dopamine dysfunction

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal inputs, which causes striatal network dysfunction and leads to pronounced motor deficits. Recent evidence highlights astrocytes as a potential local source of striatal network modulation. However, it remains unknown how dopamine loss affects striatal astrocyte activity and whether astrocyte activity regulates behavioral deficits in PD. We addressed these questions by performing astrocyte-specific calcium recordings and manipulations using in vivo fiber photometry and chemogenetics...

Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords...

The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well as maternal and reproductive behaviors. Dopamine is a neurotransmitter that binds to G-protein-coupled receptors. Dopamine also works together with other neurotransmitters and various neuropeptides to maintain the balance of synaptic functions. The dysfunction of the dopamine system leads to several conditions, including Parkinson's disease, Huntington's disease, major depression, schizophrenia, and drug addiction...

Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson's disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou's impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate-severe TBI (msTBI)...

The alteration of metabolic processes has been found to have significant impacts on the development of hepatocellular carcinoma (HCC). Nevertheless, the effects of dysfunction of tyrosine metabolism on the development of HCC remains to be discovered. This research demonstrated that tyrosine hydroxylase (TH), which responsible for the initial and limiting step in the bio-generation of the neuro-transmitters dopamine and adrenaline, et al. was shown to be reduced in HCC. Increased expression of TH was found facilitates the survival of HCC patients...

Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions...

BACKGROUND: The effects of vitamin C supplementation on patients with septic shock remain controversial. We aimed to evaluate the effects of different vitamin C dosages on norepinephrine (NE) synthesis in adult patients with septic shock. METHODS: A total of 58 patients with septic shock admitted to our intensive care unit (ICU) between July 2021 and December 2022 were included. Patients were randomly divided into 3 groups: high-dose vitamin C (150 mg/kg/d, group A), low-dose vitamin C (50 mg/kg/d, group B), and placebo (group C)...

BACKGROUND: Sleep disorders negatively impact quality of life in Parkinson's disease (PD), yet the role of antiparkinsonian drugs on sleep quality is still unclear. We aimed to explore the correlation between sleep dysfunction and dopaminergic therapy in a large cohort of advanced PD patients. METHODS: Patients consecutively evaluated for device-aided therapies eligibility were evaluated by means of the PD Sleep Scale (PDSS-2; score ≥ 18 indicates poor sleep quality), and the Epworth Sleepiness Scale (ESS score ≥ 10 indicates excessive daytime sleepiness-EDS)...

BACKGROUND AND PURPOSE: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function. EXPERIMENTAL APPROACH: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility...

Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway...

Brain disturbances during development can have a lasting impact on neural function and behavior. Seizures during this critical period are linked to significant long-term consequences such as neurodevelopmental disorders, cognitive impairments, and psychiatric symptoms, resulting in a complex spectrum of multimorbidity. The hippocampus-prefrontal cortex (HPC-PFC) circuit emerges as a potential common link between such disorders. However, the mechanisms underlying these outcomes and how they relate to specific behavioral alterations are unclear...

The lateral habenula (LHb) projects to the ventral tegmental area (VTA) and dorsal raphe nuclei (DRN) that deliver dopamine (DA) and serotonin (5-HT) to cortical and limbic regions such as the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). Dysfunctions of VTA-related mesocorticolimbic dopaminergic and DRN-related serotonergic systems contribute to non-motor symptoms in Parkinson's disease (PD). However, how the LHb affects the VTA and DRN in PD remains unclear. Here, we used electrophysiological and neurochemical approaches to explore the effects of LHb lesions on the firing activity of VTA and DRN neurons, as well as the levels of DA and 5-HT in related brain regions in unilateral 6-ydroxydopamie (6-OHDA)-induced PD rats...

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations leading to mitochondrial dysfunction are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E-variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished...

Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion of evoked dopamine (DA) and altered maintenance of the axonal dopamine transporter (DAT) in the Synj1+/- neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we demonstrated that axons of cultured Synj1+/- neurons exhibit an increase of total DAT but a reduction of the surface DAT, which could be exacerbated by neuronal activity...

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesised that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition...

Uncontrollable stress exposure impairs working memory and reduces the firing of dorsolateral prefrontal cortex (dlPFC) "Delay cells", involving high levels of norepinephrine and dopamine release. Previous work has focused on catecholamine actions on dlPFC pyramidal cells, but inhibitory interneurons may contribute as well. The current study combined immunohistochemistry and multi-scale microscopy with iontophoretic physiology and behavioral analyses to examine the effects of beta1-noradrenergic receptors (β1-ARs) on inhibitory neurons in layer III dlPFC...

Chronic exposure to manganese (Mn) results in motor dysfunction, biochemical and pathological alterations in the brain. Oxidative stress, inflammation, and dysfunction of dopaminergic and GABAergic systems stimulate activating transcription factor-6 (ATF-6) and protein kinase RNA-like ER kinase (PERK) leading to apoptosis. This study aimed to investigate the protective effect of sesame oil (SO) against Mn-induced neurotoxicity. Rats received 25mg/kg MnCl2 and were concomitantly treated with 2.5, 5, or 8ml/kg of SO for 5 weeks...

Dopamine, the main catecholamine neurotransmitter plays an important role in renal, cardiovascular, central nervous systems, and pathophysiological processes. The abnormal dopamine levels can result in neurological disorders such as Parkinson's, Alzheimer's, schizophrenia, acute anxiety, neuroblastoma and also contribute to cognitive dysfunctions. Given the widespread importance of dopamine concentration levels, it is imperative to develop sensors that are able to monitor dopamine. Herein, we have developed pre-anodized disposable paper electrode modified with 1-pyrenebutyric acid, for the selective and sensitive determination of dopamine...

The vertebrate basal ganglia play an important role in action selection-the resolution of conflicts between alternative motor programs. The effective operation of basal ganglia circuitry is also known to rely on appropriate levels of the neurotransmitter dopamine. We investigated reducing or increasing the tonic level of simulated dopamine in a prior model of the basal ganglia integrated into a robot control architecture engaged in a foraging task inspired by animal behaviour. The main findings were that progressive reductions in the levels of simulated dopamine caused slowed behaviour and, at low levels, an inability to initiate movement...

Recent and pioneering animal research has revealed the brain utilizes a variety of molecular, cellular, and network-level mechanisms used to forget memories in a process referred to as "active forgetting". Active forgetting increases behavioral flexibility and removes irrelevant information. Individuals with impaired active forgetting mechanisms can experience intrusive memories, distressing thoughts, and unwanted impulses that occur in neuropsychiatric diseases. The current evidence indicates that active forgetting mechanisms degrade, or mask, molecular and cellular memory traces created in synaptic connections of "engram cells" that are specific for a given memory...