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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 Cognitive Neuroscience Feb 2019The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive...
The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between C-raclopride BP and cognitive performance. In accordance with previous findings, we show that C-raclopride BP was increased in T-homozygotes. Importantly, C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest C-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.
Topics: Aged; Brain; Dopamine D2 Receptor Antagonists; Female; Homozygote; Humans; Male; Memory, Episodic; Memory, Short-Term; Middle Aged; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Psychomotor Performance; Raclopride; Receptors, Dopamine D2
PubMed: 30407135
DOI: 10.1162/jocn_a_01354 -
EJNMMI Physics Apr 2022There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [C]raclopride with older data. This typically means...
BACKGROUND
There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [C]raclopride with older data. This typically means harmonizing data across different scanners. Previous harmonization studies have utilized either phantoms or human subjects, but the use of both phantoms and humans in one harmonization study is not common. The purpose herein was (1) to use phantom images to develop an inter-scanner harmonization technique and (2) to test the harmonization technique in human subjects.
METHODS
To develop the harmonization technique (Experiment 1), the Iida brain phantom was filled with F-18 solution and scanned on the two scanners in question (HRRT, HR+, Siemens/CTI). Phantom images were used to determine the optimal isotropic Gaussian filter to harmonize HRRT and HR+ images. To evaluate the harmonization on human images (Experiment 2), inter-scanner variability was calculated using [C]raclopride scans of 3 human subjects on both the HRRT and HR+ using percent difference (PD) in striatal non-displaceable binding potential (BP between HR+ and HRRT (with and without Gaussian smoothing). Finally, (Experiment 3), PD was calculated for test-retest (T/RT) variability of striatal BP for 8 human subjects scanned twice on the HR+.
RESULTS
Experiment 1 identified the optimal filter as a Gaussian with a 4.5 mm FWHM. Experiment 2 resulted in 13.9% PD for unfiltered HRRT and 3.71% for HRRT filtered with 4.5 mm. Experiment 3 yielded 5.24% PD for HR+.
CONCLUSIONS
The PD results show that the variability of harmonized HRRT is less than the T/RT variability of the HR+. The harmonization technique makes it possible for BP estimates from the HRRT to be compared to (and/or combined with) those from the HR+ without adding to overall variability. Our approach is applicable to all pairs of scanners still in service.
PubMed: 35416555
DOI: 10.1186/s40658-022-00457-z -
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 -
Molecular Pharmaceutics Mar 2020The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D receptor antagonists were used to...
The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D receptor antagonists were used to assess changes in [F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate () was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted > 0.07, Cohen's 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [F]-FEOBV was significantly higher after haloperidol treatment (adjusted = 0.022, Cohen's = 2.51) than in controls. Compared to controls, the AUC of [F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted = 0.4, Cohen's = 1.77) and raclopride (adjusted = 0.052, Cohen's = 1.49) treatment, respectively. No changes in the AUC of [F]-FEOBV were found in the cerebellum (Cohen's 0.63-0.74). Raclopride treatment nonsignificantly increased in the striatum 1.3-fold compared to control rats (adjusted = 0.1, Cohen's = 1.1) while it reduced in the cerebellum by 28% (adjusted = 0.0004, Cohen's = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in in the striatum (10%, adjusted = 1, Cohen's = 0.44) and a 40-50% lower than controls in all other brain regions (adjusted < 0.0005, Cohen's = 3.3-4.7). The changes in induced by the selective D receptor antagonist raclopride can in part be quantified using [F]-FEOBV PET imaging. Haloperidol, a nonselective D/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.
Topics: Animals; Cerebellum; Corpus Striatum; Dopamine D2 Receptor Antagonists; Fluorine Radioisotopes; Haloperidol; Kinetics; Male; Parkinson Disease; Piperidines; Positron-Emission Tomography; Protein Binding; Raclopride; Radiopharmaceuticals; Rats; Rats, Wistar; Receptors, sigma; Vesicular Acetylcholine Transport Proteins
PubMed: 32011892
DOI: 10.1021/acs.molpharmaceut.9b01129 -
Biological & Pharmaceutical Bulletin 2021The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious...
The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.
Topics: Animals; Benzazepines; Catalepsy; Corpus Striatum; Dopamine Antagonists; Mice, Inbred C57BL; Mice, Transgenic; Prefrontal Cortex; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Mice
PubMed: 33642553
DOI: 10.1248/bpb.b20-01006 -
Alcoholism, Clinical and Experimental... Sep 2016Cue-evoked drug-seeking behavior likely depends on interactions between frontal activity and ventral striatal (VST) dopamine (DA) transmission. Using [(11) C]raclopride...
BACKGROUND
Cue-evoked drug-seeking behavior likely depends on interactions between frontal activity and ventral striatal (VST) dopamine (DA) transmission. Using [(11) C]raclopride (RAC) positron emission tomography (PET), we previously demonstrated that beer flavor (absent intoxication) elicited VST DA release in beer drinkers, inferred by RAC displacement. Here, a subset of subjects from this previous RAC-PET study underwent a similar paradigm during functional magnetic resonance imaging (fMRI) to test how orbitofrontal cortex (OFC) and VST blood oxygenation level-dependent (BOLD) responses to beer flavor are related to VST DA release and motivation to drink.
METHODS
Male beer drinkers (n = 28, age = 24 ± 2, drinks/wk = 16 ± 10) from our previous PET study participated in a similar fMRI paradigm wherein subjects tasted their most frequently consumed brand of beer and Gatorade(®) (appetitive control). We tested for correlations between BOLD activation in fMRI and VST DA responses in PET, and drinking-related variables.
RESULTS
Compared to Gatorade, beer flavor increased wanting and desire to drink, and induced BOLD responses in bilateral OFC and right VST. Wanting and desire to drink correlated with both right VST and medial OFC BOLD activation to beer flavor. Like the BOLD findings, beer flavor (relative to Gatorade) again induced right VST DA release in this fMRI subject subset, but there was no correlation between DA release and the magnitude of BOLD responses in frontal regions of interest.
CONCLUSIONS
Both imaging modalities showed a right-lateralized VST response (BOLD and DA release) to a drug-paired conditioned stimulus, whereas fMRI BOLD responses in the VST and medial OFC also reflected wanting and desire to drink. The data suggest the possibility that responses to drug-paired cues may be rightward biased in the VST (at least in right-handed males) and that VST and OFC responses in this gustatory paradigm reflect stimulus wanting.
Topics: Adult; Alcohol Drinking; Beer; Cues; Dopamine; Dopamine Antagonists; Flavoring Agents; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Prefrontal Cortex; Raclopride; Ventral Striatum; Young Adult
PubMed: 27459715
DOI: 10.1111/acer.13158 -
Journal of Cerebral Blood Flow and... Jul 2023The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3...
Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [C]PE2I, [F]FE-PE2I and [C]raclopride PET in healthy individuals.
The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [C]PE2I (n = 20) and [F]FE-PE2I (n = 20) and the D2/3 tracer [C]raclopride (n = 18). Subjects with a [C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [C]DASB. Binding potential (BP) and relative tracer delivery (R) values were calculated on regional and voxel-level. Striatal R and BP values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BP image. An inter-tracer comparison between [C]PE2I BP and [C]DASB R was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BP and R for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [C]PE2I BP and [C]DASB R. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.
Topics: Humans; Raclopride; Dopamine; Dopamine Plasma Membrane Transport Proteins; Retrospective Studies; Positron-Emission Tomography; Cerebrovascular Circulation
PubMed: 36912083
DOI: 10.1177/0271678X231160881 -
Frontiers in Human Neuroscience 2022Autonomous motivation to exercise occurs when the activity is voluntary and with a perceived inherent satisfaction from the activity itself. It has been suggested that...
BACKGROUND
Autonomous motivation to exercise occurs when the activity is voluntary and with a perceived inherent satisfaction from the activity itself. It has been suggested that autonomous motivation is related to striatal dopamine D2/3-receptor (D2/3R) availability within the brain. In this study, we hypothesized that D2/3R availability in three striatal regions (nucleus accumbens, caudate nucleus, and putamen) would be positively associated with self-reported autonomous motivation to exercise. We also examined this relationship with additional exploratory analyses across a set of extrastriatal regions of interest (ROI).
METHODS
Our sample comprised 49 older adults (28 females) between 64 and 78 years of age. The D2/3R availability was quantified from positron emission tomography using the non-displaceable binding potential of [C]-raclopride ligand. The exercise-related autonomous motivation was assessed with the Swedish version of the Behavioral Regulations in Exercise Questionnaire-2.
RESULTS
No significant associations were observed between self-reported autonomous motivation to exercise and D2/3R availability within the striatum (nucleus accumbens, caudate nucleus, and putamen) using semi-partial correlations controlling for ROI volume on D2/3R availability. For exploratory analyses, positive associations were observed for the superior ( = 0.289, = 0.023) and middle frontal gyrus ( = 0.330, = 0.011), but not for the inferior frontal gyrus, orbitofrontal cortex, anterior cingulate cortex, or anterior insular cortex.
CONCLUSION
This study could not confirm the suggested link between striatal D2/3R availability and subjective autonomous motivation to exercise among older adults. The exploratory findings, however, propose that frontal brain regions may be involved in the intrinsic regulation of exercise-related behaviors, though this has to be confirmed by future studies using a more suitable ligand and objective measures of physical activity levels.
PubMed: 36438629
DOI: 10.3389/fnhum.2022.997131 -
Social Cognitive and Affective... May 2022Mothers are highly responsive to their offspring. In non-human mammals, mothers secrete dopamine in the nucleus accumbens (NAcc) in response to their pups. Yet, it is...
Mothers are highly responsive to their offspring. In non-human mammals, mothers secrete dopamine in the nucleus accumbens (NAcc) in response to their pups. Yet, it is still unknown which aspect of the offspring behavior elicits dopaminergic responses in mothers. Here, we tested whether infants' affective signals elicit dopaminergic responses in the NAcc of human mothers. First, we conducted a behavioral analysis on videos of infants' free play and quantified the affective signals infants spontaneously communicated. Then, we presented the same videos to mothers during a magnetic resonance-positron emission tomography scan. We traced the binding of [11C]raclopride to free D2/3-type receptors to assess maternal dopaminergic responses during the infant videos. When mothers observed videos with many infant signals during the scan, they had less [11C]raclopride binding in the right NAcc. Less [11C]raclopride binding indicates that less D2/3 receptors were free, possibly due to increased endogenous dopamine responses to infants' affective signals. We conclude that NAcc D2/3 receptors are involved in maternal responsiveness to affective signals of human infants. D2/3 receptors have been associated with maternal responsiveness in nonhuman animals. This evidence supports a similar mechanism in humans and specifies infant-behaviors that activate the maternal dopaminergic system, with implications for social neuroscience, development and psychopathology.
Topics: Animals; Dopamine; Humans; Mammals; Nucleus Accumbens; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2
PubMed: 34750627
DOI: 10.1093/scan/nsab116