-
Redox Biology Apr 2024Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms...
Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms underlying AKI, effective clinical tools for prediction and treatment remain scarce. Oxidative stress and mitochondrial damage play a critical role in AKI and dopamine D4 receptor (DRD4) has been confirmed to be associated with oxidative stress. In this study, we hypothesized that DRD4 could attenuate AKI through its antioxidative and antiapoptotic effects. In vivo, DRD4 was remarkably decreased in the kidneys of mice subjected to ischemia/reperfusion injury (IRI) or cisplatin treatment. Notably, DRD4 significantly attenuated nephrotoxicity by suppressing oxidative stress and enhancing mitochondrial bioenergetics through the downregulation of reactive oxygen species (ROS) generation and NADPH oxidase 4 (NOX4) expression. In vitro, DRD4 demonstrated the ability to ameliorate oxidative stress-induced apoptosis in HK-2 cells subjected to hypoxia/reoxygenation- or cisplatin treatment. Transcriptome sequencing revealed that, mechanistically, DRD4 reduced the expression of its downstream target, interferon-stimulated gene 15 (ISG15), suppressing NOX4 ISGylation, enhancing the ubiquitination of NOX4, leading to its degradation, and ultimately counteracting oxidative stress-induced AKI. Altogether, these findings underscore the significance of DRD4 in AKI and elucidate DRD4 as a potential protectant against IRI or cisplatin-induced nephrotoxicity.
Topics: Mice; Animals; Cisplatin; NADPH Oxidase 4; Interferons; Receptors, Dopamine D4; Cell Line; Oxidative Stress; Acute Kidney Injury; Kidney; Reactive Oxygen Species; Reperfusion Injury; Apoptosis
PubMed: 38354631
DOI: 10.1016/j.redox.2024.103078 -
Proceedings of the National Academy of... Dec 2023Hilar mossy cells (MCs) are principal excitatory neurons of the dentate gyrus (DG) that play critical roles in hippocampal function and have been implicated in brain...
Hilar mossy cells (MCs) are principal excitatory neurons of the dentate gyrus (DG) that play critical roles in hippocampal function and have been implicated in brain disorders such as anxiety and epilepsy. However, the mechanisms by which MCs contribute to DG function and disease are poorly understood. A defining feature of MCs is the promoter activity of the dopamine D2 receptor (D2R) gene (), and previous work indicates a key role for dopaminergic signaling in the DG. Additionally, the involvement of D2R signaling in cognition and neuropsychiatric conditions is well known. Surprisingly, though, the function of MC D2Rs remains largely unexplored. In this study, we show that selective and conditional removal of from MCs of adult mice impaired spatial memory, promoted anxiety-like behavior, and was proconvulsant. To determine the subcellular expression of D2Rs in MCs, we used a D2R knockin mouse which revealed that D2Rs are enriched in the inner molecular layer of the DG, where MCs establish synaptic contacts with granule cells (GCs). D2R activation by exogenous and endogenous dopamine reduced MC to dentate GC synaptic transmission, most likely by a presynaptic mechanism. In contrast, exogenous dopamine had no significant impact on MC excitatory inputs and passive and active properties. Our findings support that MC D2Rs are essential for proper DG function by reducing MC excitatory drive onto GCs. Lastly, impairment of MC D2R signaling could promote anxiety and epilepsy, therefore highlighting a potential therapeutic target.
Topics: Animals; Mice; Dentate Gyrus; Dopamine; Epilepsy; Hippocampus; Mossy Fibers, Hippocampal; Receptors, Dopamine D2; Anxiety
PubMed: 38064513
DOI: 10.1073/pnas.2307509120 -
Parkinsonism & Related Disorders Sep 2023The human immunodeficiency virus (HIV) causes movement disorders in persons living with HIV (PLH). (Review)
Review
BACKGROUND
The human immunodeficiency virus (HIV) causes movement disorders in persons living with HIV (PLH).
OBJECTIVES AND METHODS
We conducted a systematic review on the spectrum of movement disorders in PLH using standard terms for each of the phenomenologies and HIV.
RESULTS
Movement disorders in PLH were commonly attributed to opportunistic infections (OI), dopamine receptor blockade reactions, HIV-associated dementia (HAD), presented during seroconversion, developed due to drug reactions or antiretroviral therapy (ART) itself and lastly, movement disorders occurred as a consequence of the HIV-virus. Parkinsonism in ART naïve PLH was associated with shorter survival, however when Parkinsonism presented in PLH on ART, the syndrome was indistinguishable from Idiopathic Parkinson's disease and responded to therapy. Tremor was often postural due to HAD, drugs or OI. Generalized chorea was most frequent in HIV encephalopathy and toxoplasmosis gondii caused most cases of hemichorea. Ataxia was strongly associated with JCV infection, ART efavirenz toxicity or due to HIV itself. Dystonia was reported in HAD, secondary to drugs and atypical facial dystonias. Both cortical/subcortical and segmental/spinal origin myoclonus were noted mainly associated with HAD. In patients with HIV related opsoclonus-myoclonus-ataxia-syndrome, seroconversion illness was the commonest cause of followed by IRIS and CSF HIV viral escape phenomenon.
CONCLUSIONS
Aetiology of movement disorders in PLH depend on the treatment state. Untreated, PLH are prone to develop OI and HAD and movement disorders. However, as the number of PLH on ART increase and survive longer, the frequency of ART and non-AIDS related complications are likely to increase.
Topics: Humans; HIV; Myoclonus; Movement Disorders; HIV Infections; Parkinson Disease; Parkinsonian Disorders; Ataxia
PubMed: 37532621
DOI: 10.1016/j.parkreldis.2023.105774 -
JAMA Psychiatry May 2024A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents....
IMPORTANCE
A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia.
OBJECTIVE
To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS
EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023.
INTERVENTIONS
Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks.
MAIN OUTCOMES AND MEASURES
The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated.
RESULTS
A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups.
CONCLUSIONS AND RELEVANCE
Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04738123.
PubMed: 38691387
DOI: 10.1001/jamapsychiatry.2024.0785 -
Biological Psychiatry Sep 2023A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is...
BACKGROUND
A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown.
METHODS
Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum.
RESULTS
We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele.
CONCLUSIONS
Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.
Topics: Humans; Dopamine; Receptors, Dopamine D2; Behavior, Addictive; Neurons; Reward
PubMed: 36805080
DOI: 10.1016/j.biopsych.2023.02.010 -
Frontiers in Physiology 2024GPCR-G protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of... (Review)
Review
GPCR-G protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-G protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP and releases DAG and IP. This IP increases intracellular Ca and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-G protein antibodies in GI smooth muscle, indicating the involvement of Gα protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active Gα proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by G proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY amino acids at ARD of TRPC5 binds with G protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for G and G pathway as G pathway increases intracellular Ca and the increased Ca facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (I) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-G protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.
PubMed: 38384797
DOI: 10.3389/fphys.2024.1362987 -
Clinical Parkinsonism & Related... 2023Dopamine agonists (DAs) have demonstrated efficacy for the treatment of Parkinson's disease (PD) but are limited by adverse effects (AEs). DAs can vary considerably in... (Review)
Review
Dopamine agonists (DAs) have demonstrated efficacy for the treatment of Parkinson's disease (PD) but are limited by adverse effects (AEs). DAs can vary considerably in their receptor subtype selectivity and affinity, chemical composition, receptor occupancy, and intrinsic activity on the receptor. Most currently approved DAs for PD treatment primarily target D2/D3 (D2-like) dopamine receptors. However, selective activation of D1/D5 (D1-like) dopamine receptors may enable robust activation of motor function while avoiding AEs related to D2/D3 receptor agonism. Full D1/D5 receptor-selective agonists have been explored in small, early-phase clinical studies, and although their efficacy for motor symptoms was robust, challenges with pharmacokinetics, bioavailability, cardiovascular AEs, and dyskinesia rates similar to levodopa prevented clinical advancement. Generally, repeated dopaminergic stimulation with full DAs is associated with frontostriatal dysfunction and sensitization that may induce plastic changes in the motor system, and neuroadaptations that produce long-term motor and nonmotor complications, respectively. Recent preclinical and clinical studies suggest that a D1/D5 receptor-selective partial agonist may hold promise for providing sustained, predictable, and robust motor control, while reducing risk for motor complications (e.g., levodopa-induced dyskinesia) and nonmotor AEs (e.g., impulse control disorders and excessive daytime sleepiness). Clinical trials are ongoing to evaluate this hypothesis. The potential emerging availability of novel dopamine receptor agonists with selective dopamine receptor pharmacology suggests that the older terminology "dopamine agonist" may need revision to distinguish older-generation D2/D3-selective agonists from D1/D5-selective agonists with distinct efficacy and tolerability characteristics.
PubMed: 37497384
DOI: 10.1016/j.prdoa.2023.100212 -
Cell Reports Jul 2023The dorsal bed nucleus of stria terminalis (dBNST) is a pivotal hub for stress response modulation. Dysfunction of dopamine (DA) network is associated with chronic...
The dorsal bed nucleus of stria terminalis (dBNST) is a pivotal hub for stress response modulation. Dysfunction of dopamine (DA) network is associated with chronic stress, but the roles of DA network of dBNST in chronic stress-induced emotional disorders remain unclear. We examine the role of dBNST Drd1 and Drd2 neurons in post-weaning social isolation (PWSI)-induced behavior deficits. We find that male, but not female, PWSI rats exhibit negative emotional phenotypes and the increase of excitability and E-I balance of dBNST Drd2 neurons. More importantly, hypofunction of dBNST Drd2 receptor underlies PWSI-stress-induced male-specific neuronal plasticity change of dBNST Drd2 neurons. Furthermore, chemogenetic activation of dBNST Drd2 neurons is sufficient to induce anxiogenic effects, while Kir4.1-mediated chronic inhibition of dBNST Drd2 neurons ameliorate PWSI-induced anxiety-like behaviors. Our findings reveal an important neural mechanism underlying PWSI-induced sex-specific behavioral abnormalities and potentially provide a target for the treatment of social stress-related emotional disorder.
Topics: Female; Male; Rats; Animals; Anxiety; Neurons; Septal Nuclei; Stress, Psychological; Social Isolation; Receptors, Dopamine D2
PubMed: 37453056
DOI: 10.1016/j.celrep.2023.112799 -
Journal of Psychopharmacology (Oxford,... Nov 2023Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the magnitude and consistency of the findings are unknown. We address this by systematically reviewing in vivo imaging evidence for dopamine measures in MDD and meta-analysing these where there are sufficient studies.
METHODS
Studies investigating the dopaminergic system using positron emission tomography or single photon emission computed tomography in MDD and a control group were included. Demographic, clinical and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted.
RESULTS
We identified 43 studies including 662 patients and 801 controls. Meta-analysis of 38 studies showed no difference in mean or mean variability of striatal D receptor availability ( = 0.06, = 0.620), or combined dopamine synthesis and release capacity ( = 0.19, = 0.309). Dopamine transporter (DAT) availability was lower in the MDD group in studies using DAT selective tracers ( = -0.56, = 0.006), but not when tracers with an affinity for serotonin transporters were included ( = -0.21, = 0.420). Subgroup analysis showed greater dopamine release ( = 0.49, = 0.030), but no difference in dopamine synthesis capacity ( = -0.21, = 0.434) in the MDD group. Striatal D receptor availability was lower in patients with MDD in two studies.
CONCLUSIONS
The meta-analysis indicates striatal DAT availability is lower, but D receptor availability is not altered in people with MDD compared to healthy controls. There may be greater dopamine release and lower striatal D receptors in MDD, although further studies are warranted. We discuss factors associated with these findings, discrepancies with preclinical literature and implications for future research.
Topics: Humans; Dopamine; Depressive Disorder, Major; Tomography, Emission-Computed, Single-Photon; Positron-Emission Tomography; Receptors, Dopamine D2; Dopamine Plasma Membrane Transport Proteins
PubMed: 37811803
DOI: 10.1177/02698811231200881 -
Nature Communications Sep 2023Foraging behavior requires weighing costs of time to decide when to leave one reward patch to search for another. Computational and animal studies suggest that striatal...
Foraging behavior requires weighing costs of time to decide when to leave one reward patch to search for another. Computational and animal studies suggest that striatal dopamine is key to this process; however, the specific role of dopamine in foraging behavior in humans is not well characterized. We use positron emission tomography (PET) imaging to directly measure dopamine synthesis capacity and D and D receptor availability in 57 healthy adults who complete a computerized foraging task. Using voxelwise data and principal component analysis to identify patterns of variation across PET measures, we show that striatal D and D receptor availability and a pattern of mesolimbic and anterior cingulate cortex dopamine function are important for adjusting the threshold for leaving a patch to explore, with specific sensitivity to changes in travel time. These findings suggest a key role for dopamine in trading reward benefits against temporal costs to modulate behavioral adaptions to changes in the reward environment critical for foraging.
Topics: Adult; Animals; Humans; Dopamine; Receptors, Dopamine D2; Reward; Corpus Striatum; Positron-Emission Tomography
PubMed: 37777515
DOI: 10.1038/s41467-023-41897-0