
Frontiers in Psychiatry 2022Positron emission tomography (PET) with [C]raclopride has been applied to measure changes in the concentration of endogenous dopamine induced by pharmacological...
OBJECTIVES
Positron emission tomography (PET) with [C]raclopride has been applied to measure changes in the concentration of endogenous dopamine induced by pharmacological challenge or neuropsychological stimulation by evaluating the binding potential (BP) between the baseline and activated state. Recently, to reliably estimate BP in the activated state, a new approach with dual-bolus injections in a single PET scan was developed. In this study, we investigated the feasibility of applying this dual-bolus injection approach to measure changes in endogenous dopamine levels induced by cognitive tasks in humans.
METHODS
First, the reproducibility of BP estimation using the dual-bolus injection approach was evaluated using PET scans without stimulation in nine healthy volunteers. A 90-min scan was performed with bolus injections of [C]raclopride administered at the beginning of the scan and 45 min after the first injection. BPs in the striatum for the first injection (BP) and second injection (BP) were estimated using an extended simplified reference tissue model, and the mean absolute difference (MAD) between the two BPs was calculated. The MAD was also compared with the conventional bolus-plus-continuous infusion approach. Next, PET studies with a cognitive reinforcement learning task were performed on 10 healthy volunteers using the dual-bolus injection approach. The BP at baseline and BP at the activated state were estimated, and the reduction in BP was evaluated.
RESULTS
In the PET scans without stimulation, the dual-bolus injection approach showed a smaller MAD (<2%) between BP and BP than the bolus-plus-continuous infusion approach, demonstrating good reproducibility of this approach. In the PET scans with the cognitive task performance, the reduction in BP was not observed in the striatum by either approach, showing that the changes in dopamine level induced by the cognitive tasks performed in this study were not sufficient to be detected by PET.
CONCLUSION
Our results indicate that the cognitive task-induced changes in dopamine-related systems may be complex and difficult to measure accurately using PET scans. However, the proposed dual-bolus injection approach provided reliable BP estimates with high reproducibility, suggesting that it has the potential to improve the accuracy of PET scans for measuring changes in dopamine concentrations.
PubMed: 35903633
DOI: 10.3389/fpsyt.2022.811136 -
Neuropharmacology Oct 2022Neurochemical, electrophysiological and behavioral evidence indicate that the potent α-adrenoceptor antagonist RS 79948 is also a dopamine (DA) D receptor antagonist....
Neurochemical, electrophysiological and behavioral evidence indicate that the potent α-adrenoceptor antagonist RS 79948 is also a dopamine (DA) D receptor antagonist. Thus, results from ligand binding and adenylate cyclase activity indicate that RS 79948 binds to D receptors and antagonized D receptor-mediated inhibition of cAMP synthesis at nanomolar concentrations. Results from microdialysis indicated that RS 79948 shared with the selective α-adrenergic antagonist atipamezole the ability to increase the co-release of DA and norepinephrine (NE) from noradrenergic terminals in the medial prefrontal cortex (mPFC), except that RS 79948-induced DA release persisted after noradrenergic denervation, unlike atipamezole effect, indicating that RS 79948 releases DA from dopaminergic terminals as well. Similarly to the D antagonist raclopride, but unlike atipamezole, RS 79948 increased extracellular DA and DOPAC in the caudate nucleus. Electrophysiological results indicate that RS 79948 shared with raclopride the ability to activate the firing of ventral tegmental area (VTA) DA neurons, while atipamezole was ineffective. Results from behavioral studies indicated that RS 79948 exerted effects mediated by independent, cooperative and contrasting inhibition of α-and D receptors. Thus, RS 79948, but not atipamezole, prevented D-autoreceptor mediated hypomotility produced by a small dose of quinpirole. RS 79948 potentiated, more effectively than atipamezole, quinpirole-induced motor stimulation. RS 79948 antagonized, less effectively than atipamezole, raclopride-induced catalepsy. Future studies should clarify if the dual α-adrenoceptor- and D-receptor antagonistic action might endow RS 79948 with potential therapeutic relevance in the treatment of schizophrenia, drug dependence, depression and Parkinson's disease.
Topics: Animals; Dopamine; Isoquinolines; Naphthyridines; Norepinephrine; Quinpirole; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Receptors, Dopamine; Receptors, Dopamine D1
PubMed: 35850212
DOI: 10.1016/j.neuropharm.2022.109192 -
Molecular Pharmaceutics Aug 2022Adenosine A and dopamine D receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric...
Adenosine A and dopamine D receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A receptor-mediated modulation of D receptor binding in vivo using positron emission tomography (PET) with the D antagonist tracer [C]raclopride. Healthy male Wistar rats ( = 8) were scanned (60 min dynamic scan) with [C]raclopride at baseline and 7 days later following an acute administration of the A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BP) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [C]raclopride BP ( = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BP from the / ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [C]raclopride scans after pretreatment with a vehicle ( = 5), a single dose of CGS21680 (1 mg/kg, = 5), or a single dose of the A antagonist KW6002 (1 mg/kg, = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group ( = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal / ratio ( < 0.01), but and estimates may be less reliable. The BP (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 ( = 0.080) or 1.961 ± 0.11 ( = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A agonist CGS21680, but not the antagonist KW6002, may reduce the D receptor availability in the striatum.
Topics: Adenosine; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Carbon Radioisotopes; Corpus Striatum; Dopamine; Ligands; Male; Positron-Emission Tomography; Raclopride; Rats; Rats, Wistar; Receptor, Adenosine A2A; Receptors, Dopamine; Rodentia
PubMed: 35849844
DOI: 10.1021/acs.molpharmaceut.2c00450 -
Scientific Reports Jul 2022The dopamine blockade by antipsychotics trigger subjective dysphoria. Compared with D2 antagonists, aripiprazole, a D2 partial agonist, was expected to produce a...
The dopamine blockade by antipsychotics trigger subjective dysphoria. Compared with D2 antagonists, aripiprazole, a D2 partial agonist, was expected to produce a different experience. Indeed, a previous study reported no relationship between the D2 receptor occupancy by aripiprazole and subjective dysphoria, while the D2 receptor occupancy by antagonists was associated with negative subjective experiences. This study revisited the relationship in patients treated with aripiprazole by using an inhibitory E model, which enables the individual drug-free binding potential and D2 receptor occupancy to be properly estimated. Eight patients with schizophrenia who have been clinically stable on aripiprazole were enrolled. Assessments including Positive and Negative Syndrome Scale (PANSS) and Subjective Well-being under Neuroleptics Scale (Kv-SWN) were administered. [C]raclopride PET scan were conducted 2, 26, and 74 h after aripiprazole administration. Regression analysis showed a significant negative association between the D2 receptor occupancy by aripiprazole in the striatum and the Kv-SWN (R = 0.55, p = 0.036), but the PANSS total score was not associated with the Kv-SWN (R = 0.42, p = 0.080). The negative association between D2 receptor occupancy by aripiprazole and subjective well-being implies that clinicians should find the lowest effective doses of aripiprazole for clinically stable patients to improve their subjective experiences and clinical outcomes.
Topics: Antipsychotic Agents; Aripiprazole; Humans; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2
PubMed: 35840763
DOI: 10.1038/s41598-022-16130-5 -
Neurology Sep 2022Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline...
BACKGROUND AND OBJECTIVES
Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates.
METHODS
We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity.
RESULTS
Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion.
DISCUSSION
These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.
Topics: Aged; Aging; Cross-Sectional Studies; Dopamine; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 35790424
DOI: 10.1212/WNL.0000000000200891 -
Molecular Pharmaceutics Jul 2022: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between...
: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D/D agonist/H antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). : Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D/D receptor ligand [C]raclopride or the histamine H receptor ligand [C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution () as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. : Dopamine D receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the values of [C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. : Target engagement of AG-0029 as an agonist at dopamine D/D receptors and an antagonist at histamine H receptors could be demonstrated in the rat brain with [C]raclopride and [C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D/D and moderate (submicromolar) affinity to H receptors.
Topics: Animals; Brain; Dopamine; Histamine; Ligands; Male; Mammals; Pharmaceutical Preparations; Positron-Emission Tomography; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 35732005
DOI: 10.1021/acs.molpharmaceut.2c00121 -
Frontiers in Pharmacology 2022The misuse of stimulant drugs such as methamphetamine is a global public health issue. One important neurochemical mechanism of methamphetamine use disorder may be...
The misuse of stimulant drugs such as methamphetamine is a global public health issue. One important neurochemical mechanism of methamphetamine use disorder may be altered dopaminergic neurotransmission. For instance, previous studies using positron emission tomography (PET) have consistently shown that striatal dopamine D2-type receptor availability (quantified as binding potential; BP) is lower in methamphetamine use disorder. Further, methamphetamine use is known to induce chronic neuroinflammation through multiple physiological pathways. Upregulation of D2-type receptor and/or attenuation of neuroinflammation may therefore provide a therapeutic effect for this disorder. studies have shown that blockage of adenosine 2A (A2A) receptors may prevent D2-receptor downregulation and neuroinflammation-related brain damage. However, no study has examined this hypothesis yet. Using a within-subject design, this trial will assess the effect of the selective A2A receptor antagonist, istradefylline, primarily on D2-type BP in the striatum, and secondarily on neuroinflammation in the whole brain in individuals with methamphetamine use disorder. The research hypotheses are that istradefylline will increase striatal D2-type BP and attenuate neuroinflammation. Twenty participants with methamphetamine use disorder, aged 20-65, will be recruited to undergo [C]raclopride PET (for every participant) and [C]DAA1106 PET (if applicable) once before and once after administration of 40 mg/day istradefylline for 2 weeks. Neuropsychological measurements will be performed on the same days of the PET scans.
PubMed: 35645814
DOI: 10.3389/fphar.2022.820447