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Psychopharmacology Jun 2024Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid...
BACKGROUND
Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention.
OBJECTIVES
The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms.
RESULTS
In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT, 5-HT, and 5-HT receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition.
CONCLUSIONS
These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression.
PubMed: 38856765
DOI: 10.1007/s00213-024-06629-2 -
Psychopharmacology Jun 2024Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). The neurobiological...
Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). The neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6; DAT-iCreER mice to determine the role of RGS6 in DA neurons on EtOH consumption, reward, and relapse behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse ventral tegmental area (VTA), and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6 mice. Strikingly, RGS6 loss from DA neurons before or after EtOH behavioral reward is established significantly reduced (~ 50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies identify DA neurons as the locus of RGS6 action in promoting EtOH consumption, preference, reward, and relapse. RGS6 is unique among R7 RGS proteins in promoting rather than suppressing behavioral responses to drugs of abuse and to modulate EtOH behavioral reward. This is a result of RGS6's pre-synaptic actions that we hypothesize promote VTA DA transmission by suppressing GPCR-Gα-DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.
PubMed: 38856764
DOI: 10.1007/s00213-024-06631-8 -
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 -
Journal of Psychopharmacology (Oxford,... Jun 2024A better understanding of the mechanisms underlying cognitive impairment in schizophrenia is imperative, as it causes poor functional outcomes and a lack of effective...
BACKGROUND
A better understanding of the mechanisms underlying cognitive impairment in schizophrenia is imperative, as it causes poor functional outcomes and a lack of effective treatments.
AIMS
This study aimed to investigate the relationships of two proposed main pathophysiology of schizophrenia, altered prefrontal-striatal connectivity and the dopamine system, with cognitive impairment and their interactions.
METHODS
Thirty-three patients with schizophrenia and 27 healthy controls (HCs) who are right-handed and matched for age and sex were recruited. We evaluated their cognition, functional connectivity (FC) between the dorsolateral prefrontal cortex (DLPFC)/middle frontal gyrus (MiFG) and striatum, and the availability of striatal dopamine transporter (DAT) using a cognitive battery investigating attention, memory, and executive function, resting-state functional magnetic resonance imaging with group independent component analysis and single-photon emission computed tomography with 99mTc-TRODAT.
RESULTS
Patients with schizophrenia exhibited poorer cognitive performance, reduced FC between DLPFC/MiFG and the caudate nucleus (CN) or putamen, decreased DAT availability in the left CN, and decreased right-left DAT asymmetry in the CN compared to HCs. In patients with schizophrenia, altered imaging markers are associated with cognitive impairments, especially the relationship between DLPFC/MiFG-putamen FC and attention and between DAT asymmetry in the CN and executive function.
CONCLUSIONS
This study is the first to demonstrate how prefrontal-striatal hypoconnectivity and altered striatal DAT markers are associated with different domains of cognitive impairment in schizophrenia. More research is needed to evaluate their complex relationships and potential therapeutic implications.
Topics: Humans; Male; Female; Schizophrenia; Adult; Cognitive Dysfunction; Magnetic Resonance Imaging; Tomography, Emission-Computed, Single-Photon; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dopamine; Prefrontal Cortex; Dorsolateral Prefrontal Cortex; Case-Control Studies; Middle Aged; Executive Function; Neuropsychological Tests; Young Adult
PubMed: 38853592
DOI: 10.1177/02698811241257877 -
Journal of Alzheimer's Disease : JAD 2024Dementia with Lewy bodies (DLB) presents with various symptoms, posing challenges for early diagnosis challenging. Dopamine transporter (123I-FP-CIT) single-photon...
BACKGROUND
Dementia with Lewy bodies (DLB) presents with various symptoms, posing challenges for early diagnosis challenging. Dopamine transporter (123I-FP-CIT) single-photon emission tomography (SPECT) and 123I-meta-iodobenzylguanidine (123I-MIBG) imaging are crucial diagnostic biomarkers. Hypothesis about body- and brain-first subtypes of DLB indicate that some DLB may show normal 123I-FP-CIT or 123I-MIBG results; but the characteristic expression of these two subtypes remains unclear.
OBJECTIVE
This study aimed to evaluate the diagnostic sensitivity of 123I-FP-CIT and 123I-MIBG imaging alone, combined in patients with DLB and explore symptoms associated with the abnormal imaging results.
METHODS
Demographic data, clinical status, and imaging results were retrospectively collected from patients diagnosed with possible DLB. Both images were quantified using semi-automated software, and the sensitivity of each imaging modality and their combination was calculated. Demographic data, cognition, and motor and non-motor symptoms were compared among the subgroups based on the imaging results. Symptoms related to each imaging abnormality were examined using binomial logistic regression analyses.
RESULTS
Among 114 patients with DLB, 80 underwent 123I-FP-CIT SPECT (sensitivity: 80.3%), 83 underwent 123I-MIBG imaging (68.2%), and 66 both (sensitivity of either abnormal result: 93.9%). Visual hallucinations differed among the four subgroups based on imaging results. Additionally, nocturia and orthostatic hypotension differed between abnormal and normal 123I-MIBG images.
CONCLUSIONS
Overall, 123I-FP-CIT SPECT was slightly higher sensitivity than 123I-MIBG imaging, with combined imaging increasing diagnostic sensitivity. Normal results of a single imaging test may not refute DLB. Autonomic symptoms may lead to abnormal 123I-MIBG scintigraphy findings indicating body-first subtype of patients with DLB.
Topics: Humans; Lewy Body Disease; Male; Female; Aged; Tomography, Emission-Computed, Single-Photon; Dopamine Plasma Membrane Transport Proteins; 3-Iodobenzylguanidine; Retrospective Studies; Tropanes; Aged, 80 and over; Sensitivity and Specificity; Radiopharmaceuticals; Myocardial Perfusion Imaging; Brain; Middle Aged; Dopaminergic Imaging
PubMed: 38848178
DOI: 10.3233/JAD-231395 -
Journal of Neurology Jun 2024Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease...
BACKGROUND
Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown.
METHODS
In this retrospective cohort study, we enrolled 113 patients who underwent F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region.
RESULTS
More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia.
DISCUSSION
Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis.
PubMed: 38839638
DOI: 10.1007/s00415-024-12477-z -
Journal of Nuclear Medicine Technology Jun 2024Ethnic differences exist among patients with Parkinson disease (PD). PD is more common in the White than the African American population. This study aimed to explore...
Ethnic differences exist among patients with Parkinson disease (PD). PD is more common in the White than the African American population. This study aimed to explore whether differences exist in [I]ioflupane binding, which reflects dopamine transporter binding, between African American and White individuals. Medical charts were reviewed for patients who underwent [I]ioflupane SPECT imaging as part of routine practice in a single academic medical center. All images were visually graded as showing normal or abnormal presynaptic dopaminergic function (normal or abnormal scan status). Quantitative [I]ioflupane uptake as measured by the specific binding ratios in the right and left striata and their subregions (caudate nucleus and anterior and posterior putamen) and by bilateral putamen-to-caudate ratios were compared between African American and White patients using multiple linear regression adjusted for age, sex, and abnormal scan status. Additional models included an ethnicity-by-abnormal-scan-status interaction term to determine whether abnormal scan status was modulated by ethnicity effect. The percentage of patients with abnormal scan status was comparable between African American and White patients. Compared with White patients ( = 173), African American patients ( = 82) had statistically significantly higher uptake as measured by specific binding ratios in the right and left striata and some of their subregions (right and left caudate nuclei and right posterior putamen). Ethnicity-by-abnormal-scan-status interactions were not statistically supported for any models. We observed differences in [I]ioflupane binding between African American and White patients independent of presynaptic dopaminergic dysfunction status. Future studies are needed to examine whether and how ethnicity affects dopamine transporter binding activities and its clinical relevance.
Topics: Humans; Nortropanes; Male; Female; Black or African American; White People; Tomography, Emission-Computed, Single-Photon; Aged; Middle Aged; Neostriatum; Corpus Striatum; Parkinson Disease; Retrospective Studies
PubMed: 38839126
DOI: 10.2967/jnmt.123.265806 -
Neuroscience Jun 2024Transient nigrostriatal dopaminergic signalling is well known for its role in reinforcement learning and increasingly so for its role in the initiation of voluntary...
Transient nigrostriatal dopaminergic signalling is well known for its role in reinforcement learning and increasingly so for its role in the initiation of voluntary movement. However, how transient bursts of dopamine modulate voluntary movement remains unclear, likely due to the heterogeneity of the nigrostriatal system, the focus of optogenetic studies on locomotion at sub-sec time intervals, and the overlapping roles of phasic dopamine in behaviour and novelty signalling. In this study we investigated how phasic activity in the lateral substantia nigra pars compacta (lateral SNc) over time affects voluntary behaviours during exploration. Using a transgenic mouse model of both sexes expressing channelrhodopsin (ChR2) in dopamine transporter-expressing cells, we stimulated the lateral SNc while mice explored an open field over two consecutive days. We found that phasic activation of the lateral SNc induced an increase in exploratory behaviours including horizontal movement activity, locomotion initiation, and rearing specifically on the first open field exposure, but not on the second day. In addition, stimulated animals did not habituate to the same extent as their ChR2-negative counterparts, as indicated by a lack of decrease in baseline activity. These findings suggest that rather than prompting voluntary movement in general, phasic nigrostriatal dopamine prompts context-appropriate behaviours. In addition, dopamine signalling that modulates movement acts over longer timescales than the transient signal, affecting behaviour even after the signal has ended.
PubMed: 38838978
DOI: 10.1016/j.neuroscience.2024.05.025 -
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