-
Translational Psychiatry Sep 2021Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown...
Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [C]raclopride-PET dataset to measure D receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (p < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (p < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.
Topics: Analgesics, Opioid; Dopamine; Humans; Male; Naloxone; Retrospective Studies; Substance Withdrawal Syndrome; Ventral Striatum
PubMed: 34471102
DOI: 10.1038/s41398-021-01548-8 -
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 -
Nature Communications Apr 2020Carbon-11 (C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation...
Carbon-11 (C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS) C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [C]CO and [C]CHI into molecules with diversified structures. It provides facile and rapid access to C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology.
Topics: Acetoacetates; Carbon Radioisotopes; Fluorides; Methylation; Organosilicon Compounds; Raclopride; Radiopharmaceuticals
PubMed: 32269227
DOI: 10.1038/s41467-020-15556-7 -
NeuroImage Feb 2023Converging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing underlying reward learning behaviors, based on the...
Converging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing underlying reward learning behaviors, based on the computation of reward prediction errors. However, competing evidence supports human dopamine signaling in the basal ganglia as also contributing to the generation of higher order learning heuristics. Here, we present data from a large (N = 81, 18-30yo), multi-modal neuroimaging study using simultaneously acquired task fMRI, affording temporal resolution of reward system function, and PET imaging with [C]Raclopride (RAC), assessing striatal dopamine (DA) D2/3 receptor binding, during performance of a probabilistic reward learning task. Both fMRI activation and PET DA measures showed ventral striatum involvement for signaling rewards. However, greater DA release was uniquely associated with learning strategies (i.e., learning rates) that were more task-optimal within the best fitting reinforcement learning model. This DA response was associated with BOLD activation of a network of regions including anterior cingulate cortex, medial prefrontal cortex, thalamus and posterior parietal cortex, primarily during expectation, rather than prediction error, task epochs. Together, these data provide novel, human in vivo evidence that striatal dopaminergic signaling interacts with a network of cortical regions to generate task-optimal learning strategies, rather than representing reward outcomes in isolation.
Topics: Animals; Humans; Dopamine; Motivation; Magnetic Resonance Imaging; Corpus Striatum; Reward; Positron-Emission Tomography
PubMed: 36586541
DOI: 10.1016/j.neuroimage.2022.119831 -
Brain and Behavior Jan 2021Dopamine is well-known to contribute to emergence from anesthesia. Previous studies have demonstrated that the paraventricular thalamus (PVT) in the midline nuclei is...
BACKGROUND AND PURPOSE
Dopamine is well-known to contribute to emergence from anesthesia. Previous studies have demonstrated that the paraventricular thalamus (PVT) in the midline nuclei is crucial for wakefulness. Moreover, the PVT receives dopaminergic projections from the brainstem. Therefore, we hypothesize that the dopaminergic signaling in the PVT plays a role in emergence from isoflurane anesthesia.
METHODS
We used c-Fos immunohistochemistry to reveal the activity of PVT neurons in three groups: The first group (iso EM ) underwent the anesthesia protocol and was sacrificed before emergence. The second group (iso EM ) underwent passive emergence from the same anesthesia protocol. The last group (oxy ) received oxygen. D2-like agonist quinpirole (2 or 4 mM) or D2-like antagonist raclopride (2 or 5 mM) was microinjected into the PVT, and their effects on emergence and induction time were analyzed. Surface cortical electroencephalogram (EEG) recordings were used to explore the effects of quinpirole injection into the PVT on cortical excitability during isoflurane anesthesia. The activity of PVT neurons after quinpirole injection was assessed by c-Fos immunohistochemistry.
RESULTS
The number of c-Fos-positive nuclei for the iso EM group was significantly higher than the oxy and iso EM groups. Application of quinpirole (4 mM) into the PVT shortened emergence time compared with the saline group (p < .01). In contrast, administration of raclopride (2 mM) delayed emergence time (p < .05). Neither quinpirole nor raclopride exerted an effect on induction time. EEG analyses showed that quinpirole (4 mM) decreased the burst suppression ratio during isoflurane anesthesia (p < .01). The number of c-Fos-positive nuclei for the quinpirole (4 mM) group was significantly higher than saline group (p < .01).
CONCLUSIONS
Our findings suggest that the activity of PVT neurons is enhanced after emergence from anesthesia, and the dopaminergic signaling in the PVT may facilitate emergence from isoflurane anesthesia.
Topics: Anesthesia; Animals; Dopamine Agonists; Isoflurane; Mice; Quinpirole; Thalamus
PubMed: 33128305
DOI: 10.1002/brb3.1903 -
Frontiers in Pharmacology 2023Migraine is a common and debilitating pain disorder associated with dysfunction of the central nervous system. Advanced magnetic resonance imaging (MRI) studies have...
Migraine is a common and debilitating pain disorder associated with dysfunction of the central nervous system. Advanced magnetic resonance imaging (MRI) studies have reported relevant pathophysiologic states in migraine. However, its molecular mechanistic processes are still poorly understood . This study examined migraine patients with a novel machine learning (ML) method based on their central -opioid and dopamine D2/D3 profiles, the most critical neurotransmitters in the brain for pain perception and its cognitive-motivational interface. We employed compressive Big Data Analytics (CBDA) to identify migraineurs and healthy controls (HC) in a large positron emission tomography (PET) dataset. 198 PET volumes were obtained from 38 migraineurs and 23 HC during rest and thermal pain challenge. 61 subjects were scanned with the selective -opioid receptor (μOR) radiotracer [C]Carfentanil, and 22 with the selective dopamine D2/D3 receptor (DOR) radiotracer [C]Raclopride. PET scans were recast into a 1D array of 510,340 voxels with spatial and intensity filtering of non-displaceable binding potential (BP), representing the receptor availability level. We then performed data reduction and CBDA to power rank the predictive brain voxels. CBDA classified migraineurs from HC with accuracy, sensitivity, and specificity above 90% for whole-brain and region-of-interest (ROI) analyses. The most predictive ROIs for μOR were the insula (anterior), thalamus (pulvinar, medial-dorsal, and ventral lateral/posterior nuclei), and the putamen. The latter, putamen (anterior), was also the most predictive for migraine regarding DOR D2/D3 BP levels. CBDA of endogenous -opioid and D2/D3 dopamine dysfunctions in the brain can accurately identify a migraine patient based on their receptor availability across key sensory, motor, and motivational processing regions. Our ML-based findings in the migraineur's brain neurotransmission partly explain the severe impact of migraine suffering and associated neuropsychiatric comorbidities.
PubMed: 37383727
DOI: 10.3389/fphar.2023.1173596 -
Journal of Neuroscience Research Jun 2022Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging....
Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain's structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20-80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [ C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [ C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.
Topics: Adult; Brain; Cognition; Cognitive Aging; Connectome; Dopamine; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Prospective Studies
PubMed: 35293013
DOI: 10.1002/jnr.25039 -
Scientific Reports Nov 2019Excessive sucrose consumption elicits addiction-like craving that may underpin the obesity epidemic. Opioids and dopamine mediate the rewarding effects of drugs of...
Excessive sucrose consumption elicits addiction-like craving that may underpin the obesity epidemic. Opioids and dopamine mediate the rewarding effects of drugs of abuse, and of natural rewards from stimuli such as palatable food. We investigated the effects of sucrose using PET imaging with [C]carfentanil (μ-opioid receptor agonist) and [C]raclopride (dopamine D2/3 receptor antagonist) in seven female anesthetized Göttingen minipigs. We then gave minipigs access to sucrose solution for one hour on 12 consecutive days and performed imaging again 24 hours after the final sucrose access. In a smaller sample of five minipigs, we performed an additional [C]carfentanil PET session after the first sucrose exposure. We calculated voxel-wise binding potentials (BP) using the cerebellum as a region of non-displaceable binding, analyzed differences with statistical non-parametric mapping, and performed a regional analysis. After 12 days of sucrose access, BP of both tracers had declined significantly in striatum, nucleus accumbens, thalamus, amygdala, cingulate cortex and prefrontal cortex, consistent with down-regulation of receptor densities. After a single exposure to sucrose, we found decreased binding of [C]carfentanil in nucleus accumbens and cingulate cortex, consistent with opioid release. The lower availability of opioid and dopamine receptors may explain the addictive potential associated with intake of sucrose.
Topics: Animals; Biomarkers; Brain; Functional Neuroimaging; Molecular Imaging; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Opioid, mu; Sucrose; Swine; Time Factors
PubMed: 31729425
DOI: 10.1038/s41598-019-53430-9 -
MedRxiv : the Preprint Server For... Sep 2023The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for >20 years with highly...
The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for >20 years with highly discrepant results, likely due to variable methodologies and differing study populations. We conducted a controlled inpatient feeding study to measure D2BP in the striatum using positron emission tomography with both [F]fallypride and [C]raclopride in pseudo-random order in 54 young adults with a wide range of body mass index (BMI 20-44 kg/m). Within-subject D2BP measurements using the two tracers were moderately correlated (r=0.47, p<0.001). D2BP was negatively correlated with BMI as measured by [C]raclopride (r= -0.51; p<0.0001) but not [F]fallypride (r=-0.01; p=0.92) and these correlation coefficients were significantly different from each other (p<0.001). Given that [F]fallypride has greater binding affinity to dopamine type-2 receptors than [C]raclopride, which is more easily displaced by endogenous dopamine, our results suggest that adiposity is positively associated with increased striatal dopamine tone.
PubMed: 37886556
DOI: 10.1101/2023.09.27.23296169 -
Drug and Alcohol Dependence Dec 2019Previous imaging studies using Positron Emission Tomography (PET) have shown that alcohol use disorder (AUD) is associated with a decrease in dopamine type 2/3 receptor...
BACKGROUND
Previous imaging studies using Positron Emission Tomography (PET) have shown that alcohol use disorder (AUD) is associated with a decrease in dopamine type 2/3 receptor (D) binding and dopamine transmission. Although binge drinking is a risk factor for future AUD, little is known about the neurobiology of binge drinking in young adults. This study measured D receptor binding and stimulant-induced dopamine release using PET and [C]raclopride in binge drinkers without an AUD.
METHODS
This study included 14 healthy controls (HC) and 14 young adult binge drinkers (BD), aged 18-25. The BD met National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria for binge drinking and the HC subjects were social drinkers. The subjects were scanned with [C]raclopride before and after the administration of oral methylphenidate (60 mg) to measure D binding and dopamine release.
RESULTS
There was no significant difference in the PET measures of D binding or methylphenidate-induced dopamine release between the two groups. There was no significant association between Alcohol Use Disorders Identification Test (AUDIT) scores or 30-day drinking history and the imaging data.
CONCLUSION
In this sample of 18-25-year-old binge drinkers without a diagnosis of a substance use disorder, there were no significant differences in D receptor binding potential or methylphenidate-induced dopamine release relative to healthy controls.
Topics: Adolescent; Adult; Binge Drinking; Central Nervous System Stimulants; Corpus Striatum; Dopamine; Ethanol; Female; Humans; Male; Methylphenidate; Positron-Emission Tomography; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Receptors, Dopamine D3; Young Adult
PubMed: 31669800
DOI: 10.1016/j.drugalcdep.2019.107627