Dopamine Receptor Agonist Research Articles

FRI356 SIADH In Acromegaly And Cerebrovascular Accident

Abstract Disclosure: S. Siddiqui: None. I.A. Guatemala Funes: None. G. Simranpreet: None. T. Zahedi: None. F. Zhang: None. Introduction: Acromegaly is characterized by excess growth hormone secretion with distinctive features of acral overgrowth, soft tissue swelling, arthralgia, jaw prognostication, hyperglycemia, hyperhidrosis, and frontal bone bossing. Hypotonic hyponatremia may occur in patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypothyroidism, hypocortisolism, polydipsia, medications, heart failure, liver disease, or renal dysfunction. We reported a rare case of a patient with acromegaly treated with octreotide (somatostatin analogue) who was admitted for cerebrovascular accident and developed hyponatremia due to SIADH. Case Report: Patient is an 81 year old female with typical clinical features of acromegaly who presented with expressive aphasia and left sided facial droop. MRI and CT head revealed a 26 x 14 x 29 mm densely calcified/ossified extra-axial mass in the posterior fossa, displacing the brainstem and small vessel ischemia. Patient was treated with monthly intramuscular injection of octreotide for more than 20 years before she was switched to oral octreotide formula two weeks ago. Patient had nausea, vomiting, and altered mental status. Labs showed hyponatremia with serum Na 118 mmol/L, low serum osmolality 247 mOsm/kg, high urine osmolality 437 mOsm/kg, and urine Na 104 mmol/L. Serum Na further dropped to 115 mmol/L after IV normal saline which may be related to the desalination phenomenon of SIADH. Tolvaptan and hypertonic saline were initiated followed by treatment with salt tablets and furosemide. After several days, her serum Na level slowly trending up back to normal 135 mmol/L and patient recovered with no focal neurological deficits. Discussion: Treatment for acromegaly involves multiple approaches, such as somatostatin receptor ligands, GH antagonism, surgery, radiotherapy, and dopamine receptor agonists. Life-treating endocrine disorder may result from pituitary infarction or hemorrhage in patient with acromegaly. Although gastrointestinal sodium loss may precipitate hyponatremia in our patient, her elevated urine sodium and urine osmolality were consistent with SIADH. Clinicians should be cautious of the sudden onset of hyponatremia due to SIADH in acromegaly patients and prompt treatment is warranted. Presentation: Friday, June 16, 2023

Sites and mechanisms of action of colokinetics at dopamine, ghrelin and serotonin receptors in the rodent lumbosacral defecation centre.

Agonists of dopamine D2 receptors (D2R), 5-hydroxytryptamine (5-HT, serotonin) receptors (5-HTR) and ghrelin receptors (GHSR) activate neurons in the lumbosacral defecation centre, and act as 'colokinetics', leading to increased propulsive colonic motility, in vivo. In the present study, we investigated which neurons in the lumbosacral defecation centre express the receptors and whether dopamine, serotonin and ghrelin receptor agonists act on the same lumbosacral preganglionic neurons (PGNs). We used whole cell electrophysiology to record responses from neurons in the lumbosacral defecation centre, following colokinetic application, and investigated their expression profiles and the chemistries of their neural inputs. Fluorescence in situ hybridisation revealed Drd2, Ghsr and Htr2C transcripts were colocalised in lumbosacral PGNs of mice, and immunohistochemistry showed that these neurons have closely associated tyrosine hydroxylase and 5-HT boutons. Previous studies showed that they do not receive ghrelin inputs. Whole cell electrophysiology in adult mice spinal cord revealed that dopamine, serotonin, α-methylserotonin and capromorelin each caused inward, excitatory currents in overlapping populations of lumbosacral PGNs. Furthermore, dopamine caused increased frequency of both IPSCs and EPSCs in a cohort of D2R neurons. Tetrodotoxin blocked the IPSCs and EPSCs, revealing a post-synaptic excitatory action of dopamine. In lumbosacral PGNs of postnatal day 7-14 rats, only dopamine's postsynaptic effects were observed. Furthermore, inward, excitatory currents evoked by dopamine were reduced by the GHSR antagonist, YIL781. We conclude that lumbosacral PGNs are the site where the action of endogenous ligands of D2R and 5-HT2R converge, and that GHSR act as a cis-modulator of D2R expressed by the same neurons. KEY POINTS: Dopamine, 5-hydroxytryptamine (5-HT, serotonin) and ghrelin (GHSR) receptor agonists increase colorectal motility and have been postulated to act at receptors on parasympathetic preganglionic neurons (PGNs) in the lumbosacral spinal cord. We aimed to determine which neurons in the lumbosacral spinal cord express dopamine, serotonin and GHSR receptors, their neural inputs, and whether agonists at these receptors excite them. We show that dopamine, serotonin and ghrelin receptor transcripts are contained in the same PGNs and that these neurons have closely associated tyrosine hydroxylase and serotonin boutons. Whole cell electrophysiology revealed that dopamine, serotonin and GHSR receptor agonists induce an inward excitatory current in overlapping populations of lumbosacral PGNs. Dopamine-induced excitation was reversed by GHSR antagonism. The present study demonstrates that lumbosacral PGNs are the site at which actions of endogenous ligands of dopamine D2 receptors and 5-HT type 2 receptors converge. Ghrelin receptors are functional, but their role appears to be as modulators of dopamine effects at D2 receptors.

Subcutaneous adipose tissue dopamine D2 receptor is increased in prediabetes and T2D

PurposeTo evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism.MethodsmRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine).ResultsDRD1 and DRD2 gene expression in subcutaneous adipose tissue correlated positively with clinical markers of insulin resistance (e.g. HOMA-IR, insulin, and triglycerides) and central obesity in subjects without T2D. Protein expression of DRD2 in subcutaneous adipose tissue, but not DRD1, is higher in subjects with impaired fasting glucose and T2D and correlated positively with hyperglycemia, HbA1c, and glucose AUC, independent of obesity status. DRD1 and DRD2 proteins were mainly expressed in adipocytes, compared to stromal vascular cells. Dopamine and dopaminergic agonists did not affect adipocyte glucose uptake ex vivo, but DRD1 and DRD2 agonist treatment inhibited isoproterenol-stimulated lipolysis.ConclusionThe results suggest that protein expression of DRD2 in subcutaneous adipose tissue is up-regulated with hyperglycemia and T2D. Whether DRD2 protein levels contribute to T2D development or occur as a secondary compensatory mechanism needs further investigation. Additionally, dopamine receptor agonists inhibit adipocyte beta-adrenergic stimulation of lipolysis, which might contribute to the beneficial effects in lipid metabolism as observed in patients taking bromocriptine.

Side effects based network construction and drug repositioning of ropinirole as a potential molecule for Alzheimer’s disease: an in-silico, in-vitro, and in-vivo study

Alzheimer’s disease (AD) is the leading cause of dementia in older adults. Drug repositioning is a process of finding new therapeutic applications for existing drugs. One of the methods in drug repositioning is to use the side-effect profile of a drug to identify a new therapeutic indication. The drugs with similar side-effects may act on similar biological targets and could affect the same biochemical process. In this study, we explored the Food and Drug Administration-approved drugs using PROMISCUOUS database to find those that have adverse effects profile comparable with the ligands being studied or used to treat AD. Here, we found that the ropinirole, a dopamine receptor agonist, shared a maximum number of side-effects with the drugs proven beneficial for treating AD. Furthermore, molecular modelling demonstrated that ropinirole exhibited strong binding affinity (−9.313 kcal/mol) and best ligand efficiency (0.49) with sigma-1 receptor. Here, we observed that the quaternary amino group of ropinirole is essential for binding with sigma-1 receptor. Molecular dynamic simulation indicated that the movement of the carboxy-terminal helices (α4/α5) could play a major role in the receptor’s physiological functions. The neurotoxicity induced by Aβ25–35 in SH-SY5Y cells was reduced by ropinirole at concentrations 10, 30, and 50 µM. The effect on spatial learning and memory was examined in mice with Aβ25–35 induced memory deficit using the radial arm maze. Ropinirole (10 and 20 mg/kg) significantly improved the short and long-term memories in the radial arm maze test. Our results suggest that ropinirole has the potential to be repositioned for AD treatment. Communicated by Ramaswamy H. Sarma

D2 dopamine receptors and the striatopallidal pathway modulate L-DOPA-induced dyskinesia in the mouse

L-DOPA-induced dyskinesia (LID) remains a major complication of Parkinson's disease management for which better therapies are necessary. The contribution of the striatonigral direct pathway to LID is widely acknowledged but whether the striatopallidal pathway is involved remains debated. Selective optogenetic stimulation of striatonigral axon terminals induces dyskinesia in mice rendered hemiparkinsonian with the toxin 6-hydroxydopamine (6-OHDA). Here we show that optogenetically-induced dyskinesia is increased by the D2-type dopamine receptor agonist quinpirole. Although the quinpirole effect may be mediated by D2 receptor stimulation in striatopallidal neurons, alternative mechanisms may be responsible as well. To selectively modulate the striatopallidal pathway, we selectively expressed channelrhodopsin-2 (ChR2) in D2 receptor expressing neurons by crossing D2-Cre and ChR2-flox mice. The animals were rendered hemiparkinsonian and implanted with an optic fiber at the ipsilateral external globus pallidus (GPe). Stimulation of ChR2 at striatopallidal axon terminals reduced LID and also general motility during the off L-DOPA state, without modifying the pro-motor effect of low doses of L-DOPA producing mild or no dyskinesia. Overall, the present study shows that D2-type dopamine receptors and the striatopallidal pathway modulate dyskinesia and suggest that targeting striatopallidal axon terminals at the GPe may have therapeutic potential in the management of LID.

The Tungsten-Promoted Synthesis of Piperidyl-Modified erythro-Methylphenidate Derivatives.

Due to its efficacy as a dopamine receptor agonist, methylphenidate (MPH) is of interest as a potential therapeutic for cocaine addiction. While numerous derivatives of MPH have been investigated for their potential medicinal value, functionalization of the piperidine ring has not been explored. The pyridine borane ligand in WTp(NO)(PMe3)(η2-pyBH3) is dearomatized by the metal and can be elaborated to the analogous η2-mesylpyridinium complex. Installing a methyl phenylacetate moiety at the C2' position via a Reformatsky reaction followed by a tandem protonation/nucleophilic addition sequence results in a library of erythro MPH analogues functionalized at the piperidyl C5' position. The functional group is added chemoselectively to C5', cis to the methyl phenylacetate. Repeating this procedure with an enantioenriched source of the tungsten reagent results in enantioenriched MPH derivatives. All identities of the newly reported compounds are supported by comprehensive 2D NMR and HRMS data or crystallographic data.

Quinpirole inhibits levodopa-induced dyskinesias at structural and behavioral levels: Efficacy negated by co-administration of isradipine

Dopamine depletion associated with parkinsonism induces plastic changes in striatal medium spiny neurons (MSN) that are maladaptive and associated with the emergence of the negative side-effect of standard treatment: the abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Prevention of MSN dendritic spine loss is hypothesized to diminish liability for LID in Parkinson's disease. Blockade of striatal CaV1.3 calcium channels can prevent spine loss and significantly diminish LID in parkinsonian rats. While pharmacological antagonism with FDA approved CaV1 L-type channel antagonist dihydropyridine (DHP) drugs (e.g, isradipine) are potentially antidyskinetic, pharmacologic limitations of current drugs may result in suboptimal efficacy. To provide optimal CaV1.3 antagonism, we investigated the ability of a dual pharmacological approach to more potently antagonize these channels. Specifically, quinpirole, a D2/D3-type dopamine receptor (D2/3R) agonist, has been demonstrated to significantly reduce calcium current activity at CaV1.3 channels in MSNs of rats by a mechanism distinct from DHPs. We hypothesized that dual inhibition of striatal CaV1.3 channels using the DHP drug isradipine combined with the D2/D3 dopamine receptor agonist quinpirole prior to, and in conjunction with, levodopa would be more effective at preventing structural modifications of dendritic spines and providing more stable LID prevention. For these proof-of-principle studies, rats with unilateral nigrostriatal lesions received daily administration of vehicle, isradipine, quinpirole, or isradipine + quinpirole prior to, and concurrent with, levodopa. Development of LID and morphological analysis of dendritic spines were assessed. Contrary to our hypothesis, quinpirole monotherapy was the most effective at reducing dyskinesia severity and preventing abnormal mushroom spine formation on MSNs, a structural phenomenon previously associated with LID. Notably, the antidyskinetic efficacy of quinpirole monotherapy was lost in the presence of isradipine co-treatment. These findings suggest that D2/D3 dopamine receptor agonists when given in combination with levodopa and initiated in early-stage Parkinson's disease may provide long-term protection against LID. The negative interaction of isradipine with quinpirole suggests a potential cautionary note for co-administration of these drugs in a clinical setting.

Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES)

BackgroundPersisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma.MethodsAn investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment.DiscussionThe results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort.Trial RegistrationNCT05479032.

Interaction of Brain-Derived Neurotrophic Factor with the Effects of Chronic Methamphetamine on Prepulse Inhibition in Mice Is Independent of Dopamine D3 Receptors.

The aim of the present study was to gain a better understanding of the role of brain-derived neurotrophic factor (BDNF) and dopamine D3 receptors in the effects of chronic methamphetamine (METH) on prepulse inhibition (PPI), an endophenotype of psychosis. We compared the effect of a three-week adolescent METH treatment protocol on the regulation of PPI in wildtype mice, BDNF heterozygous mice (HET), D3 receptor knockout mice (D3KO), and double-mutant mice (DM) with both BDNF heterozygosity and D3 receptor knockout. Chronic METH induced disruption of PPI regulation in male mice with BDNF haploinsufficiency (HET and DM), independent of D3 receptor knockout. Specifically, these mice showed reduced baseline PPI, as well as attenuated disruption of PPI induced by acute treatment with the dopamine receptor agonist, apomorphine (APO), or the glutamate NMDA receptor antagonist, MK-801. In contrast, there were no effects of BDNF heterozygosity or D3 knockout on PPI regulation in female mice. Chronic METH pretreatment induced the expected locomotor hyperactivity sensitisation, where female HET and DM mice also showed endogenous sensitisation. Differential sex-specific effects of genotype and METH pretreatment were observed on dopamine receptor and dopamine transporter gene expression in the striatum and frontal cortex. Taken together, these results show a significant involvement of BDNF in the long-term effects of METH on PPI, particularly in male mice, but these effects appear independent of D3 receptors. The role of this receptor in psychosis endophenotypes therefore remains unclear.

Minor hallucinations in Parkinson's disease with probable rapid eye movement sleep behavior disorder.

Rapid eye movement sleep behavior disorder (RBD) and minor hallucinations (MHs) are prevalent nonmotor symptoms in Parkinson's disease (PD). The purpose of this study was to explore the association of MHs in PD patients with probable RBD (pRBD). This cross-sectional study included 291 patients diagnosed with PD. Patients who scored 6 or higher on the Rapid Eye Movement Behavior Disorder (RBD) Screening Questionnaire were defined as pRBD. A comprehensive evaluation was performed for all patients, including the collection of demographic information, clinical assessment, and MH features. Among the 291 PD patients, 69 (23.7%) had pRBD. MHs were observed in 35 (50.7%) patients with pRBD, significantly higher than 29.7% in patients without RBD (p = 0.015). The main type of MHs in pRBD was presence hallucinations with variable content. Patients with pRBD and MHs tended to be older, had a longer disease duration, and were more likely to take levodopa or dopamine-receptor agonists. Besides, the pRBD with MHs group had higher scores on the Nonmotor Symptoms Questionnaire (NMS-Quest) and Hamilton Anxiety Scale (HAMA). Binary logistic regression analysis revealed that longer disease duration and higher NMS-Quest scores were associated with MHs in PD patients with pRBD. A high prevalence of MHs was observed in PD patients with pRBD. The main type of MHs in pRBD was presence hallucinations. MHs in PD with RBD are mainly associated with disease duration and severity of nonmotor symptoms. These findings provide new insights into the interaction between MHs and RBD.

The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors

Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent ‘third’-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.

Quantification of Non-Motor Symptoms in Parkinsonian Cynomolgus Monkeys.

Parkinson's disease (PD) is a neurodegenerative disorder that features motor and non-motor deficits. The use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine neuron degeneration has been widely practiced to produce reliable animal models of PD. However, most previous preclinical studies focused on motor dysfunction, and few non-motor symptoms were evaluated. Thus far, there is a lack of comprehensive investigations of the non-motor symptoms in animal models. In this study, we aim to use a battery of behavioral methods to evaluate non-motor symptoms in MPTP-induced non-human primate PD models. Cognitive function, sleep, and psychiatric behaviors were evaluated in MPTP-treated cynomolgus monkeys. The tests consisted of a delayed matching-to-sample (DMTS) task, the use of a physical activity monitor (PAM), an apathy feeding task (AFT), the human intruder test (HIT), novel fruit test (NFT), and predator confrontation test (PCT). In addition, we tested whether the dopamine receptor agonist pramipexole (PPX) can improve these non-motor symptoms. The present results show that the MPTP-treated monkeys exhibited cognitive deficits, abnormal sleep, and anxiety-like behaviors when compared to the control monkeys. These symptoms were relieved partially by PPX. These results suggest that MPTP-induced PD monkeys displayed non-motor symptoms that were similar to those found in PD patients. PPX treatment showed moderate therapeutic effects on these non-motor symptoms. This battery of behavioral tests may provide a valuable model for future preclinical research.

Amylin Modulates a Ventral Tegmental Area–to–Medial Prefrontal Cortex Circuit to Suppress Food Intake and Impulsive Food-Directed Behavior

BackgroundA better understanding of the neural mechanisms regulating impaired satiety to palatable foods is essential to treat hyperphagia linked with obesity. The satiation hormone amylin signals centrally at multiple nuclei including the ventral tegmental area (VTA). VTA–to–medial prefrontal cortex (mPFC) projections encode food reward information to influence behaviors including impulsivity. We hypothesized that modulation of VTA-to-mPFC neurons underlies amylin-mediated decreases in palatable food-motivated behaviors. MethodsWe used a variety of pharmacological, behavioral, genetic, and viral approaches (n = 4–16/experiment) to investigate the anatomical and functional circuitry of amylin-controlled VTA-to-mPFC signaling in rats. ResultsTo first establish that VTA amylin receptor (calcitonin receptor) activation can modulate mPFC activity, we showed that intra-VTA amylin decreased food-evoked mPFC cFos. VTA amylin delivery also attenuated food-directed impulsive behavior, implicating VTA amylin signaling as a regulator of mPFC functions. Palatable food activates VTA dopamine and mPFC neurons. Accordingly, dopamine receptor agonism in the mPFC blocked the hypophagic effect of intra-VTA amylin, and VTA amylin injection reduced food-evoked phasic dopamine levels in the mPFC, supporting the idea that VTA calcitonin receptor activation decreases dopamine release in the mPFC. Surprisingly, calcitonin receptor expression was not found on VTA-to-mPFC projecting neurons but was instead found on GABAergic (gamma-aminobutyric acidergic) interneurons in the VTA that provide monosynaptic inputs to this pathway. Blocking intra-VTA GABA signaling, through GABA receptor antagonists and DREADD (designer receptor exclusively activated by designer drugs)–mediated GABAergic neuronal silencing, attenuated intra-VTA amylin-induced hypophagia. ConclusionsThese results indicate that VTA amylin signaling stimulates GABA-mediated inhibition of dopaminergic projections to the mPFC to mitigate impulsive consumption of palatable foods.

Dopamine D1-like receptor activation decreases nicotine intake in rats with short or long access to nicotine.

The use of nicotine and tobacco products is highly addictive. The dopaminergic system plays a key role in the initiation and maintenance of nicotine intake. Dopamine D1-like receptor blockade diminishes nicotine intake in rats with daily short (1h) access to nicotine, but little is known about the effects of dopamine receptor antagonists or agonists on nicotine intake in rats with intermittent long (23 h) access. Because of the extended access conditions and high nicotine intake, the intermittent long access procedure might model smoking and vaping better than short access models. We investigated the effects of the dopamine D1-like receptor antagonist SCH 23390 and the D1-like receptor agonist A77636 on nicotine intake in male rats with intermittent short or long access to nicotine. The rats self-administered nicotine for 5days (1h/day) and were then given 15 intermittent short (1h/day) or long (23 h/day) access sessions (3 sessions/week, 0.06 mg/kg/inf). The D1-like receptor antagonist SCH 23390 decreased nicotine intake to a similar degree in rats with short or long access to nicotine. The D1-like receptor agonist A77636 induced a greater decrease in nicotine intake in the rats with long access to nicotine than in rats with short access. Treatment with A77636 induced a prolonged decrease in nicotine intake that lasted throughout the dark and light phase in the long access rats. These findings indicate that blockade and stimulation of D1-like receptors decrease nicotine intake in an intermittent long access animal model that closely models human smoking and vaping.

Parkinson’s disease. Focus on early stages

The review presents current data on the peculiarities of the neurodegenerative process in the early stages of Parkinson’s disease (PD) and considers the hypothesis of the presence of body-first and brain-first subtypes of the disease onset. The earliest manifestations of the disease include symptoms such as parasomnia, constipation, hyposmia, anxiety-depressive disorder, daytime sleepiness, color perception changes, cognitive dysfunction, and mild motor manifestations. The diagnosis of PD can be made when characteristic motor manifestations occur: hypokinesia, rest tremor, muscle rigidity. Substantia nigra ultrasound, magnetic resonance imaging in SWI mode, and functional neuroimaging methods are used as confirmatory methods. The approach to the treatment of early stages of PD is age dependent. Patients over 70 years of age are recommended to start therapy with levodopa; younger patients – with dopamine receptor agonists (ADR), amantadines, MAO-B inhibitors. The mechanisms of ADR action, the possibility of their influence on the motor and non-motor symptoms of PD are analyzed. A special place is given to piribedil, which, due to the dual mechanism of action, has a positive effect on cognitive functions, depression, apathy, as well as a minimal effect on daytime sleepiness.

Profiling transcriptomic responses of human stem cell-derived medium spiny neuron-like cells to exogenous phasic and tonic neurotransmitters

Transcriptomic responses to neurotransmitters contribute to the complex processes driving memory and addiction. Advances in both measurement methods and experimental models continue to improve our understanding of this regulatory layer. Here we focus on the experimental potential of stem cell derived neurons, currently the only ethical model that can be used in reductionist and experimentally perturbable studies of human cells. Prior work has focused on generating distinct cell types from human stem cells, and has also shown their utility in modeling development and cellular phenotypes related to neurodegeneration. Here we seek an understanding of how stem cell derived neural cultures respond to perturbations experienced during development and disease progression. This work profiles transcriptomic responses of human medium spiny neuron-like cells with three specific goals. We first characterize transcriptomic responses to dopamine and dopamine receptor agonists and antagonists presented in dosing patterns mimicking acute, chronic, and withdrawal regimens. We also assess transcriptomic responses to low and persistent tonic levels of dopamine, acetylcholine, and glutamate to better mimic the in vivo environment. Finally, we identify similar and distinct responses between hMSN-like cells derived from H9 and H1 stem cell lines, providing some context for the extent of variability these types of systems will likely pose for experimentalists. The results here suggest future optimizations of human stem cell derived neurons to increase their in vivo relevance and the biological insights that can be garnered from these models.

Role of dopaminergic agonists on full‐length tau protein aggregation

AbstractBackgroundGlobally, a number of individuals who live with Alzheimer’s disease (AD), an incurable and debilitating disease, is increasing. Tau protein has a structural role, maintains integrity of microtubules and is one of the underlying causes of the tauopathies [1]. It is unfolded and highly soluble under physiological conditions. Dopamine receptor agonists have been used to target motor symptoms of AD [2] but there is a gap in knowledge on how these compounds play a role in tau protein aggregation.MethodHerein, we propose to evaluate the use of a unique class of multivalent inhibitors with various moieties (catechol, non‐catechol, biphenyl, piperazine, and thiazole) [3] as potential inhibitors for in vitro full‐length tau protein aggregation induced by heparin. Fluorescence aggregation assay, transmission electron microscopy and 4,4′‐Dianilino‐1,1′‐binaphthyl‐5,5′‐disulfonic acid dipotassium salt (Bis‐ANS) fluorescence spectroscopy were used to obtain IC50 values, characterize the aggregation morphologies and evaluate the hydrophobicity of tau aggregates, respectively.ResultThe catechol containing compounds, D‐519 and D‐520, prevented aggregation of tau whereas the non‐catechol and thiazole containing compounds (D‐264 and D‐636) were poor inhibitors. Based on the inhibitors’ density function theory calculations, effective aggregation inhibitors are characterized by their high polarity and polarizability.ConclusionData indicate that small molecule inhibitors may be useful therapeutics targeting tau aggregation related neurodegenerative diseases.

Non-lesional treatments for tremor in Parkinson's disease: A systematic review and meta-analysis.

Tremor is often perceived as severely disabling by patients with idiopathic Parkinson's disease (iPD) and yet ranges among the most difficult symptoms to treat. To date, no comprehensive analysis of non-lesional therapies to manage tremor in iPD exists to base recommendations upon. We therefore present a systematic literature review and meta-analysis assessing the efficacy/effectiveness and safety of non-lesional treatments for tremor in iPD. Three electronic databases were searched using a combination of title/abstract keywords complemented by hand-searching of reference lists. A random-effects meta-analysis of standardized mean change scores was conducted where appropriate. Some 114 studies met inclusion criteria involving 8045 patients. The meta-analysis revealed an overall reduction of standardized mean change scores by (-0.93 [CI: -1.42; -0.43], p < 0.001) by 14 different dopaminergic and non-dopaminergic classes of agents. No significant differences were identified between direct comparisons. Subgroup analysis comparing dopamine receptor agonists resulted in superior effects of pramipexole and rotigotine compared with ropinirole. There was little cumulative evidence to support the use of individual non-pharmacological interventions for tremor, except for electrical stimulation. The results of this meta-analysis suggest a large but nonspecific effect of established pharmacological therapies on tremor in iPD. Based on high-quality studies, there is sufficient evidence to support that levodopa, dopamine receptor agonists, and monoamine oxidase inhibitors provide tremor relief in most patients, while evidence supporting other treatments is less well established. Sufficient evidence to draw conclusions on effects of non-lesional treatments in cases with refractory tremor is lacking.

Differential effects of dopamine receptor agonists ropinirole and quinpirole on locomotor and anxiolytic behaviors in larval zebrafish (Danio rerio): A role for the GABAergic and glutamate system?

Zebrafish are frequently used as a vertebrate model to elucidate toxicological and pharmacological mechanisms of action in the central nervous system. Pharmacological studies demonstrate that dopamine, signaling via several receptor subtypes, regulates zebrafish larval behavior. Quinpirole is a selective dopamine receptor agonist for D2 and D3 subtypes while ropinirole exhibits selectivity toward D2, D3, and D4 receptors. The main objective of this study was to determine the short-term actions of quinpirole and ropinirole on the locomotor activity and anxiolytic/anti-anxiolytic behaviors of zebrafish. Furthermore, dopamine signaling can cross talk with other neurotransmitter systems, including the GABAergic and glutamatergic system. As such, we measured transcriptional responses in these systems to determine whether dopamine receptor activation modulated GABAergic and glutaminergic systems. Ropinirole reduced locomotor activity of larval fish at concentrations of 1 μM and greater but quinpirole did not affect locomotor activity at all concentrations tested. Anxiolytic-related behaviors were also compared between the two pharmaceuticals. Noteworthy was that both dopamine receptor agonists at 1 μM increased the activity of zebrafish in the light phase of a light-dark preference test, which may be related to the activation of D2 and/or D3 receptors. In terms of interactions with other neurotransmitter systems, ropinirole up-regulated transcripts in larvae zebrafish related to both the GABAergic and glutamatergic systems (abat, gabra1, gabrb1, gad1b, gabra5, gabrg3, and grin1b). Conversely, quinpirole did not alter the abundance of any transcript measured, suggesting that dopamine-GABA interaction may involve D4-receptors, which has been noted in mammalian models. This study demonstrates pleiotropic actions of dopamine agonism on the GABA and glutamate system in larval zebrafish. This study has relevance for characterizing toxicants that act via dopamine receptors and for elucidating mechanisms of neurological disorders that involve motor circuits and multiple neurotransmitter systems, like Parkinson's disease.

Prefrontal allopregnanolone synergizes with D1 receptor activation to disrupt sensorimotor gating in male Sprague-Dawley rats.

The prepulse inhibition (PPI) of the startle reflex is the best-established index of sensorimotor gating. We documented that the neurosteroid allopregnanolone (AP) is necessary to reduce PPI in response to D1 dopamine receptor agonists. Since Sprague-Dawley (SD) rats are poorly sensitive to the PPI-disrupting effects of these drugs, we hypothesized that AP might increase this susceptibility. We tested whether AP is sufficient to increase the vulnerability of SD rats to PPI deficits in response to the D1 receptor full agonist SKF82958. SD rats were tested for PPI after treatment with SKF82958 (0.05-0.3 mg/kg, SC) in combination with either intraperitoneal (1-10 mg/kg) or intracerebral (0.5 μg/μl/side) AP administration into the medial prefrontal cortex (mPFC) or nucleus accumbens shell. To rule out potential confounds, we measured whether SKF82958 affected the endogenous mPFC levels of AP. SD rats exhibited marked PPI deficits in response to the combination of systemic and intra-mPFC AP with SKF82958 but not with the D2 receptor agonist quinpirole (0.3-0.6 mg/kg, SC). SKF82958 did not elevate mPFC levels of AP but enhanced the content of its precursor progesterone. The PPI deficits caused by SKF82958 in combination with AP were opposed by the AP antagonist isoallopregnanolone (10 mg/kg, IP) and the glutamate NMDA receptor positive modulator CIQ (5 mg/kg, IP). These results suggest that AP enables the detrimental effects of D1 receptor activation on sensorimotor gating. AP antagonism or glutamatergic modulation counters these effects and may have therapeutic potential for neuropsychiatric disorders characterized by gating deficits.