Dopamine Transporter Research Articles

Corticosteroid receptor antagonism in the medial prefrontal cortex reduces morphine-induced place preference and dopamine transporter expression decline in rats.

Corticosteroid signaling plays a critical role in modulating the neural systems underlying reward and addiction, but the specific contributions of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the medial prefrontal cortex (mPFC) to opioid reward and dopaminergic plasticity remain unclear. Here, we investigated the effects of intra-mPFC injection of corticosteroid receptor ligand (corticosterone; CORT), glucocorticoid receptor antagonist (RU38486; RU), and mineralocorticoid receptor antagonist (spironolactone; SP) on morphine-induced conditioned place preference (CPP) and dopamine transporter (DAT) expression in the mPFC. Adult male Wistar rats received intra-mPFC injections of CORT, RU, SP, or their respective vehicles prior to morphine CPP conditioning. Blockade of GRs with RU (10 or 100ng) or MRs with a low dose of SP (10ng) attenuated the expression of morphine CPP. Morphine reduced DAT expression in the mPFC, but RU and SP prevented this effect. These findings demonstrate that corticosteroid receptor signaling within the mPFC modulates the rewarding properties of morphine and morphine-induced dopaminergic plasticity. This preclinical study suggests that targeting GRs and MRs in the mPFC could be a possible therapeutic approach for treating opioid addiction. By targeting these receptors, it may be possible to reduce opioid reward and counteract the neuroadaptations in dopamine systems associated with addiction.

Physiological change of striatum and ventral midbrain's glia cell in response to different exercise modalities.

Exercise not only regulates neurotransmitters and synapse formation but also enhances the function of multiple brain regions, beyond cortical activation. Prolonged aerobic or resistance exercise modality has been widely applied to reveal the beneficial effects on the brain, but few studies have investigated the direct effects of different exercise modalities and variations in exercise intensity on the neuroinflammatory response in the brain and overall health. Therefore, in this study, we investigated changes in brain cells and the immune environment of the brain according to exercise modalities. This study was conducted to confirm whether different exercise modalities affect the location and function of dopaminergic neurons, which are responsible for regulating voluntary movement, before utilizing animal models of disease. The results showed that high-intensity interval exercise (HIE) increased the activity of A2-reactive astrocytes in the striatum (STR), which is directly involved in movement control, resulting in neuroprotective effects. Both HIE and combined exercises (CE) increased the expression of dopamine transporter (DAT) in the STR without damaging dopamine neurons in the ventral midbrain (VM). This means that exercise training can help improve and maintain exercise capacity. In conclusion, specific exercise modalities or intensity of exercise may contribute to preventing neurodegenerative diseases such as Parkinson's disease or enhancing therapeutic effects when combined with medication for patients with neurodegenerative diseases.

Indicative biomarkers of Lewy body disease as predictors of treatment resistance in late-onset depression.

Late-onset depression (LOD) may indicate the prodromal phase of Lewy body disease (LBD) and is often associated with treatment resistance. However, the relationship between treatment resistance and indicative biomarkers of LBD is still unknown. This retrospective study investigated whether 123I-ioflupane dopamine transporter single-photon emission computed tomography (DaT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy can predict treatment resistance in hospitalized patients with LOD. The study included 79 inpatients diagnosed with LOD between October 2018 and September 2023 at a geriatric psychiatry ward. DaT-SPECT and MIBG cardiac scintigraphy were used to assess dopaminergic and autonomic function, respectively. Treatment resistance was defined as an inadequate response to antidepressant monotherapy, where cases require electroconvulsive therapy (ECT) analyzed as a distinct group. Logistic regression showed that DaT-SPECT abnormalities significantly predicted nonresponse to antidepressant monotherapy (OR = 4.70, p=0.013). While oral sensory hallucinations, another clinical marker linked to dopaminergic dysfunction, did not significantly predict treatment response, MIBG cardiac scintigraphy findings enhanced predictive accuracy for severe cases requiring ECT. Additionally, the Cochran-Armitage test indicated that the likelihood of nonresponse to antidepressant monotherapy and the need for ECT increased significantly with a higher number of abnormal LBD biomarkers (z=7.37, p=0.007; z=10.91, p<0.001, respectively). These results suggest that neurodegenerative processes in the prodromal phase of LBD may contribute to treatment resistance in LOD. The combination of DaT-SPECT and MIBG cardiac scintigraphy improves early identification of treatment resistance, supporting more timely and personalized interventions for hospitalized patients with LOD.

Systemic bupropion treatment reduces long-access cocaine self-administration in male and female rats.

More than 1 million people in the United States meet the criteria for cocaine use disorder (CUD), and over 19,000 people died from cocaine-related overdoses in 2020, but there are currently no FDA-approved medications for the treatment of CUD. Bupropion is an antidepressant currently prescribed to treat depression and nicotine addiction that acts by inhibiting norepinephrine and dopamine transporters. In this study, we tested the effect of several doses of systemic bupropion on cocaine self-administration in male and female Wistar rats. In our first experiment, rats self-administered cocaine solution intravenously and were pretreated with systemic bupropion before self-administration sessions. In our second experiment, rats were pre-treated with bupropion before completing tests of locomotor activity and anxiety-like behavior. We found that high doses of systemically administered bupropion (60 mg/kg) attenuated cocaine self-administration in male and female rats during extended-access (6 h) sessions. We also found that the highest dose (60 mg/kg) of systemic bupropion was more efficacious in females relative to males during the first hour of operant sessions. Systemic bupropion did not alter locomotor activity, inactive lever presses, or food intake. The Estrous cycle did not influence cocaine intake with or without bupropion. Our finding that bupropion attenuates cocaine self-administration suggests that bupropion may have promise for reducing cocaine use in humans.

Toxicological evaluation, postmortem case descriptions, and pharmacological activity of N,N-dimethylpentylone and related analogues.

Identification of N,N-dimethylpentylone (DMP) in counterfeit "Ecstasy" and "Molly" tablets poses risk to public health due to its adverse effects. Little information is available regarding the pharmacological activity or relevant blood or tissue concentrations of DMP, and even less is known about other structurally related beta-keto methylenedioxyamphetamine analogues on recreational drug markets, such as N-propyl butylone. Here, a novel toxicological assay utilizing liquid chromatography-tandem quadrupole mass spectrometry (LC-QQQ-MS) was developed and validated for the quantitation of DMP and five related synthetic cathinones (eutylone, pentylone, N-ethyl pentylone (NEP), N-propyl butylone, and N-cyclohexyl butylone), with chromatographic resolution from isomeric variants and quantitation performed by standard addition. A forensic series of 125 cases is presented for DMP and related analogs, along with pharmacological activity assessments using monoamine transporter and mouse behavioral assays. The blood concentration range for DMP in postmortem forensic cases was 3.3-4,600 ng/mL (mean: 320±570 ng/mL, median: 150 ng/mL), whereas pentylone, the primary N-desmethyl metabolite of DMP, was identified in 98% of cases with a concentration range 1.3-710 ng/mL (mean±SD: 105±120 ng/mL, median: 71 ng/mL). N-Propyl butylone, a newly identified synthetic cathinone, was quantitated in seven cases (mean±SD: 82±75 ng/mL, median: 50 ng/mL, range: 1.7-200 ng/mL). DMP displayed potent uptake inhibition at the dopamine transporter (IC50=49 nM), with 100-fold weaker potency at the serotonin transporter (IC50=4990 nM). DMP was a locomotor stimulant in mice (ED50=3.5 mg/kg) exhibiting potency relatively similar to eutylone, N-ethyl pentylone, and pentylone. Our results show that DMP is a psychomotor stimulant associated with adverse clinical outcomes leading to death. Forensic laboratories must continue to update testing methods to capture emerging drugs, with specific emphasis on resolution and identification of isomeric species. Following the scheduling of DMP in early-2024, there could be an anticipated market shift towards a new unregulated synthetic stimulant to replace DMP.

Contribution of the dopaminergic system in toxoplasmic encephalitis neuroimmunopathogenesis.

Toxoplasma gondii (T. gondii), a parasitic intracellular protozoan, can establish a chronic infection in the host brain and cause significant neuropathology. The current study aimed to determine the role of Tyrosine Hydroxylase (TH), Dopamine Receptor D1 (D1R), Nuclear Receptor Related-1 (Nurr1), and Dopamine Transporter (DAT) expression in the neuroimmunopathogenesis of toxoplasmic encephalitis (TE) at 15, 30, 45, and 60 days after infection with T. gondii. Additionally, the study investigated whether there was a correlation between the markers on these critical days, which had yet to be explored. The results showed that TH expression in brain tissue of BALB/c mice was significantly increased in all infected groups compared with healthy controls (P<0.05). However, other striking findings of the study were that D1R, DAT, and Nurr1 expression were significantly decreased in all infected groups compared with healthy controls, in contrast to TH expression (P<0.05). Study findings regarding behavioral changes in chronic T. gondii-infected laboratory animals and humans with TE provide important evidence of the relationship between neuropsychiatric diseases and T. gondii infection. By elucidating the pathogenesis of the disease in detail, treatment protocols that consider these coordinated changes in expression that vary from day to day can be developed.

Hinokinin Decreases Methamphetamine-Induced Hyperlocomotion via the Regulatory Effects on Dopamine Levels.

The global abuse of stimulant methamphetamine (METH) imposes a significant social burden. Despite this, effective therapeutic interventions for mitigating the harmful effects associated with METH-induced central nervous system (CNS) stimulation remain elusive. Chamaecyparis obtusa (hinoki), containing hinokinin as its active constituent, has been identified to exhibit CNS depressant properties. Here, we explored the potential of the hinoki extract and hinokinin in modulating METH-induced hyperlocomotion through the regulation of dopaminergic neuronal activity. We discovered that pretreatment with hinokinin significantly attenuates METH-induced locomotor activity, indicative of reduced CNS stimulation. Furthermore, treatment with hinokinin was observed to inhibit the METH-induced elevation in dopamine levels and the concomitant decrease in dopamine transporter (DAT) function within striatal brain slices of mice. In silico analysis coupled with pull-down assays and the dose-response curve substantiated the direct binding of hinokinin to DAT. We propose that hinokinin mitigates METH-induced hyperlocomotion via the inhibition of dopaminergic neurotransmission, with allosteric modulation of DAT playing a critical role in this regulatory mechanism. Collectively, our research suggests the potential of hinokinin to mitigate dopamine-mediated central nervous system excitation.

Exploring Genetic and Receptor-Based Dopaminergic Strategies for Antidepressant Drug Development.

The dopamine (DA) system is central to mood regulation, motivation, and reward processing, making it a critical focus for understanding Major Depressive Disorder (MDD). While the dopaminergic system's role in MDD pathophysiology has been acknowledged, gaps remain in linking specific receptor subtypes and genetic factors to depression-like phenotypes. This study explores the interplay between dopamine receptor subtypes (D1-D5) and associated genetic variations, particularly focusing on receptor heterodimers and polymorphisms influencing dopamine biosynthesis, signalling, and metabolism. A comprehensive review of molecular mechanisms highlights key findings: alterations in D1-D2 heterodimers contribute to mood dysregulation; D3 receptor downregulation correlates with depressive behaviour; and genetic polymorphisms, including those in tyrosine hydroxylase and dopamine transporter (DAT) genes, influence dopamine levels and receptor functions. Emerging data from neuroimaging and animal models confirm the pivotal role of dopamine receptor subtypes in MDD, offering insights into their therapeutic targeting. Here, we show that dopaminergic dysfunction underpins MDD's pathophysiology, with receptor-specific mechanisms presenting novel drug targets. Understanding these pathways facilitates precision medicine approaches, bridging the gap between genetic predisposition and receptor pharmacology, and paving the way for tailored antidepressant strategies with improved efficacy and reduced side effects.

Cross-modality PET image synthesis for Parkinson's Disease diagnosis: a leap from [18F]FDG to [11C]CFT.

Dopamine transporter [11C]CFT PET is highly effective for diagnosing Parkinson's Disease (PD), whereas it is not widely available in most hospitals. To develop a deep learning framework to synthesize [11C]CFT PET images from real [18F]FDG PET images and leverage their cross-modal correlation to distinguish PD from normal control (NC). We developed a deep learning framework to synthesize [11C]CFT PET images from real [18F]FDG PET images, and leveraged their cross-modal correlation to distinguish PD from NC. A total of 604 participants (274 with PD and 330 with NC) who underwent [11C]CFT and [18F]FDG PET scans were included. The quality of the synthetic [11C]CFT PET images was evaluated through quantitative comparison with the ground-truth images and radiologist visual assessment. The evaluations of PD diagnosis performance were conducted using biomarker-based quantitative analyses (using striatal binding ratios from synthetic [11C]CFT PET images) and the proposed PD classifier (incorporating both real [18F]FDG and synthetic [11C]CFT PET images). Visualization result shows that the synthetic [11C]CFT PET images resemble the real ones with no significant differences visible in the error maps. Quantitative evaluation demonstrated that synthetic [11C]CFT PET images exhibited a high peak signal-to-noise ratio (PSNR: 25.0-28.0) and structural similarity (SSIM: 0.87-0.96) across different unilateral striatal subregions. The radiologists achieved a diagnostic accuracy of 91.9% (± 2.02%) based on synthetic [11C]CFT PET images, while biomarker-based quantitative analysis of the posterior putamen yielded an AUC of 0.912 (95% CI, 0.889-0.936), and the proposed PD Classifier achieved an AUC of 0.937 (95% CI, 0.916-0.957). By bridging the gap between [18F]FDG and [11C]CFT, our deep learning framework can significantly enhance PD diagnosis without the need for [11C]CFT tracers, thereby expanding the reach of advanced diagnostic tools to clinical settings where [11C]CFT PET imaging is inaccessible.

Fusobacterium nucleatum determines the expression of amphetamine-induced behavioral responses through an epigenetic phenomenon.

Amphetamines (AMPHs) are psychostimulants commonly used for the treatment of neuropsychiatric disorders. They are also misused (AMPH use disorder; AUD), with devastating outcomes. Recent studies have implicated dysbiosis in the pathogenesis of AUD. However, the mechanistic roles of microbes in AUD are unknown. Fusobacterium nucleatum ( Fn ) is a bacterium that increases in abundance in both rats and humans upon AMPH exposure. Fn releases short-chain fatty acids (SCFAs), bacterial byproducts thought to play a fundamental role in the gut-brain axis as well as the pathogenesis of AUD. We demonstrate that in gnotobiotic Drosophila melanogaster, colonization with Fn or dietary supplementation of the SCFA butyrate, a potent inhibitor of histone deacetylases (HDACs), enhances the psychomotor and rewarding properties of AMPH as well as its ability to promote male sexual motivation. Furthermore, solely HDAC1 RNAi targeted inhibition recapitulates these enhancements, pointing to a specific process underlying this Fn phenomenon. Of note is that the expression of these AMPH behaviors is determined by the increase in extracellular dopamine (DA) levels that result from AMPH-induced reversal of DA transporter (DAT) function, termed non-vesicular DA release (NVDR). The magnitude of AMPH-induced NVDR is dictated, at least in part, by DAT expression levels. Consistent with our behavioral data, we show that Fn , butyrate, and HDAC1 inhibition enhance NVDR by elevating DAT expression. Thus, the participation of Fn in AUD stems from its ability to release butyrate and inhibit HDAC1. These data offer a microbial target and probiotic interventions for AUD treatment.

Challenges in the management of visual and tactile hallucinations in elderly people.

This letter provides a concise review of the pertinent literature on visual and tactile hallucinations in elderly patients. The discussion addresses differential diagnoses and potential underlying mechanisms, as well as the psychopathology associated with tactile hallucinations, and emphasizes the necessity for investigation into the possibility of coexisting delusional infestation (parasitosis). These symptoms frequently manifest in patients with primary psychotic disorders, organic mental disorders, and substance use disorders. The proposed pathophysiological mechanisms may involve dopaminergic imbalances and dysfunction of the striatal dopamine transporter.

Epigenetic regulation-mediated disorders in dopamine transporter endocytosis: A novel mechanism for the pathogenesis of Parkinson's disease

Epigenetic regulation-mediated disorders in dopamine transporter endocytosis: A novel mechanism for the pathogenesis of Parkinson's disease

Gestational stress disrupts dopamine and oxytocin signaling in the postpartum reward system of rats: implications for mood, motivation and mothering

Postpartum depression (PPD) affects up to 20% of new mothers and has adverse consequences for the well-being of both mother and child. Exposure to stress during pregnancy as well as dysregulation in the mesolimbic dopamine (DA) reward system and its upstream modulator oxytocin (OT) have been independently linked to PPD. However, no studies have directly examined DA or OT signaling in the postpartum brain after gestational stress. Here we employed a chronic variable stress procedure during pregnancy and evaluated behavioral measures of mood and reward along with assessments of DA and OT signaling in postpartum rats. Our results show that gestational stress induced postpartum depressive-like and anxiety-like behavior in addition to producing reward-related deficits including anhedonia, impaired maternal care, and reduced maternal motivation. Consistent with a hypodopaminergic state, histological analysis revealed reduced expression of tyrosine hydroxylase in the NAc shell and core as well as reduced expression of the dopamine transporter and dopamine D2 receptor in the NAc shell of postpartum females exposed to gestational stress. A reduction in accumbal DA content as determined by liquid chromatography-mass spectrometry was also observed in gestationally-stressed dams. Lastly, we assessed mRNA expression of OT and OT receptors (OTR) and found that gestational stress increased OT expression in the hypothalamus but reduced OTR expression in the postpartum ventral tegmental area (VTA), a target of hypothalamic OT neurons. In the VTA, a reduction in OT-immunoreactive fibers following gestational stress was also seen. Taken together, these data demonstrate that the DA and OT systems within the postpartum reward circuit are sensitive to gestational stress and suggest that mood and maternal disruptions in PPD may arise from dysfunctional oxytocinergic regulation of the dopaminergic reward system.

Differential striatal dopamine binding in Parkinson's Disease with and without REM sleep behavior disorder: A Tc-99m TRODAT-1 SPECT study.

Rapid eye movement (REM) sleep behavior disorder (RBD) is an early and significant prodromal marker for Parkinson's disease (PD). While the association between RBD and PD has been well-documented, the underlying pathophysiology differentiating PD patients with RBD (PD-RBD +) from those without RBD (PD-RBD-) remained unclear. This study aims to investigate the possible relationship between RBD and striatal dopamine depletion in de novo PD patients. A retrospective, cross-sectional study was conducted on 151 PD patients. We used standard questionnaires and measurements to assess motor and nonmotor symptoms. The dopaminergic function was assessed utilizing Tc-99m TRODAT-1 SPECT imaging, and statistical analyses were performed to compare dopamine transporter (DAT) binding between patients with or without probable RBD (pRBD). The PD-pRBD + group exhibited significantly lower DAT binding in the caudate nucleus (OR 0.618; 95% CI 0.392-0.618; p = 0.039) and putamen (OR 0.554; 95% CI 0.319-0.962; p = 0.036) compared to the PD-pRBD- group. The PD-pRBD + group also had a higher prevalence of non-motor symptoms, including depression (OR 7.499; 95% CI 2.770-20.299; p < 0.001) and constipation (OR 2.356; 95% CI 1.090-5.092; p = 0.029). Although trends toward increased dementia (12.3% in PD-pRBD + , 6.4% in PD-pRBD-, p = 0.266) and falls (16.4% in PD-pRBD + , 11.5% in PD-pRBD-, p = 0.482) were observed in the PD-pRBD + group, these did not reach statistical significance. The presence of RBD in PD patients is associated with greater striatal dopaminergic dysfunction, suggesting a distinct subtype with potentially faster disease progression. These findings highlight the importance of early RBD identification in PD patients to guide more personalized interventions.

Chemistry to cognition: Therapeutic potential of (m-CF3-PhSe)2 targeting rats' striatum dopamine proteins in amphetamine dependence.

Amphetamine (AMPH) abuse represents a major global public health issue, highlighting the urgent need for effective therapeutic interventions to manage addiction caused by this psychostimulant. This study aimed to assess the potential of m-trifluoromethyl-diphenyldiselenide [(m-CF3-PhSe)2] in preventing the addictive effects induced by AMPH through targeting dopamine metabolism proteins. (m-CF3-PhSe)2 is of interest due to its demonstrated efficacy in mitigating opioid abuse, establishing it as a promising candidate for addiction treatment research. Initially, in silico studies examined the affinity of AMPH and (m-CF3-PhSe)2 for dopamine 1, 2, and 3 receptors (D1R, D2R, D3R), and dopamine transporter (DAT). In our experimental design, male Wistar rats were divided into four groups: I) Control; II) (m-CF3-PhSe)2; III) AMPH; IV) (m-CF3-PhSe)2+AMPH. Animals were administered (m-CF3-PhSe)2 (0.1mg/kg, by gavage) or canola oil (vehicle) 30min before AMPH (4.0mg/kg, i.p.) administration. Drug administration occurred for 8days in the conditioned place preference (CPP) paradigm. Twenty-four hours after the last CPP conditioning section, preference for the drug-compartment was assessed, with anxiety-related effects and working memory were evaluated using the Y-maze test. Finally, animals were euthanized for striatal dissection to quantify D1R, D2R, D3R, and DAT levels in western blot. In silico findings suggest that (m-CF3-PhSe)2 may prevent AMPH activation in DAT, interacting with Asp46 and Phe319, preventing possible addictive effects of AMPH in DAT. In vivo results showed that (m-CF3-PhSe)2 attenuated AMPH effects, reducing preference for the drug-compartment in CPP test. Furthermore, (m-CF3-PhSe)2 prevented AMPH-induced anxiogenic effects in the elevated plus maze (EPM) test, similarly to light/dark test. No differences in locomotion or working memory were observed among the experimental groups in the Y-maze test. Ex vivo western blot analyses of the entire striatum indicates that (m-CF3-PhSe)2 prevented the AMPH-induced increase in D1R levels and decrease in D2R and DAT levels, with no changes in D3R levels. Overall, our study suggests that (m-CF3-PhSe)2 may interact with DAT sites similarly to AMPH, reducing drug-compartment preference and anxiogenic behaviors while maintaining dopaminergic metabolism proteins in the striatum, a key region involved in the onset and perpetuation of addiction.

Dopamine transporter imaging to predict the risk of aspiration in patients with Parkinson's disease.

Aspiration is a critical complication of dysphagia in Parkinson's disease (PD). Current methods for predicting aspiration are unsuitable for routine implementation owing to time constraints, cost, or insufficient predictive accuracy. We assessed the predictive performance of clinical measures, including dopamine transporter (DaT) imaging, for aspiration risk in patients with PD. We retrospectively analyzed data from patients with PD who underwent videofluoroscopic swallowing examinations (VF) and DaT imaging within 12 months. Patients were divided into aspiration and non-aspiration groups based on VF findings. Logistic regression and receiver operating characteristic (ROC) analyses evaluated the predictive performance of DaT imaging parameters including striatal specific binding ratio (SBR) and subregional SBRs, calculated using DaT View and DaTQUANT software. Among 87 patients (38 females; mean age: 64 years; disease duration: 8.3 years [range: 1-20 years]; modified Hoehn and Yahr stages: 2 [range: 1-4]), 14.9% experienced aspiration. DaT View striatal SBRs consistently showed significantly lower values in the aspiration group and negative associations with aspiration in logistic regression models, whereas DaTQUANT exhibited limited significance in intergroup differences and associations. ROC analysis showed DaT View striatal SBR of the better side (SBRbetter) as the optimal predictor (sensitivity 0.62, specificity 0.93at cutoff: 2.03). DaTQUANT subregional analysis identified the anterior putamen as key in aspiration risk. Reduced SBR in DaT imaging shows potential as an indicator of aspiration risk in patients with PD. These findings can help clinicians identify patients at risk of aspiration, allowing for proactive referral for detailed evaluation.

The psychoplastogens ibogaminalog and ibogainalog induce antidepressant-like activity in naïve and depressed mice by mechanisms involving 5-HT2A receptor activation and serotonergic transmission.

The antidepressant-like activity of two psychoplastogens, ibogainalog (IBG) and ibogaminalog (DM506), was studied in naïve mice using the forced swim test (FST) and tail suspension test (TST). The behavioral results showed that a single administration of 25mg/kg DM506 or 10mg/kg IBG induced antidepressant-like activity in naïve mice in a volinanserin-sensitive manner that persisted for 72h. Similar results were observed using the chronic immobilization stress (CIS) test, in which depression symptoms were reduced for 48h. To assess the contribution of serotonergic and/or norepinephrinergic neurotransmission, serotonin (5-HT) and norepinephrine (NE) levels were depleted. The reduction in 5-HT levels, but not NE levels, inhibited the antidepressant-like activity of ibogalogs, suggesting that serotonergic transmission may play a more significant role than norepinephrinergic transmission. Concurrently, DM506, IBG, and TBG (derived from tabernanthine) inhibited monoamine transporters with the following order of selectivity: SERT > NE transporter > dopamine transporter. The IBG exhibited the highest selectivity for SERT. Only TBG inhibited monoamine oxidase A activity, indicating its relatively minor role. Radioligand and functional assays showed that all ibogalogs bind to the 5-HT2 receptor subfamily (DM506>IBG>TBG) and fully activate 5-HT2A/2C receptors with similar potency in the nM range. However, they act as competitive antagonists of the 5-HT2B receptor, with DM506 as an exception, exhibiting partial but potent agonist activity. In conclusion, ibogalogs induce acute and sustained antidepressant-like activity in naïve and depressed mice through mechanisms involving 5-HT2A receptor activation and serotonergic transmission.

Olanzapine exposure disordered lipid metabolism, gut microbiota and behavior in zebrafish (Danio rerio).

Olanzapine (OLZ) is widely used in the treatment of schizophrenia, and its metabolic side effects have garnered significant attention in recent years. Despite this, the specific side effects of OLZ and the underlying mechanisms remain inadequately understood. To address this gap, zebrafish (Danio rerio) were exposed to OLZ at concentrations of 35.5, 177.5, and 355.5μg/L. The results indicated that exposure to OLZ significantly increased body weight, total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG). Histological analysis revealed notable lipid accumulation in the liver. Furthermore, lipid synthesis genes, including sterol regulatory element binding protein (srebp), acetyl CoA carboxylase (acc), and fatty acid synthesis gene (fas), were up-regulated. In contrast, genes related to lipid decomposition, such as lipoprotein lipase (lpl), hormone-sensitive triglyceride lipase (hsl), and carnitine palmitoyltransferase 1b (cpt1b), were down-regulated. Subsequent analysis of zebrafish behavior showed reduced motor activity, sociability, and anxiety-like behavior in OLZ-exposed zebrafish, consistent with the results of neurotransmitter related gene expression. Following OLZ treatment, the expression of tryptophan hydroxylase (tph), tyrosine hydroxylase (th), dopamine transporter (dat), glutaminase (glsa), and glutamic acid decarboxylase 1b (gad1b) was upregulated. Additionally, the diversity of intestinal flora decreased after OLZ exposure, and the structure of the intestinal microbiota changed significantly compared to the control group. At the genus level, the abundance of Plesiomonas was upregulated, while the abundances of Bacillus and Cetobacterium were downregulated in the OLZ-exposed group. Furthermore, the results of the correlation analysis indicated that lipid metabolism and behavioral changes were closely associated with the microbiota. This study clarified the side effects of OLZ, and also provided a basis for the reasonable discharge concentration of OLZ in water and clinical drug use.

Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease

Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB. This hints that pathological synaptic α-Syn aggregates may be the main trigger for the retrograde synapse-to-cell body degeneration pattern characterizing early prodromal phases of PD. Identifying reliable biomarkers of synaptopathy is therefore crucial for early diagnosis. Here, we studied the alterations of key dopaminergic and non-dopaminergic striatal synaptic markers during the initial phases of axonal and cell body degeneration in mice subjected to 3 or 10 administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine + probenecid (MPTPp), a model for early prodromal PD. We found that MPTPp administration resulted in progressive deposition of α-Syn, advancing from synaptic terminals to axons and dopaminergic neuron cell bodies. This was accompanied by marked co-accumulation of Synapsin III (Syn III), a synaptic protein previously identified as a component of α-Syn fibrils in post-mortem PD brains and as a main stabilizer of α-Syn aggregates, as well as very early and severe reduction of vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity in nigrostriatal neurons. Results also showed that striatal α-Syn accumulation and VMAT2 decrease, unlike other markers, did not recover following washout from 10 MPTPp administrations, supporting that these changes were precocious and severe. Finally, we found that early changes in striatal α-Syn, Syn III, VMAT2 and DAT observed following 3 MPTPp administrations, correlated with nigrostriatal neuron loss after 10 MPTPp administrations. These findings indicate that α-Syn/Syn III co-deposition characterizes very early stages of striatal dopaminergic dysfunction in the MPTPp model and highlight that VMAT2 and Syn III could be two reliable molecular imaging biomarkers to predict dopamine neuron denervation and estimate α-Syn-related synaptopathy in prodromal and early symptomatic phases of PD.

Prenatal Valproic Acid Induces Autistic-Like Behaviors in Rats via Dopaminergic Modulation in Nigrostriatal and Mesocorticolimbic Pathways.

Autism spectrum disorder (ASD) is a complex developmental disorder characterized by several behavioral impairments, especially in socialization, communication, and the occurrence of stereotyped behaviors. In rats, prenatal exposure to valproic acid (VPA) induces autistic-like behaviors. Previous studies by our group have suggested that the autistic-like phenotype is possibly related to dopaminergic system modulation because tyrosine hydroxylase (TH) expression was affected. The objective of the present study was to understand the dopaminergic role in autism. Wistar rats on gestational day 12.5 received VPA (400 mg/kg) and behaviors related to rat models of ASD were evaluated in juvenile offspring. Neurochemical and genetic dopaminergic components were studied in different brain areas of both juvenile and adult rats. Prenatal VPA-induced autistic-like behaviors in comparison to a control group: decreased maternal solicitations by ultrasonic vocalizations, cognitive inflexibility and stereotyped behavior in the T-maze test, decreased social interaction and play behavior, as well as motor hyperactivity. Prenatal VPA also decreased dopamine synthesis and activity in the striatum and prefrontal cortex, as well as dopamine transporter, D1 and D2 receptors, and TH expressions. Moreover, prenatal VPA increased TH+ immunoreactive neurons of the ventral tegmental area-substantia nigra complex. In conclusion, the dopaminergic hypoactivity associated with the behavioral impairments exhibited by the rats that received prenatal VPA suggests the important role of this system in the establishment of the characteristic symptoms of ASD in juvenile and adult males. Dopamine was demonstrated to be an important biomarker and a potential pharmacological target for ASD.