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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 -
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 -
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 -
Scientific Reports Jul 2022The dopamine blockade by antipsychotics trigger subjective dysphoria. Compared with D2 antagonists, aripiprazole, a D2 partial agonist, was expected to produce a...
The dopamine blockade by antipsychotics trigger subjective dysphoria. Compared with D2 antagonists, aripiprazole, a D2 partial agonist, was expected to produce a different experience. Indeed, a previous study reported no relationship between the D2 receptor occupancy by aripiprazole and subjective dysphoria, while the D2 receptor occupancy by antagonists was associated with negative subjective experiences. This study revisited the relationship in patients treated with aripiprazole by using an inhibitory E model, which enables the individual drug-free binding potential and D2 receptor occupancy to be properly estimated. Eight patients with schizophrenia who have been clinically stable on aripiprazole were enrolled. Assessments including Positive and Negative Syndrome Scale (PANSS) and Subjective Well-being under Neuroleptics Scale (Kv-SWN) were administered. [C]raclopride PET scan were conducted 2, 26, and 74 h after aripiprazole administration. Regression analysis showed a significant negative association between the D2 receptor occupancy by aripiprazole in the striatum and the Kv-SWN (R = 0.55, p = 0.036), but the PANSS total score was not associated with the Kv-SWN (R = 0.42, p = 0.080). The negative association between D2 receptor occupancy by aripiprazole and subjective well-being implies that clinicians should find the lowest effective doses of aripiprazole for clinically stable patients to improve their subjective experiences and clinical outcomes.
Topics: Antipsychotic Agents; Aripiprazole; Humans; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2
PubMed: 35840763
DOI: 10.1038/s41598-022-16130-5 -
NeuroImage May 2022Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis...
Head motion during PET scans causes image quality degradation, decreased concentration in regions with high uptake and incorrect outcome measures from kinetic analysis of dynamic datasets. Previously, we proposed a data-driven method, center of tracer distribution (COD), to detect head motion without an external motion tracking device. There, motion was detected using one dimension of the COD trace with a semiautomatic detection algorithm, requiring multiple user defined parameters and manual intervention. In this study, we developed a new data-driven motion detection algorithm, which is automatic, self-adaptive to noise level, does not require user-defined parameters and uses all three dimensions of the COD trace (3DCOD). 3DCOD was first validated and tested using 30 simulation studies (F-FDG, N = 15; C-raclopride (RAC), N = 15) with large motion. The proposed motion correction method was tested on 22 real human datasets, with 20 acquired from a high resolution research tomograph (HRRT) scanner (F-FDG, N = 10; C-RAC, N = 10) and 2 acquired from the Siemens Biograph mCT scanner. Real-time hardware-based motion tracking information (Vicra) was available for all real studies and was used as the gold standard. 3DCOD was compared to Vicra, no motion correction (NMC), one-direction COD (our previous method called 1DCOD) and two conventional frame-based image registration (FIR) algorithms, i.e., FIR1 (based on predefined frames reconstructed with attenuation correction) and FIR2 (without attenuation correction) for both simulation and real studies. For the simulation studies, 3DCOD yielded -2.3 ± 1.4% (mean ± standard deviation across all subjects and 11 brain regions) error in region of interest (ROI) uptake for F-FDG (-3.4 ± 1.7% for C-RAC across all subjects and 2 regions) as compared to Vicra (perfect correction) while NMC, FIR1, FIR2 and 1DCOD yielded -25.4 ± 11.1% (-34.5 ± 16.1% for C- RAC), -13.4 ± 3.5% (-16.1 ± 4.6%), -5.7 ± 3.6% (-8.0 ± 4.5%) and -2.6 ± 1.5% (-5.1 ± 2.7%), respectively. For real HRRT studies, 3DCOD yielded -0.3 ± 2.8% difference for F-FDG (-0.4 ± 3.2% for C-RAC) as compared to Vicra while NMC, FIR1, FIR2 and 1DCOD yielded -14.9 ± 9.0% (-24.5 ± 14.6%), -3.6 ± 4.9% (-13.4 ± 14.3%), -0.6 ± 3.4% (-6.7 ± 5.3%) and -1.5 ± 4.2% (-2.2 ± 4.1%), respectively. In summary, the proposed motion correction method yielded comparable performance to the hardware-based motion tracking method for multiple tracers, including very challenging cases with large frequent head motion, in studies performed on a non-TOF scanner.
Topics: Algorithms; Brain; Humans; Image Processing, Computer-Assisted; Kinetics; Motion; Movement; Positron-Emission Tomography
PubMed: 35257856
DOI: 10.1016/j.neuroimage.2022.119031