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Behavioural Brain Research Apr 2024Dopamine (DA) is mainly involved in locomotor activity, reward processes and maternal behaviors. Rats with KO gene for dopamine transporter (DAT), coding for a truncated...
Dopamine (DA) is mainly involved in locomotor activity, reward processes and maternal behaviors. Rats with KO gene for dopamine transporter (DAT), coding for a truncated DAT protein, are in hyperdopaminergic conditions and thus develop stereotyped behaviors and hyperactivity. Our aim was to test the prior transgenerational modulation of wild and truncated alleles as expressed in heterozygous DAT rats: specifically, we addressed the possible sequelae due to genotype and gender of the ancestors, with regard to behavioral differences in F, F, F rats. We studied non-classical DAT heterozygotes (HETs) based on two specular lines, with putative grand-maternal vs. grand-paternal imprinting. MAT females (F; offspring of KO male and WT female) mated with a KO male to generate MIX offspring (F). Specularly, PAT females (F; offspring of KO female and WT male) mated with a KO male to generate PIX offspring (F). Similarly to PAT, we obtained MUX (F; HET offspring of MAT sire and KO dam); we also observed the F (MYX: HET offspring of KO male and MUX female, thus with DAT-KO maternal grandmother like also for PIX). We studied their circadian cycle of locomotor activity and their behavior in the elevated-plus-maze (EPM). Locomotor hyper-activity occurs in F, the opposite occurs in F, with MYX rats appearing undistinguishable from WT ones. Open-arm preference emerged in PIX and MIX rats. Only MAT and MYX rats showed a significant vulnerability for ADHD-like inattentive symptoms (duration of rearing in the EPM; Viggiano et al., 2002). A risk-taking profile is evident in the F phenotype, while inattentiveness from F progeny tends to be transferred to F. We hypothesize that DAT-related phenotypes result from effective inheritance through pedigree of imprints that are dependent on grandparents, suggesting a protective role for gestation within a hyperdopaminergic uterus. For major features, similar odd (F, F) generations appear opposed to even (F) ones; for minor specific features, the phenotype transfer may affect the progenies with a male but not a female DAT-KO ancestor.
Topics: Rats; Male; Female; Animals; Dopamine Plasma Membrane Transport Proteins; Heterozygote; Reproduction; Phenotype; Cognition
PubMed: 38408522
DOI: 10.1016/j.bbr.2024.114921 -
BioRxiv : the Preprint Server For... Feb 2024The thiazide-sensitive sodium chloride cotransporter (NCC) is the major apical sodium transporter located in the mammalian renal distal convoluted tubule (DCT). The...
BACKGROUND
The thiazide-sensitive sodium chloride cotransporter (NCC) is the major apical sodium transporter located in the mammalian renal distal convoluted tubule (DCT). The amount of sodium reabsorbed in the DCT through NCC plays an important role in the regulation of extracellular fluid volume and blood pressure. Dopamine and its receptors constitute a renal antihypertensive system in mammals. The disruption of Drd4 in mice causes kidney-related hypertension. However, the pathogenesis of D4R-deficiency associated hypertension is not well documented.
METHOD
We assessed the effects of D4R on NCC protein abundances and activities of DCT in mice with renal or global Drd4-deficiencies and expressing human D4.7 variant and in cultured mouse DCT cells, and explored the molecular mechanism.
RESULTS
NCC inhibitor hydrochlorothiazide enhanced the natriuresis in Drd4-/- mice. Renal NCC protein was greater while ubiquitination of NCC was less in Drd4-/- than Drd4+/+ mice. Silencing of D4R in cultured mouse DCT cells increased NCC protein but decreased NCC ubiquitination. D4R agonist had opposite effects that were blocked by the antagonist. In mouse kidneys and DCT cells D4R and NCC colocalized and co-immunoprecipitated. Moreover, D4R-agonist promoted the binding between the two proteins demonstrated by fluorescence resonance energy transfer. D4R agonism internalized NCC, decreased NCC in the plasma membrane, increased NCC in lysosomes and reduced NCC-dependent-intracellular-sodium transport. The lysosomal inhibitor chloroquine prevented the D4R-induced NCC-reduction. A shortened NCC half-life was suggested by its decay under cycloheximide-chase. Ubiquitin-specific-protease 48 (USP48, a deubiquitinating enzyme) was increased in the kidneys and cells with Drd4-deficiency while D4R stimulation decreased it in vitro and reduction of USP48 with siRNA decreased NCC expression. The mice carrying human D4.7 variant or with renal supcapsular-Drd4-siRNA-delivery developed hypertension with increased NCC.
CONCLUSION
Our data demonstrates that D4R downregulates NCC by promoting USP48-associated deubiquitination and subsequent internalization, lysosome relocation and degradation.
PubMed: 38405772
DOI: 10.1101/2024.02.14.580405 -
Clinical Parkinsonism & Related... 2024The present study characterized the degeneration of nigrostriatal dopaminergic neurons in the early stages of parkinsonian disorders using integrative neuroimaging...
INTRODUCTION
The present study characterized the degeneration of nigrostriatal dopaminergic neurons in the early stages of parkinsonian disorders using integrative neuroimaging analysis with neuromelanin-sensitive MRI and I-FP-CIT dopamine transporter (DAT) SPECT.
METHODS
Thirty-one, 30, and 29 patients with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) with abnormal specific binding ratio (SBR) in either hemisphere (mean ± 2SD), and parkinsonism-predominant multiple system atrophy (MSA-P), respectively, were enrolled. Neuromelanin-related contrast (NRC) in the substantia nigra (NRC) and locus coeruleus (NRC) and the SBR of DAT SPECT were measured. All the patients underwent both examinations simultaneously within five years after symptom onset. After adjusting for interhemispheric asymmetry on neuromelanin-related MRI contrast using the Z-score, linear regression analysis of the NRC and SBR was performed for the most- and least-affected hemispheres, as defined by the interhemispheric differences per variable (SBR, NRC, standardized [SBR + NRC]) in each patient.
RESULTS
Although the variables did not differ significantly between PSP and CBS, a significant correlation was found for CBS in the most-affected hemisphere for all the definitions, including the clinically defined, most-affected hemisphere. No significant correlation was found between the NRC and SBR for any of the definitions in either PSP or MSA-P.
CONCLUSION
Together with the findings of our previous study of dementia with Lewy bodies (DLB) and Parkinson's disease (PD), the present findings indicated that neural degeneration in the disorders examined may be categorized by the significance of the NRC-SBR correlation in PD and CBS and its non-significance in DLB, PSP, and MSA-P.
PubMed: 38405025
DOI: 10.1016/j.prdoa.2024.100242 -
Neurobiology of Disease Apr 2024A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and...
A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and DA-independent mechanisms, as glutamate inputs from corticostriatal projection neurons impact DA-responsive medium spiny neurons in the striatum to cause the dyskinetic behaviors. In this study, we explored whether suppression of presynaptic corticostriatal glutamate inputs might affect the behavioral and biochemical outcomes associated with LID. We first established an animal model in which 6-hydroxydopamine (6-OHDA)-lesioned mice were treated daily with L-dopa (10 mg/kg, i.p.) for 2 weeks; these mice developed stereotypical abnormal involuntary movements (AIMs). When the mice were pretreated with the NMDA antagonist, amantadine, we observed suppression of AIMs and reductions of phosphorylated ERK1/2 and NR2B in the striatum. We then took an optogenetic approach to manipulate glutamatergic activity. Slc17a6 (vGluT2)-Cre mice were injected with pAAV5-Ef1a-DIO-eNpHR3.0-mCherry and received optic fiber implants in either the M1 motor cortex or dorsolateral striatum. Optogenetic inactivation at either optic fiber implant location could successfully reduce the intensity of AIMs after 6-OHDA lesioning and L-dopa treatment. Both optical manipulation strategies also suppressed phospho-ERK1/2 and phospho-NR2B signals in the striatum. Finally, we performed intrastriatal injections of LDN 212320 in the dyskenesic mice to enhance expression of glutamate uptake transporter GLT-1. Sixteen hours after the LDN 212320 treatment, L-dopa-induced AIMs were reduced along with the levels of striatal phospho-ERK1/2 and phospho-NR2B. Together, our results affirm a critical role of corticostriatal glutamate neurons in LID and strongly suggest that diminishing synaptic glutamate, either by suppression of neuronal activity or by upregulation of GLT-1, could be an effective approach for managing LID.
Topics: Rats; Mice; Animals; Levodopa; Parkinson Disease; Oxidopamine; Glutamic Acid; Rats, Sprague-Dawley; Dopamine; Corpus Striatum; Dyskinesias; Disease Models, Animal; Antiparkinson Agents
PubMed: 38401650
DOI: 10.1016/j.nbd.2024.106452 -
Human Brain Mapping Feb 2024Attention network theory proposes three distinct types of attention-alerting, orienting, and control-that are supported by separate brain networks and modulated by...
Attention network theory proposes three distinct types of attention-alerting, orienting, and control-that are supported by separate brain networks and modulated by different neurotransmitters, that is, norepinephrine, acetylcholine, and dopamine. Here, we explore the extent of cortical, genetic, and molecular dissociation of these three attention systems using multimodal neuroimaging. We evaluated the spatial overlap between fMRI activation maps from the attention network test (ANT) and cortex-wide gene expression data from the Allen Human Brain Atlas. The goal was to identify genes associated with each of the attention networks in order to determine whether specific groups of genes were co-expressed with the corresponding attention networks. Furthermore, we analyzed publicly available PET-maps of neurotransmitter receptors and transporters to investigate their spatial overlap with the attention networks. Our analyses revealed a substantial number of genes (3871 for alerting, 6905 for orienting, 2556 for control) whose cortex-wide expression co-varied with the activation maps, prioritizing several molecular functions such as the regulation of protein biosynthesis, phosphorylation, and receptor binding. Contrary to the hypothesized associations, the ANT activation maps neither aligned with the distribution of norepinephrine, acetylcholine, and dopamine receptor and transporter molecules, nor with transcriptomic profiles that would suggest clearly separable networks. Independence of the attention networks appeared additionally constrained by a high level of spatial dependency between the network maps. Future work may need to reconceptualize the attention networks in terms of their segregation and reevaluate the presumed independence at the neural and neurochemical level.
Topics: Humans; Orientation; Acetylcholine; Brain; Magnetic Resonance Imaging; Norepinephrine
PubMed: 38401136
DOI: 10.1002/hbm.26588 -
Pharmaceuticals (Basel, Switzerland) Jan 2024Dopamine and serotonin receptors and transporters play an essential role in the pathophysiology of schizophrenia; changes in their expression have been reported in...
Risperidone Decreases Expression of Serotonin Receptor-2A (5-HT2A) and Serotonin Transporter (SERT) but Not Dopamine Receptors and Dopamine Transporter (DAT) in PBMCs from Patients with Schizophrenia.
Dopamine and serotonin receptors and transporters play an essential role in the pathophysiology of schizophrenia; changes in their expression have been reported in neurons and leukocytes. Each antipsychotic induces a unique pattern in leukocyte function and phenotype. However, the use of polytherapy to treat schizophrenia makes it challenging to determine the specific effects of risperidone on peripheral blood mononuclear cells (PBMCs). The aim of this study was to evaluate the changes in the expression of D, D, DAT, 5-HT, and SERT in PBMCs from healthy volunteers (HV), drug-naive patients with schizophrenia (PWS), drug-free PWS, and PWS treated with risperidone for up to 40 weeks using quantitative PCR. Our study revealed elevated mRNA levels of D, DAT, 5-HT, and SERT in unmedicated PWS. Treatment with risperidone led to a reduction only in the expression of 5-HT and SERT. Furthermore, we observed a moderate correlation between 5-HT expression and the positive and negative syndrome scale (PANSS), as well as SERT expression and PANSS scale. We also found a moderate correlation between 5-HT and SERT expression and the positive subscale. The duration of risperidone consumption had a significant negative correlation with the expression of 5-HT and SERT. Our study introduces the measurement of 5-HT and SERT expression in PBMCs as a useful parameter for assessing the response to risperidone in PWS.
PubMed: 38399382
DOI: 10.3390/ph17020167 -
International Journal of Molecular... Feb 2024Ekbom syndrome, also known as delusional parasitosis (DP) or delusional infestation, is an uncommon psychiatric disorder distinguished by an enduring conviction of... (Review)
Review
Ekbom syndrome, also known as delusional parasitosis (DP) or delusional infestation, is an uncommon psychiatric disorder distinguished by an enduring conviction of parasitic infestation, persisting notwithstanding the presence of medical evidence to the contrary. Primarily affecting middle-aged women, DP can manifest either as isolated psychological distress or as a component within a more intricate psychiatric framework, substantially influencing the quality of life for affected individuals. Its pathophysiological mechanism involves uncertain dopaminergic imbalances and dysfunction in the dopamine transporter system. Dermatologists often play a pivotal role in diagnosis, as patients first seek dermatological assessments of their signs and symptoms. However, DP frequently originates from underlying psychiatric disorders or medical variables, manifesting with neurological and infectious causative factors. The diagnostic complexity is attributed to patients' resolute convictions, leading to delayed psychiatric intervention. First-line DP treatment involves antipsychotics, with newer agents demonstrating promising prospects, but the lack of standardized protocols poses a significant therapeutic challenge. In this narrative review, both a comprehensive approach to this uncommon pathology and an update on the state of knowledge in this medical subfield focused on optimizing the management of DP are provided. The complexity of DP underlying its uncommon nature and the incomplete understanding of its pathophysiology highlight the need for further research through multicenter studies and multidisciplinary teams to enhance therapeutic efficacy and safety.
Topics: Middle Aged; Humans; Female; Quality of Life; Delusional Parasitosis; Antipsychotic Agents; Dopamine; Interdisciplinary Studies
PubMed: 38396826
DOI: 10.3390/ijms25042151 -
NPJ Parkinson's Disease Feb 2024Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression loss to a PD patient cohort. However, it is still unknown whether Rit2 loss itself impacts DA neuron function and/or viability. Here we report that conditional Rit2 silencing in mouse DA neurons drove motor dysfunction that occurred earlier in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreased DA release, striatal DA content, phenotypic DAergic markers, DA neurons, and DAergic terminals, with increased pSer129-alpha synuclein and pSer935-LRRK2 expression. These results provide clear evidence that Rit2 loss is causal for SNc cell death and motor dysfunction, and reveal key sex-specific differences in the response to Rit2 loss.
PubMed: 38395968
DOI: 10.1038/s41531-024-00648-8 -
PeerJ 2024The neuroendocrine system has important implications for affiliation behavior among humans and can be used to assess the correlation between social relationships,...
BACKGROUND
The neuroendocrine system has important implications for affiliation behavior among humans and can be used to assess the correlation between social relationships, stress, and health. This can be influenced by social closeness; this aspect is the closeness towards another individual or a group of individuals such as a sports team. Sports performance anxiety is considered an unpleasant emotional reaction composed of physiological, cognitive, affective, and behavioral components. This motivates us to learn about the process that can influence the outcome of competition. Hormones and genetics would seem to influence outcome and performance. In this regard, many studies have focused on the exercise response as a function of ovarian hormones and it has been observed that progesterone is a hormone that plays a key role in reducing anxiety, and thus stress, in humans and other animals. On the other hand, high cortisol concentrations are known to contribute to increased anxiety levels. However, the salivary alpha-amylase (sAA) enzyme has been suggested as marker of acute stress than cortisol. Genetics also seem to influence anxiety and stress management as in the case of brain-derived neurotrophic factor (BDNF) and striatal dopamine transporter (DAT). Therefore, the study aims to investigate social closeness, as a measure of sports team cohesion that can influence athletes' performance results, and its ability to influence the secretion of hormones, such as progesterone and cortisol, that affect the management of sports anxiety while also taking into account genetic background during a volleyball match.
METHODS
Twenty-six female volleyball players who volunteered participated in this study (mean ± SD: age, 12.07 ± 0.7 years), and played in the final of the provincial volleyball championship in Palermo. All girls were during the ovarian cycle, in detail between the follicular and early ovulatory phases.
RESULTS
The results showed a significant decrease in salivary cortisol only in the winning group ( < 0.039). In fact, whilst in the latter the pre-match level was 7.7 ng/ml and then decreased to 4.5 ng/ml after the match, in the losers group change was not statistically significant (7.8 ng/ml 6.6 ng/ml pre- and post-match). As to the sAA concentration, the winning team showed a statistically significant variation between pre- and post-match than the losers (166.01 ± 250 U/ml 291.59 ± 241 U/ml) ( = 0.01).
CONCLUSION
Analyzing the results of the SAS-2 psychological test it is highlighted that, on average, the loser group was more anxious than the winning group, and this contributed to the final result. In conclusion, there is strong evidence supporting the state of the art that many factors can affect performance anxiety and thus the performance itself.
Topics: Humans; Adolescent; Female; Child; Volleyball; Hydrocortisone; Progesterone; Saliva; Performance Anxiety
PubMed: 38390388
DOI: 10.7717/peerj.16617 -
Translational Psychiatry Feb 2024G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action...
G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.
Topics: Animals; Mice; Rats; Cannabidiol; Cocaine; Dopaminergic Neurons; Glutamic Acid; Mice, Knockout; Nicotine; Pharmaceutical Preparations; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Substance-Related Disorders
PubMed: 38374108
DOI: 10.1038/s41398-024-02820-3