Dopamine Transmission Research Articles

Neuromelanin-Sensitive MRI as a Marker of Dopamine Hyperactivity and CBT Response in Children With Obsessive-Compulsive Disorder

Positron Emission Tomography (PET) findings suggest that increased striatal dopamine neurotransmission may underlie Obsessive-Compulsive Disorder (OCD) in adults. This is untested in pediatric OCD since PET is overly invasive and untenable for pediatric research. Thus, we used neuromelanin-sensitive MRI (NM-MRI) to assess nigrostriatal dopamine transmission in children with OCD and predict response to cognitive behavioral therapy (CBT).

Imbalance between dopamine and serotonin caused by neonatal habenula lesion

Alterations in dopamine (DA) and serotonin (5-HT) transmission have been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). We have previously reported that juvenile rats with neonatal habenula lesion (NHL) exhibit an assortment of behavioral alterations resembling ADHD symptoms. In this study, we investigated the impacts of NHL on DA and 5-HT transmission in mesocorticolimbic regions of rats. Male Sprague-Dawley rats with microinjection of ibotenic acid into the habenula at postnatal day (PND) 7 were subjected for a battery of locomotion test, object exploration test and delay discounting test in the juvenile period (PND28-35), followed by DA and 5-HT brain tissue concentration measurements using high-performance liquid chromatography (HPLC). NHL rats exhibited hyperlocomotion, impulsivity, and attention deficits. NHL induced alterations of tissue DA and 5-HT concentrations only in some mesocorticolimbic regions. However, positive correlations, indicating the balance, between DA and 5-HT observed in control (CTR) rats, were more extensively disrupted across mesocorticolimbic regions in NHL rats. Pharmacological manipulations that modulated both DA and 5-HT systems simultaneously with Astragalus membranaceus (AM) and its active compound formononetin (FOR) normalized the NHL-induced DA and 5-HT imbalance in several brain areas, which consequently improved the behavioral alterations. These results suggest that behavioral alterations caused by NHL may be associated with mesocorticolimbic DA/5-HT imbalance. Drug treatments targeting multiple monoamine systems may be useful to improve the NHL-induced changes.

Selenoprotein P Modulates Methamphetamine Enhancement of Vesicular Dopamine Release in Mouse Nucleus Accumbens Via Dopamine D2 Receptors.

Dopamine (DA) transmission plays a critical role in processing rewarding and pleasurable stimuli. Increased synaptic DA release in the nucleus accumbens (NAc) is a central component of the physiological effects of drugs of abuse. The essential trace element selenium mitigates methamphetamine-induced neurotoxicity. Selenium can also alter DA production and turnover. However, studies have not directly addressed the role of selenium in DA neurotransmission. Selenoprotein P (SELENOP1) requires selenium for synthesis and transports selenium to the brain, in addition to performing other functions. We investigated whether SELENOP1 directly impacts (1) DA signaling and (2) the dopaminergic response to methamphetamine. We used fast-scan cyclic voltammetry to investigate DA transmission and the response to methamphetamine in NAc slices from C57/BL6J SELENOP1 KO mice. Recordings from SELENOP1 KO mouse slices revealed reduced levels of evoked DA release and slower DA uptake rates. Methamphetamine caused a dramatic increase in vesicular DA release in SELENOP1 KO mice not observed in wild-type controls. This elevated response was attenuated by SELENOP1 application through a selenium-independent mechanism involving SELENOP1-apolipoprotein E receptor 2 (ApoER2) interaction to promote dopamine D2 receptor (D2R) function. In wild-type mice, increased vesicular DA release in response to methamphetamine was revealed by blocking D2R activation, indicating that the receptor suppresses the methamphetamine-induced vesicular increase. Our data provide evidence of a direct physiological role for SELENOP1 in the dopaminergic response to methamphetamine and suggest a signaling role for the protein in DA transmission.

In vivo evidence for the unique kinetics of evoked dopamine release in the patch and matrix compartments of the striatum

The neurochemical transmitter dopamine (DA) is implicated in a number of diseases states, including Parkinson’s disease, schizophrenia, and drug abuse. DA terminal fields in the dorsal striatum and core region of the nucleus accumbens in the rat brain are organized as heterogeneous domains exhibiting fast and slow kinetic of DA release. The rates of dopamine release are significantly and substantially faster in the fast domains relative to the slow domains. The striatum is composed of a mosaic of spatial compartments known as the striosomes (patches) and the matrix. Extensive literature exists on the spatial organization of the patch and matrix compartments and their functions. However, little is known about these compartments as they relate to fast and slow kinetic DA domains observed by fast scan cyclic voltammetry (FSCV). Thus, we combined high spatial resolution of FSCV with detailed immunohistochemical analysis of these architectural compartments (patch and matrix) using fluorescence microscopy. Our findings demonstrated a direct correlation between patch compartments with fast domain DA kinetics and matrix compartments to slow domain DA kinetics. We also investigated the kinetic domains in two very distinct sub-regions in the striatum, the lateral dorsal striatum (LDS) and the medial dorsal striatum (MDS). The lateral dorsal striatum as opposed to the medial dorsal striatum is mainly governed by fast kinetic DA domains. These finding are highly relevant as they may hold key promise in unraveling the fast and slow kinetic DA domains and their physiological significance.Graphical abstract

Spatial and temporal scales of dopamine transmission.

Dopamine is a prototypical neuromodulator that controls circuit function through G protein-coupled receptor signalling. Neuromodulators are volume transmitters, with release followed by diffusion for widespread receptor activation on many target cells. Yet, we are only beginning to understand the specific organization of dopamine transmission in space and time. Although some roles of dopamine are mediated by slow and diffuse signalling, recent studies suggest that certain dopamine functions necessitate spatiotemporal precision. Here, we review the literature describing dopamine signalling in the striatum, including its release mechanisms and receptor organization. We then propose the domain-overlap model, in which release and receptors are arranged relative to one another in micrometre-scale structures. This architecture is different from both point-to-point synaptic transmission and the widespread organization thatis often proposed for neuromodulation. It enables the activation of receptor subsets that are within micrometre-scale domains of release sites during baseline activity and broader receptor activation with domain overlap when firing is synchronized across dopamine neuron populations. This signalling structure, together with the properties of dopamine release, may explain how switches in firing modes support broad and dynamic roles for dopamine and may lead to distinct pathway modulation.

Analysis of the Neuroproteome Associated With Cell Therapy After Intranigral Grafting in a Mouse Model of Parkinson Disease.

Advances in large-scale proteomics analysis have been very useful in understanding pathogenesis of diseases and elaborating therapeutic strategies. Proteomics has been employed to study Parkinson disease (PD); however, sparse studies reported proteome investigation after cell therapy approaches. In this study, we used liquid chromatography–tandem mass spectrometry and systems biology to identify differentially expressed proteins in a translational mouse model of PD after cell therapy. Proteins were extracted from five nigrostriatal-related brain regions of mice previously lesioned with 6-hydroxydopamine in the substantia nigra. Protein expression was compared in non-grafted brain to 1 and 7 days after intranigral grafting of E12.5 embryonic ventral mesencephalon (VM). We found a total of 277 deregulated proteins after transplantation, which are enriched for lipid metabolism, oxidative phosphorylation and PD, thus confirming that our animal model is similar to human PD and that the presence of grafted cells modulates the expression of these proteins. Notably, seven proteins (Acta1, Atp6v1e1, Eci3, Lypla2, Pip4k2a, Sccpdh, and Sh3gl2) were commonly down-regulated after engraftment in all studied brain regions. These proteins are known to be involved in the formation of lipids and recycling of dopamine (DA) vesicle at the synapse. Moreover, intranigral transplantation of VM cells decreased the expression of proteins related to oxidative stress, especially in the nigrostriatal pathway containing the DA grafted neurons. In the same regions, an up-regulation of several proteins including α-synuclein and tyrosine hydroxylase was observed, whereas expression of tetraspanin 7 was shut down. Overall, these results suggest that intranigral transplantation of VM tissue in an animal model of PD may induce a decrease of oxidative stress in the nigrostriatal pathway and a restoration of the machinery of neurotransmitters, particularly DA release to promote DA transmission through a decrease of D2 DA receptors endocytosis. Identification of new mechanistic elements involved in the nigrostriatal reconstruction process, using translational animal models and systems biology, is a promising approach to enhance the repair of this pathway in PD patients undergoing cell therapy.

Multiplexed neurochemical transmission emulated using a dual-excitatory synaptic transistor

The ability to emulate multiplexed neurochemical transmission is an important step toward mimicking complex brain activities. Glutamate and dopamine are neurotransmitters that regulate thinking and impulse signals independently or synergistically. However, emulation of such simultaneous neurotransmission is still challenging. Here we report design and fabrication of synaptic transistor that emulates multiplexed neurochemical transmission of glutamate and dopamine. The device can perform glutamate-induced long-term potentiation, dopamine-induced short-term potentiation, or co-release-induced depression under particular stimulus patterns. More importantly, a balanced ternary system that uses our ambipolar synaptic device backtrack input ‘true’, ‘false’ and ‘unknown’ logic signals; this process is more similar to the information processing in human brains than a traditional binary neural network. This work provides new insight for neuromorphic systems to establish new principles to reproduce the complexity of a mammalian central nervous system from simple basic units.

Loss of nigral excitation of cholinergic interneurons contributes to parkinsonian motor impairments

Progressive loss of dopamine inputs in Parkinson's disease leads to imbalances in coordinated signaling of dopamine and acetylcholine (ACh) in the striatum, which is thought to contribute to parkinsonian motor symptoms. As reciprocal interactions between dopamine inputs and cholinergic interneurons (ChIs) control striatal dopamine and ACh transmission, we examined how partial dopamine depletion in an early-stage mouse model for Parkinson's disease alters nigral regulation of cholinergic activity. We found region-specific alterations in how remaining dopamine inputs regulate cholinergic excitability that differ between the dorsomedial (DMS) and dorsolateral (DLS) striatum. Specifically, we found that dopamine depletion downregulates metabotropic glutamate receptors (mGluR1) on DLS ChIs at synapses where dopamine inputs co-release glutamate, abolishing the ability of dopamine inputs to drive burst firing. This loss underlies parkinsonian motor impairments, as viral rescue of mGluR1 signaling in DLS ChIs was sufficient to restore circuit function and attenuate motor deficits in early-stage parkinsonian mice.

Lack of drug- and cue-stimulated emissions of ultrasonic vocalizations in C57BL/6J mice repeatedly treated with amphetamine

The emission of ultrasonic vocalizations (USVs) is thought to communicate the behavioral and emotional states elicited in rodents by social and non-social stimuli. On this basis, studies of psychopharmacology in rats are increasingly utilizing USVs as a behavioral marker to evaluate the effects of drugs on the emotional state. Conversely, very limited information is available as to whether psychoactive drugs influence USV emissions in mice. To provide new insights in this respect, we evaluated the emission of USVs in C57BL/6J mice subjected to repeated treatment with the dopaminergic psychostimulant of abuse amphetamine. Mice were first allowed to perform social contacts in dyads, and 2 days later they received amphetamine (1−4 mg/kg, i.p.) in a test cage (× 5 administrations) on alternate days. Seven days after treatment discontinuation, mice were re-exposed to the test cage to evaluate whether the presentation of drug-paired environmental cues elicited calling behavior, and thereafter received an amphetamine challenge. An additional group of animals received the dopamine receptor agonist apomorphine (1−4 mg/kg, i.p.), to further clarify the role of dopamine transmission in calling behavior of mice. C57BL/6J mice emitted USVs during social contacts, but did not significantly vocalize after amphetamine administration, in response to amphetamine-paired environmental cues, and after apomorphine administration. These results indicate that C57BL/6J mice may respond differently to social and pharmacological stimuli in terms of USV emissions, and may lay the foundation for future studies aimed at clarifying whether USVs may be a useful behavioral marker in studies of psychopharmacology in mice.

Dopamine multilocus genetic profiles predict sex differences in reactivity of the human reward system.

Sex differences in the neural processing of decision-making are of high interest as they may have pronounced effects on reward- and addiction-related processes. In these, the neurotransmitter dopamine plays a central role by modulating the responsiveness of the reward circuitry. The present functional magnetic resonance imaging study aimed to explore sex and dopamine transmission interactions in decision-making. 172 subjects (111 women) performed a behavioral self-control task assessing reward-related activation during acceptance and rejection of conditioned rewards. Participants were genotyped for six key genetic polymorphisms in the dopamine system that have previously been associated with individual differences in reward sensitivity or dopaminergic transmission in the human striatum, such as rs7118900 (dopamine receptor D2 (DRD2) Taq1A), rs1554929 (DRD2 C957T), rs907094 (DARPP-32), rs12364283 (DRD2), rs6278 (DRD2), and rs107656 (DRD2). The selected polymorphisms were combined in a so-called multilocus genetic composite (MGC) score reflecting the additive effect of different alleles conferring relative increased dopamine transmission in every individual. We successfully demonstrated that reward-related activation in the ventral striatum and ventral tegmental area (VTA) was significantly modulated by biologically informed MGC profiles and sex. When comparing men and women with low MGC profiles that may indicate lower dopamine transmission, only women displayed a reduced down-regulation of activation in the mesolimbic system during reward rejection and additionally, a significant non-linear u-shape relationship between MGC score and VTA activation. Taken together, by integrating neuroimaging and genetics, the present findings contribute to a better understanding of the effects of sex differences on the human brain.

Intermittent theta burst stimulation for negative symptoms of schizophrenia\u2014A double-blind, sham-controlled pilot study

Optimal noninvasive brain stimulation parameters for the treatment of negative symptoms of schizophrenia remain unclear. Here, we aimed to investigate the clinical and biological effects of intermittent theta burst transcranial magnetic stimulation (iTBS) in patients with treatment-resistant negative symptoms of schizophrenia (NCT00875498). In a randomized sham-controlled 2-arm study, 22 patients with schizophrenia and treatment-resistant negative symptoms received 20 sessions of either active (n = 12) or sham (n = 10) iTBS. Sessions were delivered twice a day on 10 consecutive working days. Negative symptom severity was assessed 5 times using the Scale for the Assessment of Negative Symptoms (SANS): before iTBS, after iTBS, and 1, 3, and 6 months after iTBS. As a secondary objective, we explored the acute effects of iTBS on functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) using seed-based resting-state functional connectivity MRI (rsFC fMRI) images acquired before and after iTBS. Active iTBS over the left DLPFC significantly decreased negative symptoms severity compared to sham iTBS (F(3,60) = 3.321, p = 0.026). Post hoc analyses revealed that the difference between groups was significant 6 months after the end of stimulation sessions. Neuroimaging revealed an increase in rsFC between the left DLPFC and a brain region encompassing the right lateral occipital cortex and right angular gyrus and a right midbrain region that may encompass dopamine neuron cell bodies. Thus, iTBS over the left DLPFC can alleviate negative symptoms of schizophrenia. The effect might be driven by significant modulation of dopamine transmission.

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.

LRRK2 at the pre‐synaptic site: A 16‐years perspective

Parkinson's disease is a common neurodegenerative disorder and is clinically characterized by bradykinesia, rigidity, and resting tremor. Missense mutations in the leucine-rich repeat protein kinase-2 gene (LRRK2) are a recognized cause of inherited Parkinson's disease. The physiological and pathological impact of LRRK2 is still obscure, but accumulating evidence indicates that LRRK2 orchestrates diverse aspects of membrane trafficking, such as membrane fusion and vesicle formation and transport along actin and tubulin tracks. In the present review, we focus on the special relation between LRRK2 and synaptic vesicles. LRRK2 binds and phosphorylates key actors within the synaptic vesicle cycle. Accordingly, alterations in dopamine and glutamate transmission have been described upon LRRK2 manipulations. However, the different modeling strategies and phenotypes observed require a critical approach to decipher the outcome of LRRK2 at the pre-synaptic site.

Neurobiological Mechanisms of Transcranial Direct Current Stimulation for Psychiatric Disorders; Neurophysiological, Chemical, and Anatomical Considerations

Backgrounds: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique for the treatment of several psychiatric disorders, e.g., mood disorders and schizophrenia. Therapeutic effects of tDCS are suggested to be produced by bi-directional changes in cortical activities, i.e., increased/decreased cortical excitability via anodal/cathodal stimulation. Although tDCS provides a promising approach for the treatment of psychiatric disorders, its neurobiological mechanisms remain to be explored.Objectives: To review recent findings from neurophysiological, chemical, and brain-network studies, and consider how tDCS ameliorates psychiatric conditions.Findings: Enhancement of excitatory synaptic transmissions through anodal tDCS stimulation is likely to facilitate glutamate transmission and suppress gamma-aminobutyric acid transmission in the cortex. On the other hand, it positively or negatively modulates the activities of dopamine, serotonin, and acetylcholine transmissions in the central nervous system. These neural events by tDCS may change the balance between excitatory and inhibitory inputs. Specifically, multi-session tDCS is thought to promote/regulate information processing efficiency in the cerebral cortical circuit, which induces long-term potentiation (LTP) by synthesizing various proteins.Conclusions: This review will help understand putative mechanisms underlying the clinical benefits of tDCS from the perspective of neurotransmitters, network dynamics, intracellular events, and related modalities of the brain function.

Mutations of Human DopamineTransporter at Tyrosine88, Aspartic Acid206, and Histidine547 Influence Basal and HIV-1 Tat\u2010inhibited Dopamine Transport

HIV-1 transactivator of transcription (Tat) has a great impact on the development of HIV-1 associated neurocognitive disorders through disrupting dopamine transmission. This study determined the mutational effects of human dopamine transporter (hDAT) on basal and Tat-induced inhibition of dopamine transport. Compared to wild-type hDAT, the maximal velocity (Vmax) of [3H]dopamine uptake was decreased in D381L and Y88F/D206L/H547A, increased in D206L/H547A, and unaltered in D206L. Recombinant TatR1 − 86 inhibited dopamine uptake in wild-type hDAT, which was attenuated in either DAT mutants (D206L, D206L/H547A, and Y88F/D206L/H547A) or mutated TatR1 − 86 (K19A and C22G), demonstrating perturbed Tat-DAT interaction. Mutational effects of hDAT on the transporter conformation were evidenced by attenuation of zinc-induced increased [3H]WIN35,428 binding in D206L/H547A and Y88F/D206A/H547A and enhanced basal MPP+ efflux in D206L/H547A. H547A-induced outward-open transport conformational state was further validated by enhanced accessibility to MTSET ([2-(trimethylammonium)ethyl]-methanethiosulfonate) of an inserted cysteine (I159C) on a hDAT background.. Furthermore, H547A displayed an increase in palmitoylation inhibitor-induced inhibition of dopamine uptake relative to wide-type hDAT, indicating a change in basal palmitoylation in H547A. These results demonstrate that Y88F, D206L, and H547A attenuate Tat inhibition while preserving DA uptake, providing insights into identifying targets for improving DAT-mediated dopaminergic dysregulation.Graphical HIV-1 Tat inhibits dopamine uptake through human dopamine transporter (hDAT) on the presynaptic terminal through a direct allosteric interaction. Key hDAT residues D-H547, D-Y88, and D-D206 are predicted to be involved in the HIV-1 Tat-DAT binding. Mutating these residues attenuates this inhibitory effect by disrupting the Tat-hDAT interaction

Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage.

Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABAA receptors, and GABAA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing. We used fast-scan cyclic voltammetry in anesthetized female and male rats to measure dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area, before and after administration of allopregnanolone. Allopregnanolone (7.5–25 mg/kg, IP) reduced evoked dopamine release in both male and female rats, compared to β-cyclodextrin vehicle. In males, all doses of allopregnanolone decreased dopamine transmission, with stronger effects at 15 and 25 mg/kg allopregnanolone. In females, 15 and 25 mg/kg allopregnanolone reduced dopamine release, while 7.5 mg/kg allopregnanolone was no different from vehicle. Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Consistent with this, females in proestrus (high progesterone levels) were less responsive to allopregnanolone than females in other estrous cycle stages. Furthermore, 30 mg/kg progesterone reduced evoked dopamine release in males, similar to allopregnanolone. Our findings confirm that allopregnanolone reduces evoked dopamine release in both male and female rats. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects.

Activation of trace amine-associated receptor 1 selectively attenuates the reinforcing effects of morphine.

Trace amine-associated TA1 receptors play critical roles in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TA1 receptors modulates addiction-like behaviours associated with psychostimulants. However, little is known about whether TA1 receptor modulation would regulate the behavioural effects of opioids. Effects of the selective TA1 receptor partial agonist RO5263397 on the addiction-related and antinociceptive effects of morphine were systematically assessed in male rats and mice. RO5263397 attenuated the expression of morphine-induced behavioural sensitization in wildtype but not TA1 receptor knockout mice. RO5263397 shifted the dose-effect curve of morphine self-administration downward and reduced the breakpoint in a progressive ratio schedule of reinforcement but did not affect food self-administration in rats. RO5263397 decreased the cue- and drug-induced reinstatement of morphine-seeking behaviour in rats. RO5263397 alone did not trigger reinstatement of morphine-seeking behaviour or change locomotor activity in rats with a history of morphine self-administration. However, RO5263397 did not affect the expression of morphine-induced conditioned place preference in mice or rats. RO5263397 did not affect naltrexone-precipitated jumping behaviour or naltrexone-induced conditioned place aversion in morphine-dependent mice. Furthermore, RO5263397 did not affect the analgesic effects of morphine in an acute nociception model in mice and a chronic pain model in rats. These results indicated that TA1 receptor activation selectively attenuated the reinforcing, but not withdrawal or antinociceptive effects of morphine, suggesting that selective TA1 receptor agonists might be useful to combat opioid addiction, while sparing the analgesic effects.

Disrupted relationship between blood glucose and brain dopamine D2/3 receptor binding in patients with first-episode schizophrenia

An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis.We quantified blood glucose levels and binding of the dopamine D2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography.Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.

Cholinergic Neurons of the Nucleus Accumbens Enhance Cocaine-Induced Dopaminergic Signaling and Reward

Cholinergic interneurons (ChIs) of the nucleus accumbens (NAc) are important for mediating the behavioral response to rewarding stimuli. A major role for these cells is to regulate dopamine (DA) transmission by activating cholinergic receptors at local DAergic nerve terminals. Here we report that the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) in NAc ChIs mediates an enhancement in DA signaling in response to rewarding stimuli. The HCN current in NAc ChIs and its modulation by DA, as well as the increase in cholinergic efflux by local cocaine infusion were impaired in mice with deletion of HCN2 in cholinergic cells. Enhancement in the DA efflux and signaling in the NAc in response to rewarding stimuli, as well as cocaine conditioning were also dependent on HCN2 in ChIs. These results provide a mechanistic link between the activity of NAc ChIs and reward encoding.

Arbutin effectively ameliorates the symptoms of Parkinson's disease: the role of adenosine receptors and cyclic adenosine monophosphate.

An antagonistic communication exists between adenosinergic and dopaminergic signaling in the basal ganglia, which suggests that the suppression of adenosine A2A receptors-cyclic adenosine monophosphate pathway may be able to restore the disrupted dopamine transmission that results in motor symptoms in Parkinson's disease (PD). Arbutin is a natural glycoside that possesses antioxidant, anti-inflammatory, and neuroprotective properties. The purpose of this study was to investigate whether arbutin could ameliorate the symptoms of PD and to examine the underlying mechanism. In this study, Swiss albino mouse models of PD were established by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine for 4 successive days, with the concurrent intraperitoneal administration of arbutin (50 and 100 mg/kg) for 7 days. The results showed that arbutin significantly reduced lipid peroxidation, total nitrite levels, and inflammation in the substantia nigra and striatum of PD mouse models. In addition, arbutin decreased the activity of endogenous antioxidants, reduced the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and γ-aminobutyric acid, and minimized neurodegeneration in the striatum. Arbutin also reduced the abnormal performance of PD mouse models in the open field test, bar test, pole test, and rotarod test. The therapeutic efficacy of arbutin was similar to that of madopar. The intraperitoneal injection of the A2AR agonist CGS21680 (0.5 mg/kg) attenuated the therapeutic effects of arbutin, whereas the intraperitoneal injection of forskolin (3 mg/kg) enhanced arbutin-mediated improvements. These findings suggest that arbutin can improve the performance of PD mouse models by inhibiting the function of the A2AR and enhancing the effects of cyclic adenosine monophosphate. This study was approved by the Institutional Animal Ethics Committee (1616/PO/Re/S/12/CPCSEA) on November 17, 2019 (approval No. IAEC/2019/010).