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Behavioural Brain Research Oct 2023Dopamine levels in the dorsomedial striatum (DMS) are highly dynamic and are thought to underly the encoding of action-outcome associations. Although it is known that...
Dopamine levels in the dorsomedial striatum (DMS) are highly dynamic and are thought to underly the encoding of action-outcome associations. Although it is known that amphetamine disrupts the learning that is required for goal-directed action, the role of D1 and D2 receptors in this process has not been established. In this study, we examined the role of D1 and D2 receptor antagonists on learning in response to amphetamine. We used the outcome-specific devaluation task to examine goal-directed action in male C57BL6/J mice treated systemically with either a D1 antagonist (SCH-23990; 0.01 mg/kg) or a D2 antagonist (raclopride; 0.5 mg/kg) and then administered amphetamine (1 mg/kg). The mice were injected repeatedly throughout the instrumental training phase of the task to assess the impact on the learning of action-outcomes, and the subsequent choice test assessing performance of goal-directed action was conducted drug free. Effects of chronic drug administration on locomotor behaviour was assessed before and after the choice test. Treatment during learning with either amphetamine, or the D1 or D2 antagonists, impaired the subsequent performance of goal-directed action. The amphetamine-induced impairment in goal-directed action was reversed in mice treated with raclopride, but not when treated with SCH-23990. By contrast, amphetamine-induced hyperactivity was reversed in mice treated with SCH-23990, but not in mice treated with raclopride. Taken together, these data support the role of a balance of dopamine receptor signalling after amphetamine treatment. While overall D1 receptor availability is necessary to promote learning, in a state of elevated dopamine, modifying D2 receptor function can ameliorate learning deficits.
Topics: Male; Animals; Mice; Amphetamine; Raclopride; Dopamine; Conditioning, Classical; Mice, Inbred C57BL; Receptors, Dopamine D2
PubMed: 37643667
DOI: 10.1016/j.bbr.2023.114649 -
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 -
Neuropsychopharmacology : Official... Jun 2021Correlational studies of humans suggest that exposure to early life stress has long-term effects on neural circuits involved in vulnerability and resilience to mental...
Correlational studies of humans suggest that exposure to early life stress has long-term effects on neural circuits involved in vulnerability and resilience to mental health disorders. Stress-related mental health disorders are more prevalent in women than in men. Here, female squirrel monkeys are randomized to intermittently stressful (IS) social separations or a non-separated (NS) control condition conducted from 17 to 27 weeks of age. Nine years later in mid-life adulthood, resting-state functional magnetic resonance imaging was employed to parcellate prefrontal cortex (PFC). Resulting subdivisions were then used to characterize functional connectivity within PFC, and between PFC subdivisions and subcortical regions that are known to be altered by stress. Extensive hyper-connectivity of medial and orbitofrontal PFC with amygdala, hippocampus, and striatum was observed in IS compared to NS monkeys. Functional hyper-connectivity in IS monkeys was associated with previously reported indications of diminished anxiety-like behavior induced by prepubertal stress. Hyper-connectivity of PFC with amygdala and with hippocampus was also associated with increased ventral striatal dopamine D2 and/or D3 receptor (DRD2/3) availability assessed with positron emission tomography (PET) of [C]raclopride binding in adulthood. Ventral striatal DRD2/3 availability has been linked to cognitive control, which plays a key role in stress coping as an aspect of emotion regulation. These findings provide causal support for enduring neurobiological effects of early life stress and suggest novel targets for new treatments of stress-related mental health disorders.
Topics: Animals; Female; Amygdala; Hippocampus; Magnetic Resonance Imaging; Prefrontal Cortex; Stress, Psychological; Saimiri
PubMed: 33495547
DOI: 10.1038/s41386-021-00956-0 -
Nature Communications Jan 2024The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking....
The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking. Dopamine release and hemodynamic brain activity in response to unexpected changes in action-outcome probabilities are here explored using simultaneous dynamic [11C]Raclopride PET-fMRI and computational modelling of behavior. When participants encounter reversed reward probabilities during a card guessing game, dopamine release is observed in associative striatum. Individual differences in absolute reward prediction error and sensitivity to errors are associated with peak dopamine receptor occupancy. The fMRI response to perseverance errors at the onset of a reversal spatially overlap with the site of dopamine release. Trial-by-trial fMRI correlates of absolute prediction errors show a response in striatum and association cortices, closely overlapping with the location of dopamine release, and separable from a valence signal in ventral striatum. The results converge to implicate striatal dopamine release in associative striatum as a central component of reversal learning, possibly signifying the need for increased cognitive control when new stimuli-responses should be learned.
Topics: Humans; Dopamine; Reversal Learning; Corpus Striatum; Raclopride; Neostriatum; Ventral Striatum; Reward
PubMed: 38167691
DOI: 10.1038/s41467-023-44358-w -
Brain : a Journal of Neurology Jun 2022Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how... (Randomized Controlled Trial)
Randomized Controlled Trial
Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.
Topics: Adult; Cross-Over Studies; Depression; Depressive Disorder, Major; Dopamine; Humans; Modafinil; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D3; Young Adult
PubMed: 35150243
DOI: 10.1093/brain/awab429 -
IEEE Transactions on Radiation and... Apr 2022PET imaging of small animals is often used for assessing biodistribution of a novel radioligand and pharmacology in small animal models of disease. PET acquisition and...
PET imaging of small animals is often used for assessing biodistribution of a novel radioligand and pharmacology in small animal models of disease. PET acquisition and processing settings may affect reference region or image-derived input function (IDIF) kinetic modeling estimates. We examined four different factors in comparing quantitative results: 1) effect of reconstruction algorithm, 2) number of MAP iterations, 3) strength of the MAP prior, and 4) Attenuation and scatter. The effect of these parameters has not been explored for small-animal reference region and IDIF kinetic modeling approaches. Dynamic PET/CT scans were performed in 3 species with 3 different tracers: house sparrows with [C]raclopride, rats with [F]AS2471907 (11HSD1) and mice with [C]UCB-J (SV2A). FBP yielded lower kinetic modeling estimates compared to 3D-OSEM-MAP reconstructions, in sparrow and rat studies. Target resolutions (MAP prior strength) of 1.5 and 3.0mm demonstrated reduced in rats but only 3.0mm reduced BP in sparrows. Therefore, use of the highest target resolution (0.8mm) is warranted. We demonstrated using kinetic modeling that forgoing CT-based attenuation and scatter correction may be appropriate to improve animal throughput when using short-lived radioisotopes in sparrows and mice. This work provides recommendations and a framework for future optimization of kinetic modeling for preclinical PET methodology with novel radioligands.
PubMed: 36185820
DOI: 10.1109/trpms.2021.3088606 -
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 -
ACS Chemical Neuroscience Apr 2021The dopamine D receptor exists in two different states, D and D; the former is the functional form of the D receptor and associates with intracellular G-proteins. The D...
The dopamine D receptor exists in two different states, D and D; the former is the functional form of the D receptor and associates with intracellular G-proteins. The D agonist [H]MCL-536 has high affinity for the D receptor ( 0.8 nM) and potently displaces the binding of (-(-)---propylnorapomorphine (NPA; 0.16 nM) and raclopride ( 0.9 nM) in competition binding assays. Here, we further characterize [H]MCL-536. [H]MCL-536 was metabolically stable, with about 75% of the compound remaining intact after 1 h incubation with human liver microsomes. Blood-brain barrier penetration in rats was good, attaining at 15 min a % injected dose per gram of wet tissue (%ID/g) of 0.28 in males versus 0.42 in females in the striatum. Specific uptake ratios ([%ID/g striatum]/[%ID/g cerebellum]) were stable in males during the first 60 min and in females up to 15-30 min. The D-rich striatum exhibited the highest uptake and slowest washout compared to D-poor cortex or cerebellum. In peripheral organs, uptake peaked at 15 min but declined to baseline at 60 min, indicating good clearance from the body. autoradiography on transaxial and coronal brain sections showed specific binding of [H]MCL-536, which was abolished by preincubation with D/D ligands sulpiride, NPA, and raclopride and in the presence of the stable GTP analogue guanylylimidodiphosphate. In amphetamine-sensitized animals, striatal binding was higher than in controls, indicating specificity for the D receptor state. [H]MCL-536's unique properties make it a valuable tool for research on neurological disorders involving the dopaminergic system like Parkinson's disease or schizophrenia.
Topics: Animals; Apomorphine; Corpus Striatum; Dopamine; Dopamine Agonists; Nervous System Diseases; Raclopride; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 33844498
DOI: 10.1021/acschemneuro.1c00094 -
Brain Structure & Function Nov 2019The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show...
The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BP in the extrastriatal regions with [C]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [C]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [C]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.
Topics: Aged; Brain; Corpus Striatum; Female; Humans; Limbic System; Male; Middle Aged; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 31444615
DOI: 10.1007/s00429-019-01938-1 -
NeuroImage Jul 2022The dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in...
BACKGROUND
The dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved.
METHODS
In this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (DR) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018.
RESULTS
Striatal DR availability decreased through age for both sexes (2-5 % in striatal ROIs per 10 years) and was higher in females versus males throughout age (7-8% in putamen). BMI and striatal DR availability were weakly associated. There was no consistent lateralization of striatal DR. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135).
CONCLUSIONS
DR availability is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering DR expression.
Topics: Brain; Child; Corpus Striatum; Cross-Sectional Studies; Dopamine; Female; Humans; Male; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2
PubMed: 35367652
DOI: 10.1016/j.neuroimage.2022.119149