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Frontiers in Pharmacology 2020Previous results indicate that dopamine (DA) release in the medial prefrontal cortex (mPFC) is modified by α adrenoceptor- but not D2 DA receptor- agonists and...
Previous results indicate that dopamine (DA) release in the medial prefrontal cortex (mPFC) is modified by α adrenoceptor- but not D2 DA receptor- agonists and antagonists, suggesting that DA measured by microdialysis in the mPFC originates from noradrenergic terminals. Accordingly, noradrenergic denervation was found to prevent α-receptor-mediated rise and fall of extracellular DA induced by atipamezole and clonidine, respectively, in the mPFC. The present study was aimed to determine whether DA released by dopaminergic terminals in the mPFC is not detected by microdialysis because is readily taken up by norepinephrine transporter (NET). Accordingly, the D2-antagonist raclopride increased the electrical activity of DA neurons in the ventral tegmental area (VTA) and enhanced extracellular DOPAC but failed to modify DA in the mPFC. However, in rats whose NET was either inactivated by nisoxetine or eliminated by noradrenergic denervation, raclopride still elevated extracellular DOPAC and activated dopaminergic activity, but also increased DA. Conversely, the D2-receptor agonist quinpirole reduced DOPAC but failed to modify DA in the mPFC in control rats. However, in rats whose NET was eliminated by noradrenergic denervation or inhibited by locally perfused nisoxetine, quinpirole maintained its ability to reduce DOPAC but acquired that of reducing DA. Moreover, raclopride and quinpirole, when locally perfused into the mPFC of rats subjected to noradrenergic denervation, were able to increase and decrease, respectively, extracellular DA levels, while being ineffective in control rats. Transient inactivation of noradrenergic neurons by clonidine infusion into the locus coeruleus, a condition where NET is preserved, was found to reduce extracellular NE and DA in the mPFC, whereas noradrenergic denervation, a condition where NET is eliminated, almost totally depleted extracellular NE but increased DA. Both transient inactivation and denervation of noradrenergic neurons were found to reduce the number of spontaneously active DA neurons and their bursting activity in the VTA. The results indicate that DA released in the mPFC by dopaminergic terminals is not detected by microdialysis unless DA clearance from extracellular space is inactivated. They support the hypothesis that noradrenergic terminals are the main source of DA measured by microdialysis in the mPFC during physiologically relevant activities.
PubMed: 33071798
DOI: 10.3389/fphar.2020.588160 -
Physics in Medicine and Biology Dec 2020Measurement of stimulus-induced dopamine release and other types of transient neurotransmitter response (TNR) from dynamic positron emission tomography (PET) images...
Measurement of stimulus-induced dopamine release and other types of transient neurotransmitter response (TNR) from dynamic positron emission tomography (PET) images typically suffers from limited detection sensitivity and high false positive (FP) rates. Measurement of TNR of a voxel-level can be particularly problematic due to high image noise. In this work, we perform voxel-level TNR detection using artificial neural networks (ANN) and compare their performance to previously used standard statistical tests. Different ANN architectures were trained and tested using simulated and real human PET imaging data, obtained with the tracer [C]raclopride (a D2 receptor antagonist). A distinguishing feature of our approach is the use of 'personalized' ANNs that are designed to operate on the image from a specific subject and scan. Training of personalized ANNs was performed using simulated images that have been matched with the acquired image in terms of the signal, resolution, and noise. In our tests of TNR detection performance, the F-test of the linear parametric neurotransmitter PET model fit residuals was used as the reference method. For a moderate TNR magnitude, the areas under the receiver operating characteristic curves in simulated tests were 0.64 for the F-test and 0.77-0.79 for the best ANNs. At a fixed FP rate of 0.01, the true positive rates were 0.6 for the F-test and 0.8-0.9 for the ANNs. The F-test detected on average 28% of a 8.4 mm cluster with a strong TNR, while the best ANN detected 47%. When applied to a real image, no significant abnormalities in the ANN outputs were observed. These results demonstrate that personalized ANNs may offer a greater detection sensitivity of dopamine release and other types of TNR compared to previously used method based on the F-test.
Topics: Brain; Carbon Radioisotopes; Dopamine Antagonists; Humans; Metabolic Clearance Rate; Neural Networks, Computer; Neurotransmitter Agents; Positron-Emission Tomography; Precision Medicine; Raclopride; Radiopharmaceuticals; Tissue Distribution
PubMed: 33065566
DOI: 10.1088/1361-6560/abc230 -
Psychopharmacology Aug 2023Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in...
Assessing attention and impulsivity in the variable stimulus duration and variable intertrial interval rodent continuous performance test schedules using dopamine receptor antagonists in female C57BL/6JRj mice.
RATIONALE
Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in attention and impulsivity.
OBJECTIVE
To examine the roles of dopamine receptors in attention and impulsivity behaviours measured in the rCPT variable stimulus duration (vSD) and the variable intertrial interval schedules (vITI) using DA receptor antagonists.
METHODS
Two cohorts of 35 and 36 female C57BL/6JRj mice were examined separately in the rCPT, vSD, and vITI schedules, respectively. Both cohorts received antagonists of the following receptors: D (SCH23390, SCH: 0.01, 0.02, 0.04 mg/kg) and D (raclopride, RAC 0.03, 0.10, 0.30 mg/kg) in consecutive balanced Latin square designs with flanking reference measurements. The antagonists were subsequently examined for effects on locomotor activity.
RESULTS
SCH showed similar effects in both schedules, and the effects were reference-dependent in the vITI schedule. SCH reduced responding, but improved response accuracy, impulsivity, discriminability, and locomotor activity. RAC showed mixed effects on responsivity, but improved accuracy and discriminability. The discriminability improvement was driven by an increase in hit rate in the vITI schedule and a reduction in false alarm rate in the vSD schedule. RAC also decreased locomotor activity.
CONCLUSION
Both D and D receptor antagonism reduced responding, but the outcome on discriminability differed, stemming from individual effects on hit and false alarm rate, and the weight of omissions within the calculation. The effects of SCH and RAC suggest that endogenous DA increases responding and impulsivity, but reduces accuracy and shows mixed effects on discriminability.
Topics: Mice; Animals; Female; Dopamine Antagonists; Rodentia; Mice, Inbred C57BL; Receptors, Dopamine D1; Attention; Impulsive Behavior; Dopamine D2 Receptor Antagonists; Benzazepines; Dose-Response Relationship, Drug
PubMed: 37378887
DOI: 10.1007/s00213-023-06387-7 -
Journal of Cerebral Blood Flow and... Jul 2022Compartmental modeling analysis of C-raclopride (RAC) PET data can be used to measure the dopaminergic response to intra-scan behavioral tasks. Bias in estimates of...
Compartmental modeling analysis of C-raclopride (RAC) PET data can be used to measure the dopaminergic response to intra-scan behavioral tasks. Bias in estimates of binding potential (BP) and its dynamic changes (ΔBP) can arise both when head motion is present and when the compartmental model used for parameter estimation deviates from the underlying biology. The purpose of this study was to characterize the effects of motion and model bias within the context of a behavioral task challenge, examining the impacts of different mitigation strategies. Seventy healthy adults were administered bolus plus constant infusion RAC during a simultaneous PET/magnetic resonance (MR) scan with a reward task experiment. BP and ΔBP were estimated using an extension of the Multilinear Reference Tissue Model (E-MRTM2) and a new method (DE-MRTM2) was proposed to selectively discount the contribution of the initial uptake period. Motion was effectively corrected with a standard frame-based approach, which performed equivalently to a more complex reconstruction-based approach. DE-MRTM2 produced estimates of ΔBP in putamen and nucleus accumbens that were significantly different from those estimated from E-MRTM2, while also decoupling ΔBP values from first-pass k' estimation and removing skew in the spatial bias distribution of parametric ΔBP estimates within the striatum.
Topics: Adult; Bias; Corpus Striatum; Dopamine; Humans; Positron-Emission Tomography; Raclopride
PubMed: 35118904
DOI: 10.1177/0271678X221078616 -
Journal of Cerebral Blood Flow and... Jun 2022We report a novel forward-model implementation of the full reference tissue model (fFTRM) that addresses the fast-exchange approximation employed by the simplified...
We report a novel forward-model implementation of the full reference tissue model (fFTRM) that addresses the fast-exchange approximation employed by the simplified reference tissue model (SRTM) by incorporating a non-zero dissociation time constant from the specifically bound compartment. The forward computational approach avoided errors associated with noisy and nonorthogonal basis functions using an inverse linear model. Compared to analysis by a multilinear single-compartment reference tissue model (MRTM), fFTRM provided improved accuracy for estimation of binding potentials at early times in the scan, with no worse reproducibility across sessions. To test the model's ability to identify small focal changes in binding potential using a within-scan challenge, we employed a nonhuman primate model of focal dopamine release elicited by deep brain microstimulation remote to ventral striatum (VST) during imaging by simultaneous PET and fMRI. The new model reported an unambiguously lateralized response in VST consistent with fMRI, whereas the MRTM-derived response was not lateralized and was consistent with simulations of model bias. The proposed model enabled better accuracy in PET [C]raclopride displacement studies and may also facilitate challenges sooner after injection, thereby recovering some sensitivity lost to radioactive decay of the PET tracer.
Topics: Animals; Brain; Positron-Emission Tomography; Raclopride; Radionuclide Imaging; Radiopharmaceuticals; Reproducibility of Results
PubMed: 34894821
DOI: 10.1177/0271678X211065212 -
The Journal of Clinical Investigation Sep 2021BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity)...
BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).
Topics: Actigraphy; Adult; Central Nervous System Stimulants; Circadian Rhythm; Corpus Striatum; Female; Humans; Male; Methylphenidate; Middle Aged; Motor Activity; Positron-Emission Tomography; Receptors, Dopamine D1; Receptors, Dopamine D2; Rest; Reward; Substance-Related Disorders; Young Adult
PubMed: 34264865
DOI: 10.1172/JCI149722 -
NeuroImage Jan 2021To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and...
To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and tight head restraint. While such a restraint is now a routine procedure in brain imaging, the physiological and psychological consequences resulting from the restraint have not been elucidated. To address this problem, we developed a restraint-free brain PET system and conducted PET scans under both restrained and non-restrained conditions. We examined whether head restraint during PET scans could alter brain activities such as regional cerebral blood flow (rCBF) and dopamine release along with psychological stress related to head restraint. Under both conditions, 20 healthy male participants underwent [O]HO and [C]Raclopride PET scans during working memory tasks with the same PET system. Before, during, and after each PET scan, we measured physiological and psychological stress responses, including the State-Trait Anxiety Inventory (STAI) scores. Analysis of the [O]HO-PET data revealed higher rCBF in regions such as the parahippocampus in the restrained condition. We found the binding potential (BP) of [C]Raclopride in the putamen was significantly reduced in the restrained condition, which reflects an increase in dopamine release. Moreover, the restraint-induced change in BP was correlated with a shift in the state anxiety score of the STAI, indicating that less anxiety accompanied smaller dopamine release. These results suggest that the stress from head restraint could cause unsolicited responses in brain physiology and emotional states. The restraint-free imaging system may thus be a key enabling technology for the natural depiction of the mind.
Topics: Adult; Anxiety; Brain; Carbon Radioisotopes; Cerebrovascular Circulation; Dopamine; Functional Neuroimaging; Head; Healthy Volunteers; Humans; Male; Memory, Short-Term; Oxygen Radioisotopes; Positron-Emission Tomography; Putamen; Raclopride; Restraint, Physical; Stress, Physiological; Stress, Psychological; Young Adult
PubMed: 33039616
DOI: 10.1016/j.neuroimage.2020.117434 -
Frontiers in Aging Neuroscience 2022To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a...
To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D and D receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [C]Raclopride and [C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BP ), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BP for D receptors over time, whereas no significant change was found for D receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D were found, which may be attributed to altered [C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.
PubMed: 35140600
DOI: 10.3389/fnagi.2022.795132 -
Brain Research Bulletin Apr 2022Beta band (12-30 Hz) hypersynchrony within the basal ganglia-thalamocortical network has been suggested as a hallmark of Parkinson's disease (PD) pathophysiology....
Beta band (12-30 Hz) hypersynchrony within the basal ganglia-thalamocortical network has been suggested as a hallmark of Parkinson's disease (PD) pathophysiology. Abnormal beta band oscillations are found in the pedunculopontine nucleus (PPN) and primary motor cortex (M1) and are correlated with dopamine depletion. Dopamine acts locomotion and motor performance mainly through dopamine receptors (D1 and D2). However, the precise mechanism by which dopamine receptors regulate beta band electrophysiological activities between the PPN and M1 is still unknown. Here, we recorded the neuronal activity of the PPN and M1 simultaneously by the administration of the drug (SCH23390 and raclopride), selectively blocking the dopamine D1 receptor and D2 receptor. We discovered that the increased coherent activity of the beta band (12-30 Hz) between M1 and PPN in the lesioned group could be reduced and restored by injecting raclopride in the resting and wheel running states. Our studies revealed the unique role of D2 dopamine receptor signaling in regulating β band oscillatory activity in M1 and PPN and their relationship after the loss of dopamine, which contributes to elucidating the underlying mechanism of the pathophysiology of PD.
Topics: Animals; Benzazepines; Beta Rhythm; Disease Models, Animal; Dopamine Antagonists; Motor Cortex; Parkinson Disease; Pedunculopontine Tegmental Nucleus; Raclopride; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35077843
DOI: 10.1016/j.brainresbull.2022.01.012 -
Frontiers in Behavioral Neuroscience 2021The current rodent study applied fast-scan cyclic voltammetry (FSCV), paired with a pharmacological approach, to measure the release of the catecholamines (CA) dopamine...
The current rodent study applied fast-scan cyclic voltammetry (FSCV), paired with a pharmacological approach, to measure the release of the catecholamines (CA) dopamine (DA) and norepinephrine (NE) in the basolateral amygdala (BLA) following locus coeruleus (LC) stimulation. The primary goal was to determine if exposure to either social (social defeat) or non-social (forced swim) stress altered LC-evoked catecholamine release dynamics in the BLA. We used idazoxan (α2 adrenergic receptor antagonist) and raclopride (D dopamine receptor antagonist) to confirm the presence of NE and DA, respectively, in the measured CA signal. In non-stressed rats, injection of idazoxan, but not raclopride, resulted in a significant increase in the detected CA signal, indicating the presence of NE but not DA. Following exposure to either stress paradigm, the measured CA release was significantly greater after injection of either drug, suggesting the presence of both NE and DA in the LC-induced CA signal after social or non-social stress. Furthermore, acute administration of alcohol significantly decreased the CA signal in stressed rats, while it did not have an effect in naïve animals. Together, these data reveal that, while LC stimulation primarily elicits NE release in the BLA of control animals, both social and non-social stress unmask a novel dopaminergic component of LC catecholamine signaling. Future studies will be needed to identify the specific neural mechanism(s) responsible for these plastic changes in LC-BLA catecholamine signaling and to assess the possible contribution of these changes to the maladaptive behavioral phenotypes that develop following exposure to these stressors.
PubMed: 33935662
DOI: 10.3389/fnbeh.2021.640651