Direct Dopamine Research Articles

Postsynaptic Mechanisms Render Syn I/II/III Mice Highly Responsive to Psychostimulants.

BackgroundSynapsins are encoded by SYN I, SYN II, and SYN III, and they regulate neurotransmitter release by maintaining a reserve pool of synaptic vesicles.MethodsPresynaptic dopamine responses to cocaine were examined by microdialysis, and postsynaptic responses were evaluated to various dopamine receptor agonists in the open field with SynI/SynII/SynIII triple knockout mice.ResultsTriple knockout mice showed enhanced spontaneous locomotion in a novel environment and were hyper-responsive to indirect and direct D1 and D2 dopamine agonists. Triple knockout animals appeared sensitized to cocaine upon first open field exposure; sensitization developed across days in wild-type controls. When mutants were preexposed to a novel environment before injection, cocaine-stimulated locomotion was reduced and behavioral sensitization retarded. Baseline dopamine turnover was enhanced in mutants and novel open field exposure increased their striatal dopamine synthesis rates. As KCl-depolarization stimulated comparable dopamine release in both genotypes, their readily releasable pools appeared indistinguishable. Similarly, cocaine-induced hyperlocomotion was indifferent to blockade of newly synthesized dopamine and depletion of releasable dopamine pools. Extracellular dopamine release was similar in wild-type and triple knockout mice preexposed to the open field and given cocaine or placed immediately into the arena following injection. Since motor effects to novelty and psychostimulants depend upon frontocortical-striatal inputs, we inhibited triple knockout medial frontal cortex with GABA agonists. Locomotion was transiently increased in cocaine-injected mutants, while their supersensitive cocaine response to novelty was lost.ConclusionsThese results reveal presynaptic dopamine release is not indicative of agonist-induced triple knockout hyperlocomotion. Instead, their novelty response occurs primarily through postsynaptic mechanisms and network effects.

A characterization of behavior and monoamine interactions during conditioned avoidance maintained in a within‐session behavioral economic avoidance task

The mesolimbic dopamine (DA) system is generally considered to be a reward pathway, however, It is becoming increasingly evident that dopamine release events also process aversion and influence aversively motivated behavior. To investigate the role that dopamine plays in the motivation to avoid, we first developed an economics‐based shock avoidance task in which rats are given the opportunity to avoid electrical foot‐shock. Within each session, we provide rats with the opportunity to avoid footshock across a range of prices (response requirement/mA shock). A stimulus light, or warning signal, placed above the lever signals the opportunity to avoid impending footshock. Using fast‐scan cyclic voltammetry, we determined that dopamine concentration at both the warning signal and successful avoidance decreases with price. However, an attenuation of avoidance and dopamine release at session onset developed over the course of training. It is possible that session onset begins to predict an aversive session terminus because sessions terminate after a minimum of 15 footshocks occur. To further characterize this initial suppression we are currently measuring ultrasonic vocalizations (USVs) during the acquisition of avoidance in the behavioral economics task. We predict that 22khz USVs will develop at session onset in a manner that conincides with both the attenuation of dopamine release and avoidance. While characterizing a novel approach to measure conditioned fear is worthwhile in its own right, we primarily developed our task to measure changes in the price rats will pay to avoid. We measure the price rats will pay to avoid by using demand curves. Demand curves are a common tool used by economists to measure price sensitivity that depict the relationship between consumption (mA footshock avoided) and price (responses/mA). The rate at which demand curves decay can be used to make inferences regarding the value individuals place on the commodity being consumed. If the slope decays at a faster rate we would infer that the value to avoid is decreased because the rats are paying less to avoid. Using optogenetics, we found that increasing dopamine release at successful avoidance increases the price rats will pay for cocaine. Follow‐up optogenetic studies are investigating the role of the habenula‐RMTg‐mesolimbic dopamine circuitry. We predict that exciting glutamate neurons in the habenula will produce opposite behavioral effects to those occurring from direct dopamine stimulation. We are also beginning to compare the effects of discrete monoamine systems. To begin, we are simply pre‐treating rats with dopamine, serotonin and norepinephrine uptake inhibitors. Based on our preliminary optogenetics data, we predict that the dopamine uptake inhibitor will increase the price rats will pay to avoid whereas, serotonin and norephinephreine manipulations will produce distinct effects.Support or Funding InformationThis work was supported by the National Science Foundation Grant IOS‐1557755, the National Institutes of Health Grant R03DA038734, the Boettcher Young Investigator Award and the National Alliance for Research on Schizophrenia and Depression Young Investigator Award (E.B.O.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Regulation of dopamine neurotransmission from serotonergic neurons by ectopic expression of the dopamine D2 autoreceptor blocks levodopa-induced dyskinesia

Levodopa-induced dyskinesias (LID) are a prevalent side effect of chronic treatment with levodopa (L-DOPA) for the motor symptoms of Parkinson’s disease (PD). It has long been hypothesized that serotonergic neurons of the dorsal raphe nucleus (DRN) are capable of L-DOPA uptake and dysregulated release of dopamine (DA), and that this “false neurotransmission” phenomenon is a main contributor to LID development. Indeed, many preclinical studies have demonstrated LID management with serotonin receptor agonist treatment, but unfortunately, promising preclinical data has not been translated in large-scale clinical trials. Importantly, while there is an abundance of convincing clinical and preclinical evidence supporting a role of maladaptive serotonergic neurotransmission in LID expression, there is no direct evidence that dysregulated DA release from serotonergic neurons impacts LID formation. In this study, we ectopically expressed the DA autoreceptor D2Rs (or GFP) in the DRN of 6-hydroxydopamine (6-OHDA) lesioned rats. No negative impact on the therapeutic efficacy of L-DOPA was seen with rAAV-D2Rs therapy. However, D2Rs treated animals, when subjected to a LID-inducing dose regimen of L-DOPA, remained completely resistant to LID, even at high doses. Moreover, the same subjects remained resistant to LID formation when treated with direct DA receptor agonists, suggesting D2Rs activity in the DRN blocked dyskinesogenic L-DOPA priming of striatal neurons. In vivo microdialysis confirmed that DA efflux in the striatum was reduced with rAAV-D2Rs treatment, providing explicit evidence that abnormal DA release from DRN neurons can affect LID. This is the first direct evidence of dopaminergic neurotransmission in DRN neurons and its modulation with rAAV-D2Rs gene therapy confirms the serotonin hypothesis in LID, demonstrating that regulation of serotonergic neurons achieved with a gene therapy approach offers a novel and potent antidyskinetic therapy.

Molecular Imprinting: Molecularly Imprinted Fluorescent Test Strip for Direct, Rapid, and Visual Dopamine Detection in Tiny Amount of Biofluid (Small 1/2019)

Molecular Imprinting: Molecularly Imprinted Fluorescent Test Strip for Direct, Rapid, and Visual Dopamine Detection in Tiny Amount of Biofluid (Small 1/2019)

Molecularly Imprinted Fluorescent Test Strip for Direct, Rapid, and Visual Dopamine Detection in Tiny Amount of Biofluid

Paper-based assays for detection of physiologically important species are needed in medical theranostics owning to their superiorities in point of care testing, daily monitoring, and even visual readout by using chromogenic materials. In this work, a facile test strip is developed for visual detection of a neurotransmitter dopamine (DA) based on dual-emission fluorescent molecularly imprinted polymer nanoparticles (DE-MIPs). The DE-MIPs, featured with tailor-made DA affinity and good anti-interference, exhibit DA concentration-dependent fluorescent colors, due to the variable ratios of dual-emission fluorescence caused by DA binding and quenching. By facile coating DE-MIPs on a filter paper, the DA test strips are obtained. The resultant test strip, like the simplicity of a pH test paper, shows the potential for directly visual detection of DA levels just by dripping a tiny amount of biofluid sample on it. The test result of real serum samples demonstrates that the DA strip enables to visually and semiquantitatively detect DA within 3 min by using only 10 µL of serum samples and with a low detection limit ((100-150) × 10-9 m) by naked eye. This work thus offers a facile and efficient strategy for rapid, visual, and on-site detection of biofluids in clinic.

Lentiviral-mediated let-7d microRNA overexpression induced anxiolytic- and anti-depressant-like behaviors and impaired dopamine D3 receptor expression

Generalized anxiety and major depression disorders (MDD) are severe debilitating mood disorders whose etiology are not fully understood, but growing evidence indicates that microRNAs (miRNAs) might play a key role in their neuropathophysiological mechanisms. In the current study, we investigate the role of Lethal-7 (let-7d) miRNA, and its direct target dopamine D3 receptor (D3R) gain-of-function, in the hippocampus, in preclinical models of anxiety and depression in mice. For this purpose, we have constructed a lentiviral vector carrying let-7d miRNA and its anxiolytic effect was investigated by employing the open-field (OF) and the elevated plus maze (EPM) tests. The anti-depressant activity was evaluated using the tail suspension and the forced-swim tests (TST & FST). Our results show that let-7d overexpression significantly improved the measures of anxiety in the OF and EPM tests. In addition, let-7d increased the mobility time in the TST and FST. Interestingly, gene expression interaction analysis shows that the D3R mRNA negatively correlates with let-7d expression. In a different set of experiments, we used a tetracycline-inducible (tet-off) lentiviral vector to overexpress D3R to assess its gain-of-function in the hippocampus on anxiety- and depression-like behaviors. In line, we found that in the absence of doxycycline, D3R produced a significant anxiogenic and depressant-like response. Most importantly, these effects were abrogated when mice were fed doxycycline in drinking water. Our results provide the first evidence for an anxiolytic and anti-depressant-like action of let-7d through a potential D3R target-mediated mechanism which might open new avenues for anxiolytic and anti-depressant therapies.

A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1 receptor agonist SKF-81297 revealed no differences in induced locomotor activity compared to wild-type mice, but Df(h1q21)/+ mice showed increased sensitivity to the DA D2 receptor agonist quinpirole and the D1/D2 agonist apomorphine. Electrophysiological characterization of DA neuron firing in the ventral tegmental area revealed more spontaneously active DA neurons and increased firing variability in Df(h1q21)/+ mice, and decreased feedback reduction of DA neuron firing in response to amphetamine. In a range of other assays, Df(h1q21)/+ mice showed no difference from wild-type mice: gross brain morphology and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced head-to tail length, which is reminiscent of the short stature reported in humans with 1q21.1 deletion. With aspects of both construct and face validity, the Df(h1q21)/+ model may be used to gain insight into schizophrenia-relevant alterations in dopaminergic transmission.

Beneficial impact of oxygen on the electrochemical performance of dopamine sensors based on N-doped reduced graphene oxides

Graphene-based electrochemical sensors are promising devices for direct and easy dopamine determination. In this work, N-doped reduced graphene oxides (N-rGOs) were prepared via hydrothermal treatment of graphene oxide (GO) and amitrole (3-amino-1,2,4-triazole) under different experimental conditions (varying reaction temperature and time), which resulted in each material having different oxygen content. Furthermore, the dopant nitrogen content was comparable in the three N-rGOs and it was primarily pyridinic in nature. The three synthesized N-rGOs were characterized by X-ray photoelectron spectroscopy, Fourier transformed infrared spectroscopy, scanning electron microscopy, and nitrogen sorption at 77K. Glassy carbon electrodes modified with N-rGOs were prepared and used as active electrode materials in electrochemical sensors of dopamine (DA). The optimal operational pH was determined to be 7.4, which is also the physiological value. During the electrochemical detection of DA, it was found that there is a direct relationship between the oxygen content in N-rGO and electrochemical performance of these sensors. Thus, the detection of DA in the presence of ascorbic and uric acids was more sensitive and selective when the least reduced N-rGO sample was used. The attraction between the electronegative oxygen in the graphene structure and cationic DA facilitates the adsorption process which could explain these results. However, the limit of detection (LOD) was also higher in this case due to decreased conductivity.

Direct Midbrain Dopamine Input to the Suprachiasmatic Nucleus Accelerates Circadian Entrainment

Dopamine (DA) neurotransmission controls behaviors important for survival, including voluntary movement, reward processing, and detection of salient events, such as food or mate availability. Dopaminergic tone also influences circadian physiology and behavior. Although the evolutionary significance of this input is appreciated, its precise neurophysiological architecture remains unknown. Here, we identify a novel, direct connection between the DA neurons of the ventral tegmental area (VTA) and the suprachiasmatic nucleus (SCN). We demonstrate that D1 dopamine receptor (Drd1) signaling within the SCN is necessary for properly timed resynchronization of activity rhythms to phase-shifted light:dark cycles and that elevation of DA tone through selective activation of VTA DA neurons accelerates photoentrainment. Our findings demonstrate a previously unappreciated role for direct DA input to the master circadian clock and highlight the importance of an evolutionarily significant relationship between the circadian system and the neuromodulatory circuits that govern motivational behaviors.

Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.

The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia. The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

Relief of Pain-Depressed Behavior in Rats by Activation of D1-Like Dopamine Receptors

Clinically significant pain often includes a decrease in both behavior and mesolimbic dopamine signaling. Indirect and/or direct dopamine receptor agonists may alleviate pain-related behavioral depression. To test this hypothesis, the present study compared effects of indirect and direct dopamine agonists in a preclinical assay of pain-depressed operant responding. Male Sprague-Dawley rats with chronic indwelling microelectrodes in the medial forebrain bundle were trained in an intracranial self-stimulation (ICSS) procedure to press a lever for pulses of electrical brain stimulation. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to depress ICSS. Intraperitoneal lactic acid-induced depression of ICSS was dose-dependently blocked by the dopamine transporter inhibitor methylphenidate and the D1-selective agonist SKF82958, but not by the D2/3-selective agonists quinpirole, pramipexole, or sumanirole. The antinociceptive effects of methylphenidate and SKF82958 were blocked by the D1-selective antagonist SCH39166. Acid-induced stimulation of a stretching response was evaluated in separate groups of rats, but all agonists decreased acid-stimulated stretching, and antagonism experiments were inconclusive due to direct effects of the antagonists when administered alone. Taken together, these results suggest that D1-receptor stimulation is both sufficient to block acid-induced depression of ICSS and necessary for methylphenidate antinociception in this procedure. Conversely, D2/3-receptor stimulation is not sufficient to relieve pain-depressed behavior. These results support the hypothesis that pain-related depression of dopamine D1 receptor signaling contributes to pain-related depression of behavior in rats. Additionally, these results support further consideration of indirect dopamine agonists and direct D1 receptor agonists as candidate treatments for pain-related behavioral depression.

Apomorphine - pharmacological properties and clinical trials in Parkinson's disease

Apomorphine is often considered an archetypal dopamine agonist used in the treatment of Parkinson's disease (PD). However, it can be clearly differentiated from most other commonly used dopamine agonists on the basis of its pharmacology and on its unique clinical profile. Like levodopa and dopamine, apomorphine acts as a potent, direct and broad spectrum dopamine agonist activating all dopamine receptor subtypes. It also has affinity for serotonin receptors, and α-adrenergic receptors. Apomorphine is usually titrated to a dose that provides an equivalent antiparkinsonian response to that provided by levodopa, and its subcutaneous delivery allows a rapid onset of action, usually within 7–10 min. The mode of apomorphine delivery impacts on its clinical profile so as to provide two very different approaches to therapy in PD. When administered as an acute subcutaneous injection, it induces reliable and rapid relief from OFF periods underscoring its utility as a rescue medication. When given as a subcutaneous infusion, it significantly improves overall daily OFF time and there is also evidence to suggest that, in those patients who replace most or all of their oral drugs with apomorphine infusion, dyskinesia may also improve. In this paper, we review the rich pharmacology of apomorphine and review its efficacy in PD based on data from clinical trials.

Probe Sensor Using Nano-Structured Multi Walled Carbon Nanotube Yarn for Direct Selective and Sensitive Dopamine Detection

Dopamine (DA) is an important neurotransmitter in the central nervous system. Insufficient or excessive level of DA related to Schizophrenia and Parkinson diseases[ 1 ]. Therefore, early detection of DA represents a hot topic in biosensing field. Recently, electrochemical bio-sensor (ECB) based on carbon material has received a great attention as an inexpensive and simple analytical method with remarkable detection sensitivity for neurochemicals detection[ 1 ]. Therefore, ECB’s fabrication and structure have attracted researcher’s efforts to obtain higher sensitivity and highly selectivity simultaneously. Traditional film-based ECB have shown some disadvantages such as large sizes, random structure, time consuming for film fabrication and low efficient[ 2 ]. As a result, a new biosensor based on nano carbon material designed in a probe style has been considered as an excellent candidate for sensing stimulation as they have aligned and packed structure which provides a bridge for electrons transfer and that enhances electrical conductivity, also, fibres can be fabricated in small sizes which gives the ability to be implanted with low tissue damages, in addition, simplicity of handling and ability to be grafted with different materials[ 3 ]. The aim of this study is to develop hybrid multi wall carbon nanotube yarn due to fascinating properties for CNTs (i.e. high surface area, fast electron kinetics transfer, reduced electrode fouling, wide electrochemical potential window, bio-compatibility, grafting ability, and increased sensitivity and selectivity (high efficient)). In a typical bio-sensing system, DA has been used with ascorbic acid (AA) and uric acid (UA) (as coexistence compounds[ 4 ]) for investigating both sensitivity and selectivity of the prepared CNT yarn viacyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques. CV and DPV results have demonstrated selective and sensitive detection of DA in a sea of AA and UA with the potential to be a promising probe bio-sensor for real-time measurement.

Dopaminergic abnormalities in Hdac6-deficient mice

Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular basis will lead to new insights into relations between protein acetylation events and psychiatric disorders.Here we report the dopaminergic abnormalities in Hdac6 KO mice. The dopamine transmission mediated by D1-like and D2-like G protein-coupled dopamine receptors is known to play roles in controlling movement, cognition, and motivational processes, and its dysfunction causes psychiatric disorders. We found that Hdac6 KO mice showed significantly increased locomotor response to novel, but not to habituated environment. In addition, Hdac6 KO mice showed a long-lasting sensitivity to psychostimulants, increased locomotor response to D2-like, but not D1 dopamine receptor agonists, and rapid locomotor response to apomorphine, a direct dopamine agonist, in dopamine-depleted condition. Hdac6 protein was expressed in dopaminergic neurons and their terminals in adult mice brain, and Hdac6-depletion augmented acetylation levels of dopamine-enriched synaptosomal proteins. In Hdac6 KO mice, the striatal content of dopamine and its metabolites was normal in basal condition, but mRNA level of D2 dopamine receptor in the striatum was decreased by 30%. Taken together, our results provide evidence that Hdac6 deficiency leads to aberrant dopamine-dependent behaviors by enhancing postsynaptic dopamine D2 receptor response. This study points out the possibility that Hdac6 and reversible-acetylation events play a regulatory role in D2 dopamine receptor signaling, and thus participate in the pathology of the dopamine-related psychiatric disorders such as schizophrenia.

Dopaminergic inhibition of gonadotropin-releasing hormone neurons in the cichlid fish Astatotilapia burtoni.

Dopamine regulates reproduction in part by modulating neuronal activity within the hypothalamic-pituitary-gonadal (HPG) axis. Previous studies suggested numerous mechanisms by which dopamine exerts inhibitory control over the HPG axis, ultimately changing the levels of sex steroids that regulate reproductive behaviors. However, it is not known whether these mechanisms are conserved across vertebrate species. In particular, it is unknown whether mechanisms underlying dopaminergic control of reproduction are shared between mammals and teleost fish. In mammals, dopamine directly inhibits gonadotropin-releasing hormone (GnRH1) hypothalamic neurons, the gatekeepers for activation of the HPG axis. Here, we demonstrate, for the first time in teleost fish, dopaminergic control of GnRH1 neurons via direct dopamine type-2-like receptor (D2R)-mediated inhibition within the hypothalamus. These results suggest that direct dopaminergic control of GnRH1 neurons via interactions in the hypothalamus is not exclusive to tetrapod reproductive control, but is likely conserved across vertebrate species.

Formulation Of SnO2/graphene Nanocomposite Modified Electrode For Synergitic Electrochemcial Detection Of Dopamine

Pristine SnO2 and SnO2/Graphene (SnO2/GN) nanocomposites were prepared via facile hydrothermal method with amended electro catalytic activity towards Dopamine (DA) sensing. X-Ray Diffraction (XRD) pattern revealed the formation of tetragonal crystal system of SnO2 that was retained in both pure metal oxide and composite. Fourier Transform – Infrared (FT-IR) transmission spectra evidenced the stretching and bending vibration modes of pure SnO2 and SnO2/GN nanocomposites. The in-plane bending modes of SnO2 and graphatic peaks in graphene oxide (GO) and composite were identified in Raman spectral analysis. Morphology of synthesized materials and uniform distribution of SnO2 on graphene sheet in SnO2/GN composite were observed in Field Emission-Scanning Electron Microscope (FE-SEM). Electrochemical performance of SnO2 and SnO2/GN nanocomposite on modified Glassy Carbon (GC) electrode was evaluated for direct DA sensing using Cyclic Voltammetry (CV), Differential Pulse Voltammetry (DPV) and Chrono Amperometric techniques. The SnO2/GN nanocomposite showed enhanced charge carrier mobility towards DA in presence of interferences like Ascorbic acid (AA) and Uric acid (UA) compared to pristine SnO2. The limit of detection was calculated as (0.7μM) for (SnO2/GN) which is better than bare SnO2 (6.675 μM). These synergetic behaviors depicting SnO2/GN composite can serve as a promising electrode in sensor transducers in near future.

WO3 nanoparticles based direct electrochemical dopamine sensor in the presence of ascorbic acid

Tungsten trioxide (WO3) nanoparticles with monoclinic (γ) and orthorhombic (β) structures were synthesized by a simple microwave irradiation method and characterized using powder X-ray diffraction (XRD), electron energy loss spectroscopy (EELS), Raman spectroscopy, field emission scanning electron microscopy (FESEM), UV–vis absorption and photoluminescence (PL) spectroscopy studies. The γ-WO3 nanoparticles modified glassy carbon electrode (GCE) showed an excellent electrocatalytic activity towards the oxidation of dopamine (DA) in the presence of ascorbic acid (AA) at pH 7.0. Electrochemical kinetic parameters of γ-WO3/GCE such as electroactive area A (0.045cm2), electron transfer coefficient α (0.71) and electron transfer rate constant ks (1.121s−1) were calculated and compared with that of β-WO3/GCE. Differential pulse voltammetry (DPV) studies of the γ-WO3 modified GCE exhibited a linear response over a wide concentration range of 0.1μmolL−1–600μmolL−1 of DA with the lowest detection limit of 24nmolL−1. The fabricated dopamine sensor showed an excellent anti-interference ability against electroactive species and metal ions with good stability and reproducibility. Finally, the developed sensor was applied to determine DA concentration in dopamine hydrochloride injection which indicates that this electrode can be effectively used for real sample analysis.

Sensitization to apomorphine in pigeons: a multifactorial conditioning process.

Apomorphine (apo), an unspecific direct dopamine agonist, elicits an intense and lasting pecking bout in pigeons. Apo yielded orderly dose-response functions, and repeated administrations led to sensitization. Strain and individual differences in sensitivity to apo were at least partly due to genetic factors. However, a strong cage-context dependency of the sensitization, which is indicative of conditioning, occurred in both pigeon strains studied. Apo-induced pecking and sensitization also occurred in total darkness. Pigeons could be conditioned to discriminate between an apo state and a non-apo state. A small dose of apo was effective as a conditioned stimulus when paired with a high dose as an unconditioned stimulus. The conditioned response (CR) was strongly specific to the context in which the sensitization to apo took place. The resistance to extinction of the CR could be increased through an oversensitization treatment. The incremental responses arising during the sensitization treatment and the CRs shown afterward by individual pigeons correlated significantly. The sensitization to apo in pigeons is well accounted for by a conditioning schema in which an interoceptive drug state is a conditional conditioned stimulus for the full expression of the incremental response. Variants of the scheme might also account for the sensitization of rodents to psychostimulants. A neural model that embodies the characteristics of the conditioning scheme has been proposed.

Stress-induced activation of ventral tegmental mu-opioid receptors reduces accumbens dopamine tone by enhancing dopamine transmission in the medial pre-frontal cortex.

Endogenous opioids could play a major role in the mesocorticolimbic dopamine (DA) responses to stress challenge. However, there is still no direct evidence of an influence of endogenous opioids on any of these responses. We assessed whether and how endogenous opioids modulate fluctuations of mesocortical and mesoaccumbens DA tone in rats during a first experience with restraint stress. We first evaluated the effects of systemic naltrexone (NTRX) on DA outflow in the medial prefrontal cortex (mpFC) and in the nucleus accumbens (NAc) through dual-probe microdialysis. Second, we assessed the effect of perfusion, through reverse microdialysis, of direct DA receptor agonists in mpFC on NAc DA outflow in NTRX-pretreated stressed rats. Finally, we tested the effects of ventral tegmental area (VTA) perfusion of NTRX, the selective mu1 antagonist naloxonazine and the selective delta antagonist naltrindole on mpFC and NAc DA outflow in stressed rats, with multiple probe experiments. Systemic NTRX, at behaviorally effective doses, selectively prevented the increase of mpFC DA levels and the reduction of NAc DA levels observable during prolonged restraint. Local co-perfusion of D1 and D2 agonists in mpFC recovered inhibition of NAc DA in NTRX-pretreated restrained rats. Finally, intra-VTA perfusion of either NTRX or the mu1 antagonist, but not the delta antagonist, mimicked the effects of systemic NTRX. During prolonged experience with a novel unavoidable/uncontrollable stressor, endogenous opioids, through stimulation of mu1 receptors in the VTA, elevate mesocortical DA tone thus reducing DA tone in the NAc DA.

Treatment of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder diagnosed by the clinical characteristics of restlessness in the legs associated often with abnormal sensations that start at rest and are improved by activity, occurring with a diurnal pattern of worsened symptoms at night and improvement in the morning. RLS is the cause of impaired quality of life in those more severely afflicted. Treatment of RLS has undergone considerable change over the last few years. Several classes of medications have demonstrated efficacy, including the dopaminergic agents and the alpha-2-delta ligands. Levodopa was the first dopaminergic agent found to be successful. However, chronic use of levodopa is frequently associated with augmentation that is defined as an earlier occurrence of symptoms frequently associated with worsening severity and sometimes spread to other body areas. The direct dopamine agonists, including ropinirole, pramipexole, and rotigotine patch, are also effective, although side effects, including daytime sleepiness, impulse control disorders, and augmentation, may limit usefulness. The alpha-2-delta ligands, including gabapentin, gabapentin enacarbil, and pregabalin, are effective for RLS without known occurrence of augmentation or impulse control disorders, although sedation and dizziness can occur. Other agents, including the opioids and clonazepam do not have sufficient evidence to recommend them as treatment for RLS, although in an individual patient, they may provide benefit.