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Communications Biology Sep 2022Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between...
Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between blink rates, measured after oral placebo) (PL) and after a challenge with oral methylphenidate (MP; 60 mg) and striatal D1 receptor (D1R) (measured at baseline) and D2 receptor (D2R) availability (measured after PL and after MP) in healthy participants. PET measures of baseline D1R ([C]NNC112) (BL-D1R) and D2R availability ([C]raclopride) after PL (PL-D2R) and after MP (MP-D2R) were quantified in the striatum as non-displaceable binding potential. MP reduced the number of blinks and increased the time participants kept their eyes open. Correlations with dopamine receptors were only significant for the eye blink measures obtained after MP; being positive for BL-D1R in putamen and MP-D2R in caudate (PL-D2R were not significant). MP-induced changes in blink rates (PL minus MP) were negatively correlated with BL-D1R in caudate and putamen. Our findings suggest that eye blink measures obtained while stressing the dopamine system might provide a more sensitive behavioral biomarker of striatal D1R or D2R in healthy volunteers than that obtained at baseline or after placebo.
Topics: Corpus Striatum; Dopamine; Humans; Methylphenidate; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 36163254
DOI: 10.1038/s42003-022-03979-5 -
Molecular Psychiatry Feb 2022Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized....
Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).
Topics: Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Corpus Striatum; Dopamine; Female; Humans; Male; Methylphenidate; Raclopride; Sex Characteristics; Ventral Striatum
PubMed: 34707237
DOI: 10.1038/s41380-021-01294-9 -
The Journal of Medical Investigation :... Nov 2005Functional neuroimaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), provides a valuable technique for detecting... (Comparative Study)
Comparative Study
Functional neuroimaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), provides a valuable technique for detecting regional changes in brain metabolic activity associated with human disease. These techniques have been applied in different dystonic disorders including primary generalized dystonia and dopa-responsive dystonia (DRD), as well as focal dystonic syndromes such as torticollis, writer's cramp, and blepharospasm. A common finding is abnormality of the basal ganglia and associated outflow pathways to sensorimotor cortex and other regions involved with motor performance. Other recent imaging research has utilized diffusion-based MRI techniques to localize distinct microstructural abnormalities in dystonia patients and gene carriers. This presentation will focus on an integrated approach to understanding the pathophysiology of this genetic and biochemically diverse disorder.
Topics: Anisotropy; Basal Ganglia; Blepharospasm; Carbon Radioisotopes; Case-Control Studies; Dihydroxyphenylalanine; Dopamine Antagonists; Dystonia; Dystonic Disorders; Globus Pallidus; Heterozygote; Humans; Magnetic Resonance Imaging; Molecular Chaperones; Motor Cortex; Positron-Emission Tomography; Prospective Studies; Putamen; Raclopride; Receptors, Dopamine; Torticollis
PubMed: 16366514
DOI: 10.2152/jmi.52.272 -
ACS Chemical Neuroscience Jun 2018Increases in the D2 receptor high affinity state are associated with certain neurological disorders. We synthesized and characterized the high-affinity D2high ligand...
Increases in the D2 receptor high affinity state are associated with certain neurological disorders. We synthesized and characterized the high-affinity D2high ligand [H]MCL-536 in competition binding against the D2/3 agonist R-(-)- N- n-propylnorapomorphine (NPA) and the D2/3 antagonist raclopride. The total binding of [H]MCL-536 (minus that in the presence of 100 nM NPA) was measured by saturation binding in CHO cells expressing human D2long; the data yielded separable, nonsaturable nonspecific, and saturable specific components. The former represents an aporphine site common to NPA and [H]MCL-536. The latter indicated specific binding to the total D2 receptors (both high and low-affinity states). [H]MCL-536 had a K of 0.8 nM. In competition binding, NPA had a K of 0.16 nM, and raclopride had a K of 0.9 nM. Co-incubation with guanylylimidodiphosphate abolished binding to D2high. This unique profile makes radiolabeled MCL-536 a versatile tool for diagnostics and therapeutics, and may quantify D2high sites in schizophrenia and PD patients in vivo.
Topics: Animals; Apomorphine; Binding, Competitive; Corpus Striatum; Dopamine; Dopamine Agonists; Dopamine Antagonists; Raclopride; Receptors, Dopamine D2; Schizophrenia
PubMed: 29641175
DOI: 10.1021/acschemneuro.8b00096 -
The International Journal of... Aug 2014Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently...
Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward. Here we used PET with [11C]PHNO (D3R-preferring radioligand), [11C]raclopride (D2R/D3R radioligand) and [11C]NNC-112 (D1R radioligand) to measure occupancy of oral and parenteral buspirone in the primate brain. Intramuscular buspirone (0.19 and 0.5 mg/kg) blocked both [11C]PHNO and [11C]raclopride binding to striatum, exhibiting high occupancy (50-85%) at 15 min and rapid wash-out over 2-6 h. In contrast, oral buspirone (3 mg/kg) significantly blocked [11C]PHNO binding in D3-rich regions (globus pallidum and midbrain) at 3 h, but had minimal effects on [11C]raclopride binding (28-37% at 1 h and 10% at 3 h). Buspirone did not block [11C]NNC-112. Our findings provide evidence that i.m. buspirone blocks D3R and D2R, whereas oral buspirone is more selective towards D3R blockade in vivo, consistent with extensive first pass metabolism and supporting the hypothesis that its metabolites (5- and 6'-hydroxybuspirone) merit evaluation for treating SUDs. They also indicate that for oral buspirone to achieve greater than 80% sustained D3R occupancy, as might be needed to treat addiction, higher doses (at least three-fold) than those used to treat anxiety (maximal 60 mg) will be required. Nonetheless, based on previous clinical studies, these doses would be safe and well tolerated.
Topics: Administration, Oral; Animals; Anti-Anxiety Agents; Benzazepines; Benzofurans; Buspirone; Corpus Striatum; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Female; Functional Neuroimaging; Globus Pallidus; Injections, Intramuscular; Mesencephalon; Oxazines; Papio anubis; Positron-Emission Tomography; Raclopride; Radioligand Assay; Receptors, Dopamine D3
PubMed: 24679922
DOI: 10.1017/S1461145714000194 -
Journal of Neurophysiology Jul 2022Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is...
Abnormalities of auditory steady-state responses (ASSRs) and the effects of antipsychotic drugs on ASSRs have been investigated in patients with schizophrenia. It is presumed that drugs do not directly affect ASSRs because its abnormalities are associated with schizophrenia. Therefore, to investigate the direct effect of drugs on ASSRs, we established an ASSR evaluation system for common marmosets in a naïve state. Dopamine D1 receptor stimulation (SKF-81297, 2 mg/kg ip) significantly increased evoked power (EP) at 40 Hz. The phase locking factor (PLF) was increased significantly at 20, 30, 40, and 80 Hz. However, administration of a dopamine D1 receptor antagonist (SCH-39166, 0.3 mg/kg ip) resulted in a significant decrease in EP and PLF at 30 Hz. Dopamine D2 receptor stimulation (quinpirole, 1 mg/kg im) tended to increase EP and induced power (IP) at all frequencies, and a significant difference was observed at 30 Hz IP. There was no change in PLF at all frequencies. In addition, dopamine D2 receptor blockade (raclopride, 3 mg/kg ip) reduced EP and PLF at 30 Hz. Subcutaneous administration of the serotonin dopamine antagonist, risperidone (0.3 mg/kg), tended to increase IP and decrease PLF, but not significantly. Taken together, it is possible to compare the differences in the mode of action of drugs on ASSRs using naïve nonhuman primates. We measured the effects of dopamine receptor-related compounds on ASSR in marmosets. D1 receptor stimulation increased the phase locking factor (PLF) and evoked power (EP), and reduced the induced power (IP). D2 receptor stimulation increased the IP. D1 and D2 receptor blockers reduced the PLF and EP at 30 Hz. Different modes of action of various drugs related to psychiatric disorders were evaluated by administering antipsychotic drugs to naïve marmosets.
Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Callithrix; Dopamine Antagonists; Evoked Potentials, Auditory; Humans; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35583977
DOI: 10.1152/jn.00147.2022 -
Communications Biology Feb 2023Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat...
Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.
Topics: Humans; Methylphenidate; Dopamine; Raclopride; Brain; Attention Deficit Disorder with Hyperactivity; Dopamine Antagonists
PubMed: 36765261
DOI: 10.1038/s42003-023-04545-3 -
Translational Psychiatry Jan 2015The discounting of delayed rewards, also known as temporal or delay discounting, is intrinsic to everyday decisions and can be impaired in pathological states such as...
The discounting of delayed rewards, also known as temporal or delay discounting, is intrinsic to everyday decisions and can be impaired in pathological states such as addiction disorders. Preclinical and human studies suggest a role for dopaminergic function in temporal discounting but this relationship has not yet been verified using molecular imaging of the living human brain. Here, we evaluated dopaminergic function in temporal discounting using positron emission tomography (PET) with two different dopaminergic ligands assessing three populations in whom temporal discounting has been shown to be impaired. First, we show using [11C]raclopride PET that in pathological gamblers, greater temporal discounting correlates with decreased ventral striatal binding potential, convergent with translational findings of lower nucleus accumbens D2/D3 receptor density in high-impulsive rodents. Temporal discounting also correlates with lower ventral striatal dopamine release in response to high-reward magnitude suggesting that dopamine-mediated devaluation of larger delayed rewards may drive choice preferences. Second, we show using [18F]fluorodopa PET that in Parkinson's disease, temporal discounting correlates with greater left caudate dopaminergic terminal function. Finally, in subjects with Parkinson's disease and dopamine medication-induced behavioral addictions, temporal discounting is further correlated with greater dopaminergic terminal function in the anterior putamen. These findings provide insights into the relationship between striatal dopamine function and temporal discounting, and its potential role in pathological disorders and mechanisms underlying treatment interventions.
Topics: Adult; Aged; Antiparkinson Agents; Behavior, Addictive; Brain; Case-Control Studies; Caudate Nucleus; Delay Discounting; Dihydroxyphenylalanine; Dopamine; Dopamine Antagonists; Gambling; Humans; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Raclopride; Radiopharmaceuticals; Receptors, Dopamine; Synaptic Transmission; Ventral Striatum; Young Adult
PubMed: 25562841
DOI: 10.1038/tp.2014.133 -
Cerebral Cortex (New York, N.Y. : 1991) Nov 2018Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional...
Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64-68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D2/3R availability (probed with 11C-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny.
Topics: Aged; Brain; Cerebral Cortex; Cognition; Corpus Striatum; Female; Hippocampus; Humans; Latent Class Analysis; Male; Memory; Middle Aged; Multivariate Analysis; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 29028935
DOI: 10.1093/cercor/bhx253 -
Proceedings of the National Academy of... Jan 2021The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's...
The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D receptors (using C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.
Topics: Aged; Brain Mapping; Case-Control Studies; Caudate Nucleus; Dopamine; Dopamine Antagonists; Female; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuronal Plasticity; Neurons; Oxygen; Parietal Lobe; Parkinson Disease; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Saccades; Synapses
PubMed: 33431672
DOI: 10.1073/pnas.2013962118