-
Movement Disorders : Official Journal... Dec 2019The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD).
METHODS
Thirty-five participants were randomly allocated to a 36-session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [ C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation-evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS-UPDRS part III, finger tapping, Timed-up-and-go) and nonmotor assessments (Starkstein Apathy Scale, Beck Depression Inventory, reaction time, Positive and Negative Affect Schedule, Trail Making Test [A and B], and Montreal Cognitive Assessment) before and after the interventions.
RESULTS
The aerobic group exhibited increased activity in the ventral striatum during functional magnetic resonance imaging in anticipation of 75% probability of reward (P = 0.01). The aerobic group also demonstrated increased repetitive transcranial magnetic stimulation-evoked dopamine release in the caudate nucleus (P = 0.04) and increased baseline nondisplaceable binding potential in the posterior putamen of the less affected repetitive transcranial magnetic stimulation-stimulated hemisphere measured by position emission tomography (P = 0.03).
CONCLUSIONS
Aerobic exercise alters the responsivity of the ventral striatum, likely related to changes to the mesolimbic dopaminergic pathway, and increases evoked dopamine release in the caudate nucleus. This suggests that the therapeutic benefits of exercise are in part related to corticostriatal plasticity and enhanced dopamine release. © 2019 International Parkinson and Movement Disorder Society.
Topics: Aged; Aged, 80 and over; Caudate Nucleus; Dopamine; Exercise; Exercise Therapy; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Tomography, X-Ray Computed; Transcranial Magnetic Stimulation; Ventral Striatum
PubMed: 31584222
DOI: 10.1002/mds.27865 -
Psychopharmacology Dec 2022The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical...
RATIONALE
The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish (Danio rerio) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches.
OBJECTIVES
In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae.
METHODS
Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format.
RESULTS
METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems.
CONCLUSIONS
These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances.
Topics: Animals; Zebrafish; Methamphetamine; Larva; Dopamine; Seizures; Excitatory Amino Acid Antagonists
PubMed: 36269378
DOI: 10.1007/s00213-022-06252-z -
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 -
NeuroImage Feb 2020
Topics: Brain; Carbon Radioisotopes; Humans; Raclopride; Reproducibility of Results
PubMed: 31715255
DOI: 10.1016/j.neuroimage.2019.116346 -
Obesity Reviews : An Official Journal... Nov 2023This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed... (Review)
Review
Effects of bariatric surgery and dietary interventions for obesity on brain neurotransmitter systems and metabolism: A systematic review of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies.
This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low-calorie diet, three very low-calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for C-raclopride, F-fallypride, I-IBZM; one for dopamine transporter, I-FP-CIT; one used tracer for serotonin 5-HT receptor, F-altanserin; two used tracers for serotonin transporter, C-DASB or I-FP-CIT; two used tracer for μ-opioid receptor, C-carfentanil; one used tracer for noradrenaline transporter, C-MRB); seven studies assessed glucose uptake using F-fluorodeoxyglucose; four studies assessed regional cerebral blood flow using O-H O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using F-FTHA and one using C-palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies.
Topics: Humans; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon; Bariatric Surgery; Brain; Obesity; Neurotransmitter Agents
PubMed: 37699864
DOI: 10.1111/obr.13620 -
NeuroImage Nov 2021Although brain research has taken important strides in recent decades, the interaction and coupling of its different physiological levels is still not elucidated....
Although brain research has taken important strides in recent decades, the interaction and coupling of its different physiological levels is still not elucidated. Specifically, the molecular substrates of resting-state functional connectivity (rs-FC) remain poorly understood. The aim of this study was elucidating interactions between dopamine D2 receptors (D2R) and serotonin transporter (SERT) availabilities in the striatum (CPu) and medial prefrontal cortex (mPFC), two of the main dopaminergic and serotonergic projection areas, and the default-mode network. Additionally, we delineated its interaction with two other prominent resting-state networks (RSNs), the salience network (SN) and the sensorimotor network (SMN). To this extent, we performed simultaneous PET/fMRI scans in a total of 59 healthy rats using [C]raclopride and [C]DASB, two tracers used to image quantify D2R and SERT respectively. Edge, node and network-level rs-FC metrics were calculated for each subject and potential correlations with binding potentials (BP) in the CPu and mPFC were evaluated. We found widespread negative associations between CPu D2R availability and all the RSNs investigated, consistent with the postulated role of the indirect basal ganglia pathway. Correlations between D2Rs in the mPFC were weaker and largely restricted to DMN connectivity. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between and within the SN, SMN and the posterior DMN, underlining the complex role of serotonergic neurotransmission in this region. Here we show direct relationships between rs-FC and molecular properties of the brain as assessed by simultaneous PET/fMRI in healthy rodents. The findings in the present study contribute to the basic understanding of rs-FC by revealing associations between inter-subject variances of rs-FC and receptor and transporter availabilities. Additionally, since current therapeutic strategies typically target neurotransmitter systems with the aim of normalizing brain function, delineating associations between molecular and network-level brain properties is essential and may enhance the understanding of neuropathologies and support future drug development.
Topics: Animals; Brain Mapping; Corpus Striatum; Magnetic Resonance Imaging; Male; Nerve Net; Positron-Emission Tomography; Prefrontal Cortex; Rats; Receptors, Dopamine D2; Rest; Serotonin Plasma Membrane Transport Proteins
PubMed: 34428573
DOI: 10.1016/j.neuroimage.2021.118501 -
Neurology Sep 2022Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline...
BACKGROUND AND OBJECTIVES
Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates.
METHODS
We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity.
RESULTS
Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion.
DISCUSSION
These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.
Topics: Aged; Aging; Cross-Sectional Studies; Dopamine; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 35790424
DOI: 10.1212/WNL.0000000000200891 -
Experimental Neurology Aug 2021Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor...
BACKGROUND
Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration.
OBJECTIVES
In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing μ-opioid receptor expression.
METHODS
Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5 weeks. [H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and μ-opioid receptor availability were assessed with [H]Raclopride and [H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol.
RESULTS
We confirmed a dopaminegic deficit with increased striatal [H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [H]UCB-J binding while [H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic μ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold.
CONCLUSION
These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.
Topics: Animals; Brain; Exercise Test; Male; Oxidopamine; Parkinsonian Disorders; Physical Conditioning, Animal; Rats; Rats, Wistar; Synapses
PubMed: 33965411
DOI: 10.1016/j.expneurol.2021.113741 -
The Journal of Clinical Endocrinology... Sep 2021Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive.
RESEARCH DESIGN AND METHODS
We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial.
RESULTS
In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin.
CONCLUSIONS
This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.
Topics: Administration, Intranasal; Adult; Brain; Corpus Striatum; Cross-Over Studies; Dopamine; Healthy Volunteers; Humans; Insulin; Magnetic Resonance Imaging; Male; Neural Pathways; Positron-Emission Tomography; Single-Blind Method
PubMed: 34131733
DOI: 10.1210/clinem/dgab410 -
Journal of Neural Engineering Apr 2021To explore the viability of developing a computer-aided diagnostic system for Parkinsonian syndromes using dynamic [C]raclopride positron emission tomography (PET) and...
To explore the viability of developing a computer-aided diagnostic system for Parkinsonian syndromes using dynamic [C]raclopride positron emission tomography (PET) and T1-weighted magnetic resonance imaging (MRI) data.The biological heterogeneity of Parkinsonian syndromes renders their statistical classification a challenge. The unique combination of structural and molecular imaging data allowed different classifier designs to be tested. Datasets from dynamic [C]raclopride PET and T1-weighted MRI scans were acquired from six groups of participants. There were healthy controls (CTRL= 15), patients with Parkinson's disease (PD= 27), multiple system atrophy (MSA= 8), corticobasal degeneration (CBD= 6), and dementia with Lewy bodies (DLB= 5). MSA, CBD, and DLB patients were classified into one category designated as atypical Parkinsonism (AP). The distribution volume ratio (DVR) kinetic parameters obtained from the PET data were used to quantify the reversible tracer binding to D2/D3 receptors in the subcortical regions of interest (ROI). The grey matter (GM) volumes obtained from the MRI data were used to quantify GM atrophy across cortical, subcortical, and cerebellar ROI.The classifiers CTRL vs PD and CTRL vs AP achieved the highest balanced accuracy combining DVR and GM (DVR-GM) features (96.7%, 92.1%, respectively), followed by the classifiers designed with DVR features (93.3%, 88.8%, respectively), and GM features (69.6%, 86.1%, respectively). In contrast, the classifier PD vs AP showed the highest balanced accuracy (78.9%) using DVR features only. The integration of DVR-GM (77.9%) and GM features (72.7%) produced inferior performances. The classifier CTRL vs PD vs AP showed high weighted balanced accuracy when DVR (80.5%) or DVR-GM features (79.9%) were integrated. GM features revealed poorer performance (59.5%).This work was unique in its combination of structural and molecular imaging features in binary and triple category classifications. We were able to demonstrate improved binary classification of healthy/diseased status (concerning both PD and AP) and equate performance to DVR features in multiclass classifications.
Topics: Gray Matter; Humans; Magnetic Resonance Imaging; Parkinson Disease; Parkinsonian Disorders; Positron-Emission Tomography; Raclopride
PubMed: 33848996
DOI: 10.1088/1741-2552/abf772