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Addiction Biology Jun 2024Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated...
Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated with positive effects while solitary drinking is linked to negative effects. However, the neurobiological mechanism by which the social environment during alcohol intake impacts on behavioural responses remains poorly understood. We investigated whether distinct social environments affect behavioural responses to ethanol and the role of the dopamine system in this phenomenon in the fruit fly Drosophila melanogaster. The wild-type Canton-S (CS) flies showed higher locomotor response when exposed to ethanol in a group setting than a solitary setting, and there was no difference in females and males. Dopamine signalling is crucial for the locomotor stimulating effect of ethanol. When subjected to ethanol exposure alone, the dopamine transport mutant flies fumin (fmn) with hyper dopamine displayed the locomotor response similar to CS. When subjected to ethanol in a group setting, however, the fmn's response to the locomotor stimulating effect was substantially augmented compared with CS, indicating synergistic interaction of dopamine signalling and social setting. To identify the dopamine signalling pathway important for the social effect, we examined the flies defective in individual dopamine receptors and found that the D1 receptor dDA1/Dop1R1 is the major receptor mediating the social effect. Taken together, this study underscores the influence of social context on the neural and behavioural responses to ethanol.
Topics: Animals; Ethanol; Dopamine; Drosophila melanogaster; Male; Female; Drosophila Proteins; Receptors, Dopamine D1; Social Environment; Signal Transduction; Locomotion; Receptors, Dopamine; Behavior, Animal; Central Nervous System Depressants; Social Behavior; Dopamine Plasma Membrane Transport Proteins; Motor Activity
PubMed: 38898729
DOI: 10.1111/adb.13420 -
BMC Medical Genomics Jun 2024Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to...
BACKGROUND
Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake.
METHODS
421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m) calculated using the creatinine-based Berlin Initiative Study-1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform.
RESULTS
The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14-0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35-0.90; p = 0.017]. The two variants were predicted to be potentially functional.
CONCLUSIONS
The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although the associations do not survive correction for Bonferroni multiple testing, and additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Fusion Regulatory Protein 1, Heavy Chain; Genetic Predisposition to Disease; Hypertension; Levodopa; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Risk Factors; Adaptor Proteins, Signal Transducing
PubMed: 38890684
DOI: 10.1186/s12920-024-01935-2 -
Neurobiology of Disease Jun 2024Substantial work has been devoted to better understand the contribution of the myriad of genes that may underly the development of Parkinson's disease (PD) and their...
Substantial work has been devoted to better understand the contribution of the myriad of genes that may underly the development of Parkinson's disease (PD) and their role in disease etiology. The small GTPase Ras-like without CAAX2 (RIT2) is one such genetic risk factor, with one single nucleotide polymorphism in the RIT2 locus, rs12456492, having been associated with PD risk in multiple populations. While RIT2 has previously been shown to influence signaling pathways, dopamine transporter trafficking, and LRRK2 activity, its cellular function remains unclear. In the current study, we have situated RIT2 to be upstream of various diverse processes associated with PD. In cellular models, we have shown that RIT2 is necessary for activity-dependent changes in the expression of genes related to the autophagy-lysosomal pathway (ALP) by regulating the nuclear translocation of MiT/TFE3-family transcription factors. RIT2 is also associated with lysosomes and can regulate autophagic flux and clearance by regulating lysosomal hydrolase expression and activity. Interestingly, upregulation of RIT2 can augment ALP flux and protect against α-synuclein aggregation in cortical neurons. Taken together, the present study suggests that RIT2 can regulates gene expression upstream of ALP function and that enhancing RIT2 activity may provide therapeutic benefit in PD.
PubMed: 38885848
DOI: 10.1016/j.nbd.2024.106568 -
PCN Reports : Psychiatry and Clinical... Mar 2024This study aimed to clarify the abnormalities in dopamine transporter (DAT) availability in drug-naive adult patients with attention-deficit/hyperactivity disorder...
AIM
This study aimed to clarify the abnormalities in dopamine transporter (DAT) availability in drug-naive adult patients with attention-deficit/hyperactivity disorder (ADHD) and the relationship between ADHD symptoms and abnormalities in DAT availability.
METHODS
Single-photon emission tomography (SPECT) was performed using iodine-123-β-carbomethoxy-3β-(4-iodophenyltropane) (I-123 β CIT) as a tracer to measure in vivo DAT availability in 20 drug-naive patients with ADHD [mean age ± standard deviation (SD)]: 25 ± 3.44 years; male:female = 11:9] and 20 age- and sex-matched healthy controls (HCs) (mean age ± SD: 23.9 ± 2.27 years). Comparisons of DAT availability between HCs and adult patients with ADHD and the association between symptom severity and DAT availability within the ADHD group were analyzed using Statistical Parametric Mapping 12.
RESULTS
Drug-naive adults with ADHD showed significantly reduced DAT availability in the bilateral nucleus accumbens compared with HCs. Correlation analyses revealed a negative correlation between the severity of inattentive symptoms in adult patients with ADHD and DAT availability in the bilateral heads of the caudate nucleus, indicating the association between severe inattentive symptoms and lower DAT availability in the caudate nucleus.
CONCLUSION
In drug-naive adult patients with ADHD, DAT availability was reduced in the nucleus accumbens, an important part of the reward system. This finding indicates the importance of the DAT in the reward system in the pathogenesis of ADHD. Inattentiveness was associated with DAT availability in the caudate nucleus, suggesting involvement of the cortico-striato-thalamo-cortical circuit.
PubMed: 38868484
DOI: 10.1002/pcn5.177 -
PCN Reports : Psychiatry and Clinical... Sep 2023
PubMed: 38867818
DOI: 10.1002/pcn5.119 -
BioRxiv : the Preprint Server For... Jun 2024Age-related dopamine (DA) neuron loss is a primary feature of Parkinson's disease. However, it remains unclear whether similar biological processes occur during healthy...
Age-related dopamine (DA) neuron loss is a primary feature of Parkinson's disease. However, it remains unclear whether similar biological processes occur during healthy aging, albeit to a lesser degree. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no changes in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 () mRNA expression. In co-transmitting / neurons, and transcripts decreased with aging. Importantly, striatal Th and Vglut2 protein expression remained unchanged. In translating our findings to humans, we found no midbrain neurodegeneration during aging and identified age-related decreases in and mRNA expression similar to mouse. Unlike mice, we discovered diminished density of striatal TH dopaminergic terminals in aged human subjects. However, TH and VGLUT2 protein expression were unchanged in the remaining striatal boutons. Finally, in contrast to and mRNA, expression of most ribosomal genes in neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.
PubMed: 38854057
DOI: 10.1101/2024.06.01.596950 -
Research Square May 2024Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal syndrome for Parkinson's disease (PD) and related -synucleinopathies. We conducted a...
Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal syndrome for Parkinson's disease (PD) and related -synucleinopathies. We conducted a longitudinal imaging study of network changes in iRBD and their relationship to phenoconversion. Expression levels for the PD-related motor and cognitive networks (PDRP and PDCP) were measured at baseline, 2 and 4 years, along with dopamine transporter (DAT) binding. PDRP and PDCP expression increased over time, with higher values in the former network. While abnormal functional connections were identified initially within the PDRP, others bridging the two networks appeared later. A model based on the rates of PDRP progression and putamen dopamine loss predicted phenoconversion within 1.2 years in individuals with iRBD. In aggregate, the data suggest that maladaptive reorganization of brain networks takes place in iRBD years before phenoconversion. Network expression and DAT binding measures can be used together to assess phenoconversion risk in these individuals.
PubMed: 38853923
DOI: 10.21203/rs.3.rs-4427198/v1 -
Molecular and Cellular Endocrinology Jun 2024The aim of the present research was to explore the mechanisms underlying the role of dopamine in the regulation of insulin secretion in beta cells. The effect of...
The aim of the present research was to explore the mechanisms underlying the role of dopamine in the regulation of insulin secretion in beta cells. The effect of dopamine on insulin secretion was investigated on INS 832/13 cell line upon glucose and other secretagogues stimulation. Results show that dopamine significantly inhibits insulin secretion stimulated by both glucose and other secretagogues, while it has no effect on the basal secretion. This effect requires the presence of dopamine during incubation with the various secretagogues. Both electron microscopy and immunohistochemistry indicate that in beta cells the D dopamine receptor is localized within the insulin granules. Blocking dopamine entry into the insulin granules by inhibiting the VMAT2 transporter with tetrabenazine causes a significant increase in ROS production. Our results confirm that dopamine plays an important role in the regulation of insulin secretion by pancreatic beta cells through a regulated and precise compartmentalization mechanisms.
PubMed: 38838763
DOI: 10.1016/j.mce.2024.112294 -
Current Research in Physiology 2024Human monoamine transporters (MATs) are critical to regulating monoaminergic neurotransmission by translocating their substrates from the synaptic space back into the...
Human monoamine transporters (MATs) are critical to regulating monoaminergic neurotransmission by translocating their substrates from the synaptic space back into the presynaptic neurons. As such, their primary substrate binding site S1 has been targeted by a wide range of compounds for treating neuropsychiatric and neurodegenerative disorders including depression, ADHD, neuropathic pain, and anxiety disorders. We present here a comparative study of the structural dynamics and ligand-binding properties of two MATs, dopamine transporter (DAT) and serotonin transporter (SERT), with focus on the allosteric modulation of their transport function by drugs or substrates that consistently bind a secondary site S2, proposed to serve as an allosteric site. Our systematic analysis of the conformational space and dynamics of a dataset of 50 structures resolved for DAT and SERT in the presence of one or more ligands/drugs reveals the specific residues playing a consistent role in coordinating the small molecules bound to subsites S2-I and S2-II within S2, such as R476 and Y481 in dDAT and E494, P561, and F556 in hSERT. Further analysis reveals how DAT and SERT differ in their two principal modes of structural changes, PC1 and PC2. Notably, PC1 underlies the transition between outward- and inward-facing states of the transporters as well as their gating; whereas PC2 supports the rearrangements of TM helices near the S2 site. Finally, the examination of cross-correlations between structural elements lining the respective sites S1 and S2 point to the crucial role of coupled motions between TM6a and TM10. In particular, we note the involvement of hSERT residues F335 and G338, and E493-E494-T497 belonging to these two respective helices, in establishing the allosteric communication between S1 and S2. These results help understand the molecular basis of the action of drugs that bind to the S2 site of DAT or SERT. They also provide a basis for designing allosteric modulators that may provide better control of specific interactions and cellular pathways, rather than indiscriminately inhibiting the transporter by targeting its orthosteric site.
PubMed: 38836245
DOI: 10.1016/j.crphys.2024.100125 -
Neurobiology of Disease Aug 2024Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and...
BACKGROUND
Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates.
METHODS
A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity.
RESULTS
MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits.
CONCLUSIONS
Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.
Topics: Humans; Multiple System Atrophy; Parkinson Disease; Male; Female; Middle Aged; Aged; Brain; Magnetic Resonance Imaging; Iron; Neurotransmitter Agents; Brain Mapping
PubMed: 38830476
DOI: 10.1016/j.nbd.2024.106549