Dopaminergic D2 Receptors Research Articles

The antipsychotic chlorpromazine reduces neuroinflammation by inhibiting microglial voltage-gated potassium channels.

Neuroinflammation, the result of microglial activation, is associated with the pathogenesis of a wide range of psychiatric and neurological disorders. Recently, chlorpromazine (CPZ), a dopaminergic D2 receptor antagonist and schizophrenia therapy, was proposed to exert antiinflammatory effects in the central nervous system. Here, we report that the expression of Kv1.3 channel, which is abundant in T cells, is upregulated in microglia upon infection, and that CPZ specifically inhibits these channels to reduce neuroinflammation. In the mouse medial prefrontal cortex, we show that CPZ lessens Kv1.3 channel activity and reduces proinflammatory cytokine production. In mice treated with LPS, we found that CPZ was capable of alleviating both neuroinflammation and depression-like behavior. Our findings suggest that CPZ acts as a microglial Kv1.3 channel inhibitor and neuroinflammation modulator, thereby exerting therapeutic effects in neuroinflammatory psychiatric/neurological disorders.

Changes in D4 and GABAA subunit α3 receptors in the thalamic reticular nucleus caused by unilateral lesion of the globus pallidus.

The thalamic reticular nucleus controls information processing in thalamocortical neurons. GABAergic neurons present in this nucleus express the α3 subunit of post‑synaptic GABAA receptors, which bind GABA from globus pallidus neurons. Pallidal neurons, in turn, have dopaminergic D4 receptors in their axon terminals. The thalamic reticular nucleus connects reciprocally with the thalamus, and it receives afferents from the brain cortex, as well as from other brain structures that have an important role in the modulation of the thalamic network. Based on the above, the purpose of this study was to assess the electrophysiological and molecular effects of unilateral lesion of the globus pallidus on the electric activity of the thalamic reticular nucleus. Two‑month‑old male rats were used. The right globus pallidus was lesioned with quinolinic acid. Seven days after the lesion, ipsilateral turning was registered, confirming the lesion. Afterward, electrophysiological evaluation of the right thalamic reticular nucleus' electrical activity was performed. Subsequently, mRNA expression for D4 receptors and subunit α3, as well as protein content were assessed in the right reticular nucleus. Pallidum lesion caused an increase in firing frequency and decreased firing bursts of reticular neurons. In addition, dopaminergic D4 mRNA, as well as protein increased. In contrast, GABAergic GABAA subunit α3 expression was suppressed, but protein content increased. These results show that the globus pallidus regulates firing in reticular neurons through D4 receptors and subunit α3 of GABAA receptor in the reticular nucleus of the thalamus.

Modulation of neuronal morphology by antipsychotic drug: Involvement of serotonin receptor 7

Antipsychotic drugs (APDs) are the primary pharmacological treatment for schizophrenia, a complex disorder characterized by altered neuronal connectivity. Atypical or second-generation antipsychotics, such as Risperidone (RSP) and Clozapine (CZP) predominantly block dopaminergic D2 and serotonin receptor 2A (5-HT2A) neurotransmission. Both compounds also exhibit affinity for the 5-HT7R, with RSP acting as an antagonist and CZP as an inverse agonist. Our study aimed to determine whether RSP and CZP can influence neuronal morphology through a 5-HT7R-mediated mechanism. Here, we demonstrated that CZP promotes neurite outgrowth of early postnatal cortical neurons, and the 5-HT7R mediates its effect. Conversely, RSP leads to a reduction of neurite length of early postnatal cortical neurons, in a 5-HT7R-independent way.Furthermore, we found that the effects of CZP, mediated by 5-HT7R activation, require the participation of ERK and Cdk5 kinase pathways. At the same time, the modulation of neurite length by RSP does not involve these pathways.In conclusion, our findings provide valuable insights into the morphological changes induced by these two APDs in neurons and elucidate some of the associated molecular pathways. Investigating the 5-HT7R-dependent signaling pathways underlying the neuronal morphogenic effects of APDs may contribute to the identification of novel targets for the treatment of schizophrenia.

Methyleugenol Has an Antidepressant Effect in a Neuroendocrine Model: In Silico and In Vivo Evidence.

Major depressive disorder is a severe mood disorder characterized by different emotions and feelings. This study investigated the antidepressant activity of the phenylpropanoid methyleugenol (ME) in adult female mice exposed to a stress model induced by dexamethasone. The animals were randomly divided into groups containing eight animals and were pre-administered with dexamethasone (64 μg/kg subcutaneously). After 165 and 180 min, they were treated with ME (25, 50 and 100 mg/kg intraperitoneally) or imipramine (10 mg/kg intraperitoneally) after 45 min and 30 min, respectively; they were then submitted to tests which were filmed. The videos were analyzed blindly. In the tail suspension test, ME (50 mg/kg) increased latency and reduced immobility time. In the splash test, ME (50 mg/kg) decreased grooming latency and increased grooming time. In the open field, there was no statistical difference for the ME groups regarding the number of crosses, and ME (50 mg/kg) increased the number of rearing and time spent in the center. Regarding in silico studies, ME interacted with dopaminergic D1 and α1 adrenergic pathway receptors and with tryptophan hydroxylase inhibitor. In the in vivo evaluation of the pathways of action, the antidepressant potential of ME (50 mg/kg) was reversed by SCH23390 (4 mg/kg intraperitoneally) dopaminergic D1 receptor, Prazosin (1 mg/kg intraperitoneally) α1 adrenergic receptor, and PCPA (4 mg/kg intraperitoneally) tryptophan hydroxylase inhibitor. Our findings indicate that ME did not alter with the locomotor activity of the animals and shows antidepressant activity in female mice with the participation of the D1, α1 and serotonergic systems.

Increased glutamate and glutamine levels and their relationship to astrocytes and dopaminergic transmissions in the brains of adults with autism

Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with 11C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r = − 0.55, p = 0.022; r = − 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.

An updated review on phytochemistry and molecular targets of Withania somnifera (L.) Dunal (Ashwagandha).

Withania somnifera (L.) Dunal belongs to the nightshade family Solanaceae and is commonly known as Ashwagandha. It is pharmacologically a significant medicinal plant of the Indian sub-continent, used in Ayurvedic and indigenous systems of medicine for more than 3,000years. It is a rich reservoir of pharmaceutically bioactive constituents known as withanolides (a group of 300 naturally occurring C-28 steroidal lactones with an ergostane-based skeleton). Most of the biological activities of W. somnifera have been attributed to two key withanolides, namely, withaferin-A and withanolide-D. In addition, bioactive constituents such as withanosides, sitoindosides, steroidal lactones, and alkaloids are also present with a broad spectrum of therapeutic potential. Several research groups worldwide have discovered various molecular targets of W. somnifera, such as inhibiting the activation of nuclear factor kappa-B and promoting apoptosis of cancer cells. It also enhances dopaminergic D2 receptor activity (relief in Parkinson's disease). The active principles such as sitoindosides VII-X and withaferin-A possess free radical properties. Withanolide-D increases the radio sensitivity of human cancer cells via inhibiting deoxyribonucleic acid (DNA) damage to non-homologous end-joining repair (NHEJ) pathways. Withanolide-V may serve as a potential inhibitor against the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to combat COVID. The molecular docking studies revealed that the withanolide-A inhibits acetyl-cholinesterase in the brain, which could be a potential drug to treat Alzheimer's disease. Besides, withanolide-A reduces the expression of the N-methyl-D-aspartate (NMDA) receptor, which is responsible for memory loss in epileptic rats. This review demonstrates that W. somnifera is a rich source of withanolides and other bioactive constituents, which can be used as a safe drug for various chronic diseases due to the minimal side effects in various pre-clinical studies. These results are interesting and signify that more clinical trials should be conducted to prove the efficacy and other potential therapeutic effects in human settings.

Neutrocytopenia associated with a lurasidon therapy in a patient with paranoid schizophrenia

IntroductionLurasidon is a relatively new, second-generation antypsychotic drug with an interesting receptor profile. It is considered safe and has a low risk of side effects. This drug is effecitve in reducing the productive symptoms of schizophrenia, but also has a positive effect on negative symptoms and cognitive functions. It is a medicine with a multi-receptor mechanism of action: it mainly blocks dopaminergic D2 and serotonergic 5-HT2A receptors. According to the Summary of Product Characteristics, adverse reactions such as leucopenia, neutropenia and anaemia were too rare to estimate their frequency.ObjectivesThis study describes case of neutrocytopenia and leukocytopenia that are likely to be related to lurasidone and have resolved after discontinuation of this medicinal product. The aim of the article is to highlight the risk of using second-generation antipsychotics in patients and the occurence of blood cells disorders in particular neutrocytopenia.MethodsAn analysis of the medical history records were done to describe the case report.Results39-years-old patient treated psychiatrically for 18 years, initially for mood disorders, irritability, behavioural disorders. In 2014 she was diagnosed with paranoid schizophrenia, herlast psychiatric hospitalization took place in 2021. The patient had a history of neutrocytopenia and leukocytopenia. In December 2020, the patient was admitted to the psychiatric ward on account of active aggression against her mother. She was discharged in January 2021 with the recommendation to take paliperidone intramusculary. Due to incomplete remission of psychotic symptoms, the patient received 37 mg of lurasidone since August 2021. The blood count, which was ordered upon admission to the Department of Psychiatric Rehabilitation, showed moderate neutrocytopenia. After discontinuation of lurasidone and the recommended supplementation, the results gradually improved and finally reached the normal range. Blood cells type 23.09.2021 r. 04.10.2021 r. 14.10.2021 r. 28.10.2021 r. 10.11.2021 r. 24.11.2021 r. 08.12.2021 r.Leukocytes2,45 x 10^3/μl2,73 x 10^3/μl2,39 x 10^3/μl2,66 x 10^3/μl2,79 x 10^3/μl4,09 x 10^3/μl4,03 x 10^3/μlErythrocytes4,26 x 10^3/μl4,31 x 10^3/μl4,48 x 10^3/μl4,06 x 10^3/μl4,08 x 10^3/μl4,39 x 10^3/μl4,22 x 10^3/μlbNeutrocytes1,04 x 10^3/μl1,60 x 10^3/μl1,24 x 10^3/μl1,53 x 10^3/μl1,78 x 10^3/μl2,72 x 10^3/μl2,62 x 10^3/μlLymphocytes1,05 x 10^3/μl0,70 x 10^3/μl0,72 x 10^3/μl0,73 x 10^3/μl0,64 x 10^3/μl0,83 x 10^3/μl0,92 x 10^3/μlConclusionsThis case report shows the need for regular monitoring of blood cells parameters in patients treated with second generation antipsychotics, as there is a risk of neutrocytopenia or even agranulocitosis. If there is an obvious correlation, the dose should be reduced or switched to another medicinal product if possible and blood counts should monitored further.Disclosure of InterestNone Declared

Pimozide Increases a Delayed Rectifier K+ Conductance in Chicken Embryo Vestibular Hair Cells.

Pimozide is a conventional antipsychotic drug largely used in the therapy for schizophrenia and Tourette's syndrome. Pimozide is assumed to inhibit synaptic transmission at the CNS by acting as a dopaminergic D2 receptor antagonist. Moreover, pimozide has been shown to block voltage-gated Ca2+ and K+ channels in different cells. Despite its widespread clinical use, pimozide can cause several adverse effects, including extrapyramidal symptoms and cardiac arrhythmias. Dizziness and loss of balance are among the most common side effects of pimozide. By using the patch-clamp whole-cell technique, we investigated the effect of pimozide [3 μM] on K+ channels expressed by chicken embryo vestibular type-II hair cells. We found that pimozide slightly blocks a transient outward rectifying A-type K+ current but substantially increases a delayed outward rectifying K+ current. The net result was a significant hyperpolarization of type-II hair cells at rest and a strong reduction of their response to depolarizing stimuli. Our findings are consistent with an inhibitory effect of pimozide on the afferent synaptic transmission by type-II hair cells. Moreover, they provide an additional key to understanding the beneficial/collateral pharmacological effects of pimozide. The finding that pimozide can act as a K+ channel opener provides a new perspective for the use of this drug.

Associated and intermediate factors between genetic variants of the dopaminergic D2 receptor gene and harmful alcohol use in young adults.

Dopamine receptor D2 (DRD2) and ankyrin repeat and kinase domain-containing protein 1 (ANKK1) genes have received considerable attention for their involvement in alcohol use disorder (AUD), but many questions remain on their exact role. We conducted a population-based case-control and genetic association study in a large sample of young adults. Our aim was to assess the association between DRD2 and ANKK1 single nucleotide polymorphisms (SNPs) and harmful alcohol use, disentangling associated and possible intermediate factors. A total of 1841 college students from the French region Champagne-Ardennes, aged between 18 and 21 years and who reported at least one lifetime alcohol consumption, were included in this study. Allele frequencies were analysed according to harmful alcohol use (assessed through the Alcohol Use Disorder Identification Test [AUDIT] questionnaire). Different substance use disorders, including nicotine and cannabis dependences, were also assessed through questionnaires, as was a list of potential associated factors (e.g., major depressive episode, conduct disorder, attention-deficit/hyperactivity disorder [ADHD], school failure, sugar consumption, sexual trauma, parents' use of alcohol, tobacco or cannabis). We found that DRD2 rs1800498 was associated with harmful alcohol use. Many factors were detected, but a global path analysis revealed that DRD2 rs1800498 had a significant direct effect on harmful alcohol use and that early age at first alcohol consumption and depressive symptoms moderated this effect. This study suggests an interplay between harmful alcohol use, DRD2 genotypes and other risk factors that, with a full understanding, could be useful for preventive purposes.

Multi-Regulatory Effects of Agmatine on Akt/GSK-3β/β-Catenin Signaling Pathway in SH-SY5Y cells: A Potential Explanation for its Conflicting Roles in Schizophrenia

Objectives: Schizophrenia is a common psychiatric disease with its complex neurobiology. The current knowledge about the neurobiology of schizophrenia is based on dopaminergic and glutamatergic dysregulation of the central nervous system. The facts that all current antipsychotic drugs act on dopaminergic D2 receptor antagonism and glutamatergic N-Methyl D-Aspartate (NMDA) receptor antagonists reveal schizophrenia-like behavioral and structural alteration in rodents and humans are the major evidences of these hypotheses. However, they are not sufficient to explain the disease neurobiology and lead novel therapeutics. In recent years, it has been shown that the functions of certain intracellular pathways are disrupted in schizophrenia, especially Akt/glycogen synthase kinase 3beta (GSK-3β)/β-catenin signaling pathway. Certain studies showed that GSK-3β inhibition accompanied to the effects of antipsychotic drugs and specific inhibition of the GSK-3β might be a valuable approach for the novel treatments for schizophrenia. Agmatine is an endogenous amine that interacts with many receptors and enzymes including adrenergic, glutamatergic, cholinergic, serotonergic and imidazoline receptors and nitric oxide synthase enzyme. The limited number of studies showed conflicting results about the role of agmatine on schizophrenia and there was no study to evaluate the intracellular molecular mechanisms of agmatine`s schizophrenia-related effects. Herein, we aimed to investigate the effects of agmatine on MK-801 induced neurotoxicity and the disruption of the Akt/GSK-3β/β-catenin signaling pathway in SH-SY5Y human neuroblastoma cells. Methods: SH-SY5Y cells were grouped as the medium, agmatine (50μM), agmatine (100μM), olanzapine (10μM), MK-801 (100μM), MK-801+Agmatine (50μM), MK-801+Agmatine (100μM) and MK-801+Olanzapine (10μM). Real-time cell analysis (RTCA), real-time polymerase chain reaction (Rt-PCR) and western blot (WB) were used for monitoring the cell viabilities, quantifying gene and protein expressions, respectively. Cell viabilities monitored for the 24 hours and comparative viabilities (%) were calculated at the 6th, 12th and 24th hours of treatments. Akt, GSK-3β and β-Catenin gene expressions phosphorylated (p) and non-phosphorylated protein expressions were investigated at the 24th hour of treatments. Results: In RTCA, MK-801 administration decreased cell viabilities at the 6th (p<0.01) and 24th (p<0.001) hours compared to medium in cells. Agmatine (50μM) and agmatine (100μM) pre-treatments increased the cell viabilities at the 6th (p<0.05), 12th (p<0.01), and 24th (p<0.05) hours while olanzapine at 24th (p<0.05) compared to MK-801. In Rt-PCR, MK-801 administration increased GSK-3B decreased CTNNB1 gene expressions (p<0.001) compared to the medium. Agmatine (50μM) and olanzapine reversed (p<0.001) the effects of MK-801 for both gene expressions while agmatine (100μM) reversed (p<0.001) only GSK-3B. In WB, MK-801 administration decreased the p-GSK-3β/GSK-3β ratio compared to medium while only agmatine (50μM) increased the ratio compared to MK-801 administration. Conclusion: Herein, it has been shown that agmatine had a neuroprotective effect on MK-801 induced cell toxicity in SH-SY5Y cells. Our results have suggested a low dose (50μM) agmatine shows antipsychotic like effects on Akt/GSK-3β/β-catenin signaling pathway in SH-SY5Y cells bot, not high dose (100μM). We have suggested that these doses dependent regulatory effects of agmatine might be a possible explanation for its conflicting role in schizophrenia.

Molecular pattern of a decrease in the rewarding effect of cocaine after an escalating-dose drug regimen

BackgroundLong-term cocaine exposure leads to dysregulation of the reward system and initiates processes that ultimately weaken its rewarding effects. Here, we studied the influence of an escalating-dose cocaine regimen on drug-associated appetitive behavior after a withdrawal period, along with corresponding molecular changes in plasma and the prefrontal cortex (PFC).MethodsWe applied a 5 day escalating-dose cocaine regimen in rats. We assessed anxiety-like behavior at the beginning of the withdrawal period in the elevated plus maze (EPM) test. The reinforcement properties of cocaine were evaluated in the Conditioned Place Preference (CPP) test along with ultrasonic vocalization (USV) in the appetitive range in a drug-associated context. We assessed corticosterone, proopiomelanocortin (POMC), β-endorphin, CART 55–102 levels in plasma (by ELISA), along with mRNA levels for D2 dopaminergic receptor (D2R), κ-receptor (KOR), orexin 1 receptor (OX1R), CART 55–102, and potential markers of cocaine abuse: miRNA-124 and miRNA-137 levels in the PFC (by PCR).ResultsRats subjected to the escalating-dose cocaine binge regimen spent less time in the cocaine-paired compartment, and presented a lower number of appetitive USV episodes. These changes were accompanied by a decrease in corticosterone and CART levels, an increase in POMC and β-endorphin levels in plasma, and an increase in the mRNA for D2R and miRNA-124 levels, but a decrease in the mRNA levels for KOR, OX1R, and CART 55–102 in the PFC.ConclusionsThe presented data reflect a part of a bigger picture of a multilevel interplay between neurotransmitter systems and neuromodulators underlying processes associated with cocaine abuse.

Spinal dopaminergic D1 and D5 receptors contribute to reserpine-induced fibromyalgia-like pain in rats

Fibromyalgia is a complex pain syndrome without a precise etiology. Reduced monoamines levels in serum and cerebrospinal fluid in fibromyalgia patients has been reported and could lead to a dysfunction of descending pain modulatory system producing the painful syndrome. This study evaluated the role of D1-like dopamine receptors in the reserpine-induced fibromyalgia-like pain model in female Wistar rats. Reserpine-treated animals were intrathecally injected with different dopamine receptors agonists and antagonists, and small interfering RNAs (siRNAs) against D1 and D5 receptor subtypes. Withdrawal and muscle pressure thresholds were assessed with von Frey filaments and the Randall-Selitto test, respectively. Expression of D1-like receptors in lumbar spinal cord and dorsal root ganglion was determined using real time polymerase chain reaction (qPCR). Reserpine induced tactile allodynia and muscle hyperalgesia. Intrathecal dopamine and D1-like receptor agonist SKF-38393 induced nociceptive hypersensitivity in naïve rats, whilst this effect was prevented by the D1-like receptor antagonist SCH-23390. Moreover, SCH-23390 induced a sex-dependent antiallodynic effect in reserpine-treated rats. Furthermore, transient silencing of D1 and D5 receptors significantly reduced reserpine-induced hypersensitivity in female rats. Reserpine slightly increased mRNA D5 receptor expression in dorsal spinal cord, but not in DRG. This work provides new insights about the involvement of the spinal dopaminergic D1/D5 receptors in reserpine-induced hypersensitivity in rats.

Bate palmas mutant mice, a model of Kabuki syndrome, presents hyperactivity due to selective activation of central D1 dopaminergic receptor

Bate palmas mutant mice, a model of Kabuki syndrome, presents hyperactivity due to selective activation of central D1 dopaminergic receptor

Alpha-2 Adrenoreceptor Antagonist Yohimbine Potentiates Consolidation of Conditioned Fear.

BackgroundHyperconsolidation of aversive associations and poor extinction learning have been hypothesized to be crucial in the acquisition of pathological fear. Previous animal and human research points to the potential role of the catecholaminergic system, particularly noradrenaline and dopamine, in acquiring emotional memories. Here, we investigated in a between-participants design with 3 groups whether the noradrenergic alpha-2 adrenoreceptor antagonist yohimbine and the dopaminergic D2-receptor antagonist sulpiride modulate long-term fear conditioning and extinction in humans.MethodsFifty-five healthy male students were recruited. The final sample consisted of n = 51 participants who were explicitly aware of the contingencies between conditioned stimuli (CS) and unconditioned stimuli after fear acquisition. The participants were then randomly assigned to 1 of the 3 groups and received either yohimbine (10 mg, n = 17), sulpiride (200 mg, n = 16), or placebo (n = 18) between fear acquisition and extinction. Recall of conditioned (non-extinguished CS+ vs CS−) and extinguished fear (extinguished CS+ vs CS−) was assessed 1 day later, and a 64-channel electroencephalogram was recorded.ResultsThe yohimbine group showed increased salivary alpha-amylase activity, confirming a successful manipulation of central noradrenergic release. Elevated fear-conditioned bradycardia and larger differential amplitudes of the N170 and late positive potential components in the event-related brain potential indicated that yohimbine treatment (compared with a placebo and sulpiride) enhanced fear recall during day 2.ConclusionsThese results suggest that yohimbine potentiates cardiac and central electrophysiological signatures of fear memory consolidation. They thereby elucidate the key role of noradrenaline in strengthening the consolidation of conditioned fear associations, which may be a key mechanism in the etiology of fear-related disorders.

A case report of eosinophilia associated with risperidone withdrawl in a patient with schizophrenia

IntroductionRisperidone, a second generation antipsychotic, shows high affinity with serotoninergic and dopaminergic D2 receptors, but also adrenergic and H1 histaminergic receptors. Previous studies have shown an increase in eosinophile count associated with the second-generation antipsychotics through the histaminergic path.ObjectivesThe presentation of a case in which eosinophilia was associated with risperidone withdrawl which has not been described so far.MethodsA 46-year-old woman with schizophrenia diagnosed at the age of 22 was admitted in our inpatient psychiatric clinic with psychotic symptoms relapse after she voluntarily discontinued risperidone. The patient was fully evaluated with full laboratory tests, a brain CT scan, EEG and her medical and psychiatric histories were recorded.ResultsRisperidone was reinitiated but due to the persistence of symptoms it was switched to clozapine which lead to full remission. It was observed though, that while gradually decreasing risperidone dosage (Figure 1.), eosinophile count was raising and it was normalized after complete discontinuation. Eosinophilia was also present in other instances that the patient discontinued taking risperidone according to her personal history. Other causes of eosinophilia (allergic, inflammatory) were fully excluded.ConclusionsRisperidone discontinuation could lead to an elevated eosinophile count. There is limited research in this topic and it is yet to be clarified whether the elevation is due to stopping one antipsychotic or switching between two different antipsychotics. It is important to run laboratory tests regularly with every treatment modification.DisclosureNo significant relationships.

Amisulpride-induced late-onset rabbit syndrome: Case report and literature review

IntroductionAmisulpride is an atypical antipsychotic. Rabbit syndrome(RS) may be seen after antipsychotics use a few days or long‐term application. RS occurs after more frequent typical antipsychotics and also in rare cases atypical antipsychotics.Its characterized by the involuntary rhythmic movements of the lips however involves no tongue movements.ObjectivesCase report and reflection on its etiologyMethodsCase report and literature reviewResultsA 28-year-old female with a diagnosis of schizophrenia applied with the complaints and symptoms of withdrawal, do not want to leave the house, physical anergy and avolition that started after stopped taking her medications. She was admitted to the psychiatry service and amisulpride treatment was started and was gradually increased to 800 mg/day. After 30 days of hospitalization, the patient was discharged with mild recovery. 14 days after the discharge, because of the abnormal involuntary movements in mouth, the patient applied. In clinical examination without tounge involvement, rhythmic motions were observed in the lips and jaw.Neurological examination, labrotory tests and cranial screening were all normal. She was evaluated by a private psychiatrist and was diagnosed with RS. Amisulpride treatment changed to olanzapine treatment with 15 mg/day. After two months, RS spontaneously regressed.ConclusionsThe resolution of the involuntary movements following discontinuation of amisulpride in our case, supported the diagnosis of RS. Although the mechanism by which RS emerges as a side‐effect of amisulpride is not fully understood, the drug’s high affinity for and selective binding to dopaminergic D2 and D3 receptors are thought to be responsible for this involuntary motion disorder.DisclosureNo significant relationships.

Dopamine receptor D2, but not D1, mediates the reward circuit from the ventral tegmental area to the central amygdala, which is involved in pain relief.

Pain involves both sensory and affective dimensions. The amygdala is a key player in linking nociceptive stimuli to negative emotional behaviors or affective states. Relief of pain is rewarding and activates brain reward circuits. Whether the reward circuit from the ventral tegmental area (VTA) to the central amygdala (CeA) is involved in pain relief remains unexplored. Using a model of experimental postsurgical pain, we found that pain relief elicited conditioned place preference (CPP), activated CeA-projecting dopaminergic cells in the VTA, and decreased dopaminergic D2 receptor expression in the CeA. Activation of the VTA-CeA neural pathway using optogenetic approaches relieved incisional pain. Administration of a D2 receptor agonist reversed the pain relief elicited by light-induced activation of the VTA-CeA pathway. These findings indicate that the VTA-CeA circuit is involved in pain relief in mice via dopamine receptor D2 in the CeA.

VGLUT3 Ablation Differentially Modulates Glutamate Receptor Densities in Mouse Brain.

Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both nonglutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for the regulation of glutamate signaling and, therefore, modulates the activity of various brain microcircuits. However, little is known about how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we used VGLUT3 constitutive knock-out (VGLUT3–/–) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in the total expression of ionotropic NMDAR glutamate receptors were observed in the cerebral cortex of VGLUT3–/– mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reductions in dopaminergic D1 receptors and muscarinic M1 acetylcholine receptors in the hippocampus of VGLUT3–/– mice. Furthermore, mGluR2/3 total expression and mGluR5 cell surface levels were elevated in the striatum of VGLUT3–/– mice. Last, AMPAR subunit GluA1 was significantly upregulated throughout cortical, hippocampal, and striatal brain regions of VGLUT3–/– mice. Together, these findings complement and further support the evidence that VGLUT3 dynamically regulates glutamate receptor densities in several brain regions. These results suggest that VGLUT3 may play an intricate role in shaping glutamatergic signaling and plasticity in several brain areas.

The Inhibitory Effect of Selected D2 Dopaminergic Receptor Agonists on VEGF-Dependent Neovascularization in Zebrafish Larvae: Potential New Therapy in Ophthalmic Diseases.

Pathological angiogenesis is correlated with many ophthalmic diseases. The most common are exudative age-related macular degeneration and proliferative diabetic retinopathy. The current treatment for these diseases is based on regularly administered anti-VEGF antibodies injections. In the study, we investigated selected D2 dopaminergic receptor agonists, namely bromocriptine, cabergoline and pergolide, on hypoxia-induced neovascularization. We used the zebrafish laboratory model, specifically three-day post fertilization (dpf) Tg(fli-1: EGFP) zebrafish larvae. To induce abnormal angiogenesis of hyaloid-retinal vessels (HRVs) and intersegmental vessels (ISVs), the larvae were treated with cobalt chloride (II) (CoCl2) (a hypoxia-inducing agent) from 24 h post fertilization. The inhibitory role of D2 dopaminergic receptor agonists was investigated using confocal microscopy and qPCR. Additionally, the results were compared to those obtained in the group treated with CoCl2 followed by bevacizumab, the well-known antiangiogenic agent. Confocal microscopy analyses revealed severe deformation of vessels in the CoCl2 treated group, while co-incubation with bromocriptine, cabergoline, pergolide and bevacizumab, respectively, significantly inhibited abnormalities of angiogenesis. The qPCR analyses supported the protective role of the chosen dopaminergic agonists by demonstrating their influence on CoCl2-derived upregulation of vegfaa expression. The present results suggest that the D2 receptor agonists can be considered as a new direction in research for antiangiogenic therapy.

Understanding Why Muscarinic Receptor Agonists Have Antipsychotic Properties

All current antipsychotics have direct dopamine (DA) D2 receptor activity, which is associated with problems such as dysphoria, EPS, or prolactin elevation. Muscarinic receptor agonists have shown antipsychotic-like activity across preclinical models and clinical trials. This poster reviews preclinical evidence as to how muscarinic receptor agonists, such as the M1/M4 preferring agonist xanomeline, might have clinically relevant antipsychotic effects. Highlight the novel mechanisms through which muscarinic receptor agonists are associated with antipsychotic effects without having any direct dopaminergic D2 receptor activity. The muscarinic receptor family is composed of 5 G protein-coupled receptors (GPCRs). One of the leading hypotheses explaining the antipsychotic activity of muscarinic receptor agonists is preclinical studies of muscarinic receptor modulation of those DA circuits associated with psychosis. Both M1 and M4 receptors are expressed in DA neural circuits implicated in psychosis, and provide unique regulation of these circuits. Xanomeline has both functional M1 and M4 receptor agonist activity, and shows robust antipsychotic-like effects in several animal models that require the presence of functional M1 and M4 receptors. M4 receptors are autoreceptors on cholinergic neurons that regulate DA circuits in two locations: ventral tegmental area (VTA) and nucleus accumbens (NAc). Cholinergic-rich neurons from the hindbrain at the VTA, where they release acetylcholine (ACh) into DA-rich synaptic spaces. M4 autoreceptors are present on these neurons, and their activation reduces ACh release and lowers ambient synaptic ACh concentrations, leading to reduced DA cell firing. Cholinergic interneurons residing in the NAc also express M4 autoreceptors. These ACh interneurons regulate ACh release with M4 activation also turning off ACh release. Therefore, M4 receptors serve as DA regulators at VTA and NAc, both key sites for dopamine's role in psychotic processes. M1 receptors regulate DA circuits in a different, "top down" manner. M1 receptors are found on cortical inhibitory interneurons. When activated, inhibitory drive onto excitatory output neurons is enhanced, which leads to reduced excitatory tone to VTA DA neurons. Over the last 25years, a growing body of evidence has shown potential for muscarinic receptor agonists to become a new class of medicines with potent antipsychotic activity. Preclinical data at micro-and macro-circuit levels suggest that the M1 and M4 receptor subtypes are most relevant in the regulation of DA circuits. The antipsychotic effects of muscarinic agonists effects may arise from influencing these key muscarinic receptor subtypes that are integral to the regulation of DA neural circuits. In summary, there has been great progress in understanding the potential for muscarinic receptor agonists for the treatment of psychosis. Karuna Therapeutics.