Selective Dopamine D2 Receptor Agonist Research Articles

SKF82958, a dopamine D1 receptor agonist, disrupts prepulse inhibition in the medial prefrontal cortex and nucleus accumbens in C57BL/6J mice.

Prepulse inhibition (PPI) is a crucial indicator of sensorimotor gating that is often impaired in neuropsychiatric diseases. Although dopamine D1 receptor agonists have been found to disrupt PPI in mice, the underlying mechanisms are not fully understood. In this study, we aimed to identify the brain regions responsible for the PPI-disruptive effect of the D1 agonist in mice. Results demonstrated that intraperitoneal administration of the selective dopamine D1 receptor agonist SKF82958 dramatically inhibited PPI, while the dopamine D1 receptor antagonist SCH23390 enhanced PPI. Additionally, local infusion of SKF82958 into the nucleus accumbens and medial prefrontal cortex disrupted PPI, but not in the ventral hippocampus. Infusion of SCH23390 into these brain regions also failed to enhance PPI. Overall, the study suggests that the nucleus accumbens and medial prefrontal cortex are responsible for the PPI-disruptive effect of dopamine D1 receptor agonists. These findings provide essential insights into the cellular and neural circuit mechanisms underlying the disruptive effects of dopamine D1 receptor agonists on PPI and may contribute to the development of novel treatments for neuropsychiatric diseases.

Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

RationaleThe dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive.ObjectivesThe investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms.MethodsMale C57BL/6 J mice and Sprague–Dawley rats were examined in five independent experiments. We assessed APH199 (0.1–5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light–dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats.ResultsAPH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats.ConclusionsOur data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.

Behavioural effects of a selective dopamine D4 receptor agonist, APH199, in animal models

Behavioural effects of a selective dopamine D4 receptor agonist, APH199, in animal models

Fenoldopam Mesylate Enhances the Survival of Mesenchymal Stem Cells Under Oxidative Stress and Increases the Therapeutic Function in Acute Kidney Injury

Mesenchymal stem cells (MSCs) have gained interest as an alternative therapeutic option for renal diseases, including acute kidney injury (AKI). However, their use is often limited owing to low survival rates in vivo. Fenoldopam mesylate (FD) is a selective dopamine D1 receptor agonist with antioxidative and anti-apoptotic roles. Herein, we investigated whether FD can enhance the survival of MSCs undergoing oxidative stress in vitro. In addition, the therapeutic effect of MSCs and FD-treated MSCs (FD-MSCs) was compared in a mouse model of AKI induced by cisplatin. The survival of MSCs under oxidative stress was augmented by FD treatment. FD induced the phosphorylation of cAMP response element–binding protein and AKT, contributing to enhanced growth compared with untreated MSCs. The expression of nuclear factor erythroid-2-related factor 2 (NRF2) and heme oxygenase-1 was increased by FD treatment, and nuclear translocation of NRF2 was found exclusively in FD-MSCs. FD downregulated BAX expression, increased the mitochondrial membrane potential, reduced reactive oxygen species generation, and decreased the apoptotic death of MSCs induced by oxidative stress. Moreover, renal function and tubular injury were improved in FD-MSCs compared with non-treated MSCs. Furthermore, tubular injury, apoptosis, and macrophage infiltration, as well as the serum level of tumor necrosis factor-α were reduced, while tubular cell proliferation was markedly increased in FD-MSCs compared with MSCs. Our study demonstrated that FD increases the survivability of MSCs in an oxidative environment, and its use may be effective in preparing robust therapeutic MSCs.

Cabergoline treatment promotes myocardial recovery in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart-healthy women during the last month of pregnancy or the first months after delivery due to left ventricular (LV) systolic dysfunction. A common pathomechanistic pathway of PPCM includes increased oxidative stress and the subsequent generation of a cleaved prolactin fragment (16kDa PRL), which promotes the onset of heart failure (HF) in a microRNA (miR)-146a-dependent manner. Inhibition of prolactin secretion with the dopamine D2 receptor (D2R) agonist bromocriptine combined with standard HF therapy supports cardiac recovery. This study examined whether treatment with the more selective D2R agonist cabergoline prevents HF development in an experimental PPCM mouse model and might be used as an alternative treatment regime for PPCM. Postpartum (PP) female PPCM-prone mice with a cardiomyocyte restricted STAT3-deficiency (αMHC-Cretg/+ ; Stat3fl/fl ; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5mg/kg/day) and were compared with bromocriptine treated CKO (CKO Br) and postpartum-matched WT and CKO mice. Cabergoline treatment in CKO PP mice preserved cardiac function [fractional shortening (FS): CKO Cab: 34.5±9.4% vs. CKO: 22.1±9%, P<0.05] and prevented the development of cardiac hypertrophy, fibrosis, and inflammation as effective as bromocriptine therapy (FS: CKO Br: 33.4±5.6%). The myocardial up-regulation of the PPCM biomarkers plasminogen inhibitor activator 1 (PAI-1) and miR-146a were prevented by both cabergoline and bromocriptine therapy. A small cohort of three PPCM patients from the German PPCM Registry was treated with cabergoline (1mg per week for 2weeks, followed by 0.5mg per week for another 6weeks) due to a temporary unavailability of bromocriptine. All PPCM patients initially presented with a severely reduced LV ejection fraction (LVEF: 26±2%). However, at 6months of follow-up, LV function (LVEF: 56±2%) fully recovered in all three PPCM patients, and no adverse events were detected. In the experimental PPCM mouse model, the selective D2R agonist cabergoline prevents the onset of postpartum HF similar to bromocriptine. In PPCM patients, cabergoline treatment was safe and effective as all patients fully recovered. Cabergoline might serve as a promising alternative to bromocriptine. However, these findings are based on experimental data and a small case series and thus have to be interpreted with caution and should be validated in a larger clinical trial.

The selective dopamine D1 receptor agonist SKF81297 modulates NMDA receptor currents independently of D1 receptors

Dopamine D1 receptor (D1R) agonists are frequently used to study the role of D1Rs in neurotransmission and behaviour. They have been repeatedly shown to modulate glutamatergic NMDAR currents in the prefrontal cortex (PFC), giving rise to the idea that D1R activation tunes glutamatergic networks by regulating NMDAR activity. We report that the widely used D1R agonist SKF81297 potentiates NMDAR currents in a dose-dependent manner, independently of D1R activation in mPFC slices, cortical neuron cultures and NMDAR-expressing recombinant HEK293 cells. SKF81297 potentiated NMDAR currents through both GluN2A and GluN2B subtypes in the absence of D1R expression, while inhibiting NMDAR currents through GluN2C and GluN2D subtypes. In contrast, the D1R ligands SKF38393, dopamine and SCH23390 inhibited GluN2A- and GluN2B-containing NMDAR currents. SKF81297 also inhibited GluN2A- and GluN2B-containing NMDAR currents at higher concentrations and when glutamate/glycine levels were high, exhibiting bidirectional modulation. To our knowledge, these findings are the first report of a D1R-independent positive modulatory effect of a D1R ligand on NMDA receptors. Importantly, our results further emphasize the possibility of off-target effects of many D1R ligands, which has significant implications for interpreting the large body of research relying on these compounds to examine dopamine functions.

Characterization of the discriminative stimulus effect of quinpirole: Further evidence for functional interaction between central dopamine D1/D2-receptors

Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the “D1/D2-MSN” interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.

Signal transduction pathways involved in dopamine D2 receptor-evoked emesis in the least shrew (Cryptotis parva).

With its five receptor subtypes (D1-5), dopamine is implicated in a myriad of neurological illnesses. Dopamine D2 receptor-based agonist therapy evokes nausea and vomiting. The signaling mechanisms by which dopamine D2 receptors evoke vomiting remains unknown. Phosphatidylinositol 3-kinases (PI3K)- and protein kinase C (PKC)-related signaling cascades stimulate vomiting post-injection of various emetogens in emetically competent animals. This study investigated potential mechanisms involved in dopamine D2 receptor-mediated vomiting using least shrews. We found that vomiting evoked by the selective dopamine D2 receptor agonist quinpirole (2mg/kg, i.p.) was significantly suppressed by: i) a dopamine D2 preferring antagonist, sulpiride (s.c.); ii) a selective PI3K inhibitor, LY294002 (i.p.); iii) a PKCαβII inhibitor, GF109203X (i.p.); and iv) a selective inhibitor of extracellular signal-regulated protein kinase1/2 (ERK1/2), U0126 (i.p.). Quinpirole-evoked c-fos immunofluorescence in the nucleus tractus solitarius (NTS) was suppressed by pretreatment with sulpiride (8mg/kg, s.c.). Western blot analysis of shrew brainstem emetic loci protein lysates revealed a significant and time-dependent increase in phosphorylation of Akt (protein kinase B (PKB)) at Ser473 following a 30-min exposure to quinpirole (2mg/kg, i.p.). Pretreatment with effective antiemetic doses of sulpiride, LY294002, GF109203X, or U0126 significantly reduced quinpirole-stimulated phosphorylation of emesis-associated proteins including p-85PI3K, mTOR (Ser2448/2481), PKCαβII (Thr638/641), ERK1/2 (Thr202/204), and Akt (Ser473). Our results substantiate the implication of PI3K/mTOR/Akt and PI3K/PKCαβII/ERK1/2/Akt signaling pathways in dopamine D2 receptor-mediated vomiting. Potential novel antiemetics targeting emetic proteins associated with these signaling cascades may offer enhanced potency and/or efficacy against emesis.

Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist

Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like catechol moiety in their molecular structure, and their therapeutic potential is therefore limited by poor pharmacological properties in vivo. Recently, a class of non-catechol D1R selective agonists with a distinct scaffold and pharmacological properties were reported. Here, we report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 at 3.8 Å resolution. The structure reveals the ligand bound to D1R in an extended conformation, spanning from the orthosteric site to extracellular loop 2 (ECL2). Structural analysis reveals that the unique features of D1R ligand binding pocket explains the remarkable selectivity of this scaffold for D1R over other aminergic receptors, and sheds light on the mechanism for D1R activation by the non-catechol agonist.

Dopamine D1 Receptor Agonist PET Tracer Development: Assessment in Nonhuman Primates.

Non-catechol-based high-affinity selective dopamine D1 receptor (D1R) agonists were recently described, and candidate PET ligands were selected on the basis of favorable properties. The objective of this study was to characterize invivo in nonhuman primates 2 novel D1R agonist PET radiotracers, racemic 18F-MNI-800 and its more active atropisomeric (-)-enantiomer, 18F-MNI-968. Methods: Ten brain PET experiments were conducted with 18F-MNI-800 on 2 adult rhesus macaques and 2 adult cynomolgus macaques, and 8 brain PET experiments were conducted with 18F-MNI-968 on 2 adult rhesus macaques and 2 adult cynomolgus macaques. PET data were analyzed with both plasma-input-based methods and reference-region-based methods. Whole-body PET images were acquired with 18F-MNI-800 from 2 adult rhesus macaques for radiation dosimetry estimates. Results:18F-MNI-800 and 18F-MNI-968 exhibited regional uptake consistent with D1R distribution. Specificity and selectivity were demonstrated by dose-dependent blocking with the D1 antagonist SCH-23390. 18F-MNI-968 showed a 30% higher specific signal than 18F-MNI-800, with a nondisplaceable binding potential of approximately 0.3 in the cortex and approximately 1.1 in the striatum. Dosimetry radiation exposure was favorable, with an effective dose of about 0.023 mSv/MBq. Conclusion:18F-MNI-968 has significant potential as a D1R agonist PET radiotracer, and further characterization in human subjects is warranted.

A selective D2 dopamine receptor agonist alleviates depression through up-regulation of tyrosine hydroxylase and increased neurogenesis in hippocampus of the prenatally stressed rats

Prenatal stress (PNS) has its negative impact on both the infant hippocampal neurogenesis and pregnancy outcomes in the neonates that serves as a risk factor for postnatal depression in adult offsprings. Therefore, main objectives of the present study were to evaluate the effect of maternal chronic unpredictable mild stress (CUMS) on behavioural changes, levels of oxidative stress, changes in selective developmental signaling genes and neurogenesis in the adult brain of Wistar rats and its reversal through a selective non-ergoline D2 type dopamine receptor (D2R) agonist Ropinirole (ROPI). Effects of ROPI treatment on CUMS induced adult rats offspring were measured by assessment of behavioural tests (sucrose preference test and forced swim test), biomarkers of oxidative stress, protein expression of tyrosine hydroxylase (TH), mRNA expression of SHH, GSK-3β, β-catenin, Notch, brain-derived neurotrophic factor (BDNF), Dopamine receptor 2 (Drd2) and bromodeoxyuridine (BrdU) cell proliferation assay. The oxidative stress, protein and mRNA expression were determined in the hippocampus and prefrontal cortex while the BrdU cell proliferation was observed in the hippocampus of rat brain. PNS induced changes resulted in depression validated by the depression-like behaviours, increased oxidative stress, decreased TH expression, altered expression of selective developmental genes, along with the reduced hippocampal neurogenesis and BDNF expression in the brain of adult offsprings. Chronic ROPI treatment reversed those effects and was equally effective like Imipramine (IMI) treatment. So, the present study suggested that ROPI can be used as an antidepressant drug for the treatment of depressive disorders.

Allopregnanolone is required for prepulse inhibition deficits induced by D1 dopamine receptor activation

IntroductionThe extraction of salient information from the environment is modulated by the activation of dopamine receptors. Using rodent models, we previously reported that gating deficits caused by dopamine receptor activation - as measured by the prepulse inhibition (PPI) of startle - are effectively opposed by inhibitors of the steroidogenic enzyme 5α-reductase (5αR). The specific 5αR isoenzyme and steroids implicated in these effects, however, remain unknown. MethodsThe effects of the selective D1 dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D2 receptor agonist quinpirole (QUIN, 0.5 mg/kg, IP) were tested in the startle reflex and PPI of knockout (KO) mice for either 5αR type 1 (5αR1) or type 2 (5αR2). Furthermore, we established whether these effects may be modified by the 5α-reduced steroids dihydroprogesterone (DHP), allopregnanolone (AP), dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol (3α-diol), or androsterone. To test the mechanisms whereby 5αR products may alter the PPI-disrupting properties of D1 agonists, we studied the involvement of GABA-A and PXR, two receptors targeted by neuroactive steroids. Specifically, we tested the effects of SKF in combination with the GABA-A antagonist bicuculline, as well as in KO mice for the GABA-A δ subunit and PXR. Results5αR1, but not 5αR2, knockout (KO) mice were insensitive to the PPI-disrupting effects of SKF. This sensitivity was reinstated by AP (3 mg/kg, IP), but not other 5α-reduced steroids. The PPI deficits induced by SKF were not modified by bicuculline, δ-subunit KO mice and PXR KO mice. ConclusionsThese results collectively suggest that 5αR1 enables the negative effects of D1 dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D1 receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors.

Involvement of catecholaminergic and GABAAergic mediations in the anxiety-related behavior in long-term powdered diet-fed mice

Dietary habits are important factors which affect metabolic homeostasis and the development of emotion. We have previously shown that long-term powdered diet feeding in mice increases spontaneous locomotor activity and social interaction (SI) time. Moreover, that diet causes changes in the dopaminergic system, especially increased dopamine turnover and decreased dopamine D4 receptor signals in the frontal cortex. Although the increased SI time indicates low anxiety, the elevated plus maze (EPM) test shows anxiety-related behavior and impulsive behavior. In this study, we investigated whether the powdered diet feeding causes changes in anxiety-related behavior. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The percentage (%) of open arm time and total number of arm entries were increased in powdered diet-fed mice in the EPM test. We also examined the effects of diazepam, benzodiazepine anti-anxiety drug, bicuculline, GABA-A receptor antagonist, methylphenidate, dopamine transporter (DAT) and noradrenaline transporter (NAT) inhibitor, atomoxetine, selective NAT inhibitor, GBR12909, selective DAT inhibitor, and PD168077, selective dopamine D4 receptor agonist, on the changes of the EPM in powdered diet-fed mice. Methylphenidate and atomoxetine are clinically used to treat attention deficit/hyperactivity disorder (ADHD) symptoms. The % of open arm time in powdered diet-fed mice was decreased by treatments of atomoxetine, methylphenidate and PD168077. Diazepam increased the % of open arm time in control diet-fed mice, but not in powdered diet-fed mice. The powdered diet feeding induced a decrease in GABA transaminase, GABA metabolic enzymes, in the frontal cortex. Moreover, the powdered diet feeding induced an increase in NAT expression, but not DAT expression, in the frontal cortex. These results suggest that the long-term powdered diet feeding may cause low anxiety or impulsivity, possibly via noradrenergic and/or dopaminergic, and GABAAergic mediations and increase the risk for onset of ADHD-like behaviors.

Monitoring of the dopamine D2 receptor agonists hordenine and N-methyltyramine during the brewing process and in commercial beer samples.

The phenethylamine alkaloid hordenine, present in germinated barley, was identified recently as a functionally selective dopamine D2 receptor agonist contributing potentially to the rewarding effects of drinking beer. Here, it was shown that the hordenine precursor N-methyltyramine binds with a similar affinity to the dopamine D2 receptor as hordenine (Ki 31.3 µM) showing also selectivity towards the G protein-mediated pathway over the β-arrestin pathway. Using a newly developed UHPLC-ESI-MS/MS method to monitor beer production, we demonstrated that hordenine and N-methyltyramine were released continuously from barley malt during mashing and were stable during fermentation and conditioning. The amounts released from different base malt types were in a similar range but tended to be higher from caramel malts. Hordenine and N-methyltyramine concentrations in 24 types of beer varied between 1.05-6.32 and 0.59-4.61 mg/L, respectively. Thus, the human uptake of the alkaloids during beer consumption is in the low milligram range.

Dopamine D1 receptor in the medial prefrontal cortex mediates anxiety-like behaviors induced by blocking glutamatergic activity of the ventral hippocampus in rats

The medial prefrontal cortex (mPFC) receives direct and indirect projections from the ventral hippocampus (VH) and plays an important role in the regulation of anxiety. However, the effect of the mPFC dopamine D1 receptor on anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH has not been described. Here, we examined the effects of SKF38393, a selective dopamine D1 receptor agonist, on anxiety-like behaviors induced by NMDA receptor inhibition in the VH and neuron firing activity of mPFC. Injection of MK-801 (6 μg/0.5 μl) into the VH produced anxiety-like behaviors in the elevated plus maze and open field tests, increased the firing activity of pyramidal neurons in the mPFC, and decreased the level of dopamine in the mPFC. Injection of SKF38393 (0.5 μg/0.5 μl) into the mPFC produced anxiolytic effects, and normalized the hyperactive firing activity of mPFC pyramidal neurons induced by MK-801, whereas in both normal and anxiety-like rats caused by MK-801, injection of SKF38393 into the mPFC decreased the firing activity of mPFC interneurons but did not affect the dopamine content in the mPFC. The present data demonstrate that decreased D1 receptor activation in the mPFC may mediate anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH. The balance of D1 receptor activity between pyramidal neurons and interneurons is a crucial factor in maintaining normal conditions, and inhibitory glutamatergic activity in the VH induces hyperactivity of mPFC pyramidal neurons through decreases in dopamine release and in the amount of D1 receptor activation on mPFC pyramidal neurons, which may be a critical factor for anxiety disorders.

Dopamine Receptor Agonist Treatment of Idiopathic Dystonia: A Reappraisal in Humans and Mice.

Although dystonia is often associated with abnormal dopamine neurotransmission, dopaminergic drugs are not currently used to treat dystonia because there is a general view that dopaminergic drugs are ineffective. However, there is little conclusive evidence to support or refute this assumption. Therefore, to assess the therapeutic potential of these compounds, we analyzed results from multiple trials of dopamine receptor agonists in patients with idiopathic dystonias and also tested the efficacy of dopamine receptor agonists in a mouse model of generalized dystonia. Our results suggest that dopamine receptor agonists were effective in some, but not all, patients tested. Further, the mixed D1/D2 dopamine receptor agonist apomorphine was apparently more effective than subtype selective D2 dopamine receptor agonists. However, rigorously controlled trials are still needed. In a mouse model of dystonia, a selective D1 dopamine receptor agonist was not effective while a selective D2 dopamine receptor had modest efficacy. However, when combined, these receptor-selective agonists acted synergistically to ameliorate the dystonia. Coactivation of D1 and D2 dopamine receptors using apomorphine or by increasing extracellular concentrations of dopamine was also effective. Thus, results from both clinical trials and tests in mice suggest that coactivation of D1 and D2 dopamine receptors may be an effective therapeutic strategy in some patients. These results support a reconsideration of dopamine receptors as targets for the treatment of dystonia, particularly because recent genetic and diagnostic advances may facilitate the identification of the subtypes of dystonia patients who respond and those who do not.

The effects of local microinjection of selective dopamine D1 and D2 receptor agonists and antagonists into the dorsal raphe nucleus on sleep and wakefulness in the rat

The effects of the dopamine (DA) D1 and D2 receptor agonists SKF38393, bromocriptine and quinpirole, respectively, on spontaneous sleep were analyzed in adult rats prepared for chronic sleep recordings. Local administration of the DAergic agonists into the dorsal raphe nucleus (DRN) during the light phase of the light-dark cycle induced a significant reduction of rapid-eye movement sleep (REMS) and the number of REM periods. Additionally, bromocriptine and quinpirole significantly increased wakefulness (W). Opposite, the microinjection into the DRN of the DA D1 and D2 receptor antagonists SCH23390 and sulpiride, respectively, significantly augmented REMS and the number of REM periods. Pretreatment with SCH23390 and sulpiride prevented the effects of SKF38393 and bromocriptine, respectively, on sleep variables. Our results tend to indicate that DAergic neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) contribute to the regulation of predominantly W and REMS by DRN serotonergic neurons.

Japanese Encephalitis Virus Exploits Dopamine D2 Receptor-phospholipase C to Target Dopaminergic Human Neuronal Cells

Despite the availability of vaccines for Japanese encephalitis virus (JEV), the re-emerging virus remains a clinically important pathogen that causes acute encephalitis and permanent neuropsychiatric sequels. JEV highly targets dopaminergic neuron-rich brain regions including the thalamus and midbrain. The molecular mechanism contributing to the high susceptibility of these particular brain regions remains largely unclear. This study addressed whether this tissue tropism of JEV is associated with signaling of dopaminergic neurons. Three pieces of evidence indicate that JEV exploits dopamine signaling to facilitate its infection: (1) JEV infection modulates dopamine level; (2) a selective dopamine D2 receptor (D2R) agonist enhances JEV infection; and (3) stimulation of D2R activates phospholipase C (PLC) to enhance the surface expression of JEV binding/entry molecules, integrin β3 and vimentin. Overall, JEV may exploit dopamine-mediated neuronal communication to increase the susceptibility of D2R-expressing cells to JEV infection. This study identifies a potential underlying mechanism of viral invasiveness in the dopaminergic brain regions and suggests antiviral strategies against viral infection by targeting D2R-PLC signaling.

Dopamine receptor agonists modulate voluntary alcohol intake independently of individual levels of alcohol intake in rats.

RationaleIndividual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission.ObjectivesThe aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats that differ in individual levels of alcohol intake.MethodsThe effects of the dopamine D1 receptor agonist SKF 82958, the dopamine D1 receptor antagonist SCH 23390, the dopamine D2 receptor agonist sumanirole and the dopamine D2 receptor antagonist L741,626 on alcohol consumption and preference were assessed at different time points after treatment in subgroups of low and high alcohol drinking rats (LD and HD) using an intermittent alcohol access paradigm.ResultsSKF 82958 decreased alcohol intake and alcohol preference throughout the 24-h session. Sumanirole decreased alcohol intake during the first 2 h, but increased alcohol intake during the remainder of the session. The effects of SKF 82958 and sumanirole on alcohol intake and alcohol preference were comparable in LD and HD. By contrast, the dopamine receptor antagonists SCH 23390 and L741,626 did not alter alcohol consumption in either group at any time point.ConclusionsThese data indicate that stimulation of dopamine D1 receptors reduces alcohol intake, but that endogenous dopamine does not play a primary role in alcohol consumption. Moreover, the difference in alcohol consumption between LD and HD does not involve altered dopamine signaling.

Proteomic profiling reveals dopaminergic regulation of progenitor cell functions of goldfish radial glial cells in vitro

Radial glial cells (RGCs) are stem-like cells found in the developing and adult central nervous system. They function as both a scaffold to guide neuron migration and as progenitor cells that support neurogenesis. Our previous study revealed a close anatomical relationship between dopamine neurons and RGCs in the telencephalon of female goldfish. In this study, label-free proteomics was used to identify the proteins in a primary RGC culture and to determine the proteome response to the selective dopamine D1 receptor agonist SKF 38393 (10μM), in order to better understand dopaminergic regulation of RGCs. A total of 689 unique proteins were identified in the RGCs and these were classified into biological and pathological pathways. Proteins such as nucleolin (6.9-fold) and ependymin related protein 1 (4.9-fold) were increased in abundance while proteins triosephosphate isomerase (10-fold) and phosphoglycerate dehydrogenase (5-fold) were decreased in abundance. Pathway analysis revealed that proteins that consistently changed in abundance across biological replicates were related to small molecules such as ATP, lipids and steroids, hormones, glucose, cyclic AMP and Ca2+. Sub-network enrichment analysis suggested that estrogen receptor signaling, among other transcription factors, is regulated by D1 receptor activation. This suggests that these signaling pathways are correlated to dopaminergic regulation of radial glial cell functions. Most proteins down-regulated by SKF 38393 were involved in cell cycle/proliferation, growth, death, and survival, which suggests that dopamine inhibits the progenitor-related processes of radial glial cells. Examples of differently expressed proteins including triosephosphate isomerase, nucleolin, phosphoglycerate dehydrogenase and capping protein (actin filament) muscle Z-line beta were validated by qPCR and western blot, which were consistent with MS/MS data in the direction of change. This is the first study to characterize the RGC proteome on a large scale in a vertebrate species. These data provide novel insight into glial protein networks that are associated with neuroendocrine function and neurogenesis in the teleost brain. Biological significanceWhile the role of radial glial cells in organizing brain structure and neurogenesis has been well studied, protein profiling experiments in this unique cell type has not been conducted. This study is the first to profile the proteome of goldfish radial glial cells in culture and to study the regulation of progenitor functions of radial glial cells by the neurotransmitter dopamine. This study provides the foundation for molecular network analysis in fish radial glial cells, and identifies cellular processes and signaling pathways in these cells with roles in neurogenesis and neuroendocrine function. Lastly, this study begins to characterize signatures and biomarkers for specific neuroendocrine and neurogenesis disruptors.