D2 Antagonist Research Articles

Discovery of eight alkaloids with D1 and D2 antagonist activity in leaves of Nelumbo nucifera Gaertn. Using FLIPR assays

Ethnopharmacological relevanceDopamine receptors are long-standing primary targets in the treatment of mental diseases and there is growing evidence that suggests relationships between obesity and the dopamine system, especially dopamine D1 and D2 receptors. Leaves of Nelumbo nucifera Gaertn. (lotus leaves) have been medically used for helping long-term maintenance of weight loss. Whether and how components of lotus leaves function through the dopamine receptors remains unclear. Aim of the studyThis work aimed to discover dopamine receptor-active alkaloids isolated from the lotus leaves, to evaluate their potencies and to analyze their structure activity relationship. Materials and methodsDried lotus leaves were prepared and total extract was divided into alkaloids and flavones. Eight alkaloids were separated and characterized by a combination of high-performance liquid chromatography, quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance, and assayed by a fluorometric imaging plate reader platform. Human embryonic kidney 239 cell lines expressing dopamine D1, D2 and serotonin 2A (5-HT2A) receptors, respectively, were cultured and used in the assay. ResultsAlkaloids in the lotus leaves were the bioactive phytochemicals and inhibited dopamine from accessing the D1 and D2 receptors. All eight compounds functioned as D1-receptor antagonists and except N-nornuciferine, seven alkaloids functioned as D2-receptor antagonists. (S)-coclaurine and (R)-coclaurine are optical isomers and antagonized both D1 and D2 with equivalent potencies, suggesting that the optical rotation of the methylene linker in the monobenzyl isoquinoline backbone did not influence their activity. Among the eight alkaloids, O-nornuciferine was the potent antagonist to both receptors (the lowest IC50 values, D1: 2.09 ± 0.65 μM and D2: 1.14 ± 0.10 μM) while N-nornuciferine was found to be the least potent as it moderately antagonized D1 and was inactive on D2. O-nornuciferine was also a 5-HT2A antagonist (IC50~20 μM) while N-nornuciferine had no activity. These hinted the importance of a methyl group attached to the nitrogen atom in the aporphine backbone. Armepavine showed a nearly 10-fold selectivity to D2. ConclusionsIn this work, eight alkaloids were isolated from the leaves of Nelumbo nucifera Gaertn. and assayed on the D1 and D2 receptors. They were D1/D2 antagonists with IC50 values in the mid- to low-micromolar range and O-nornuciferine was the most potent alkaloid among the eight. This family of alkaloids was biochemically evaluated on the dopamine receptors by the same platform for the first time.

A Prepubertal Girl with Delusions of Pregnancy.

A Prepubertal Girl with Delusions of Pregnancy.

Ethanol inhibition of lateral orbitofrontal cortex neuron excitability is mediated via dopamine D1/D5 receptor-induced release of astrocytic glycine

Recent findings from this laboratory demonstrate that ethanol reduces the intrinsic excitability of orbitofrontal cortex (OFC) neurons via activation of strychnine-sensitive glycine receptors. Although the mechanism linking ethanol to the release of glycine is currently unknown, astrocytes are a source of neurotransmitters including glycine and activation of dopamine D1-like receptors has been reported to enhance extracellular levels of glycine via a functional reversal of the astrocytic glycine transporter GlyT1. We recently reported that like ethanol, dopamine or a D1/D5 receptor agonist increases a tonic current in lateral OFC (lOFC) neurons. Therefore, in this study, we used whole-cell patch-clamp electrophysiology to examine whether ethanol inhibition of OFC spiking involves the release of glycine from astrocytes and whether this release is dopamine receptor dependent. Ethanol, applied acutely, decreased spiking of lOFC neurons and this effect was blocked by antagonists of GlyT1, the norepinephrine transporter or D1-like but not D2-like receptors. Ethanol enhanced the tonic current of OFC neurons and occluded the effect of dopamine suggesting that ethanol and dopamine may share a common pathway. Altering astrocyte function by suppressing intracellular astrocytic calcium signaling or blocking the astrocyte-specific Kir4.1 potassium channels reduced but did not completely abolish ethanol inhibition of OFC neuron firing. However, when both astrocytic calcium signaling and Kir4.1 channels were inhibited, ethanol had no effect on firing. Ethanol inhibition was also prevented by inhibitors of phospholipase C and conventional isoforms of protein kinase C (cPKC) previously shown to block D1R-induced GlyT1 reversal and PKC inhibition of Kir4.1 channels. Finally, the membrane potential of OFC astrocytes was depolarized by bath application of a Kir4.1 blocker, a D1 agonist or ethanol and ethanol effect was blocked by a D1 antagonist. Together, these findings suggest that acute ethanol inhibits OFC neuron excitability via a D1 receptor-mediated dysregulation of astrocytic glycine transport.

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium-dependent, non-D2 receptor-dependent, manner.

Dopamine D2‐like receptor antagonists have been suggested as being potential anticancer therapeutics with specific utility for central nervous system cancers due to their ability to cross the blood‐brain barrier. Despite a plethora of data reporting anticancer effects for D2R antagonists in cell or animal studies, the ligand concentrations or doses required to achieve such effects greatly exceed the levels known to cause high degrees of occupancy of the D2 receptor. To resolve this conundrum, we interrogated a panel of glioblastoma multiforme (GBM) cell lines using D2 antagonists of varying chemotype. We studied the cytotoxic effects of these compounds, and also ascertained the expression of D2 receptors (D2R) on these cells. Although several chemotypes of D2R antagonists, including phenothiazines and phenylbutylpiperidines, were effective against GBM cell line cultures, the highly selective antagonist remoxipride had no anticancer activity at biologically relevant concentrations. Moreover the D2R antagonist‐induced cytotoxicity in monolayer cultures was independent of whether the cells expressed D2R. Instead, cytotoxicity was associated with a rapid, high‐magnitude calcium flux into the cytoplasm and mitochondria, which then induced depolarization and apoptosis. Blocking this flux protected the GBM cell lines U87MG, U251MG, and A172. Together, these data suggest that the cytotoxicity of these D2R antagonists involves calcium signaling mechanisms, not D2R antagonism. Repurposing of existing drugs should focus on the former, not latter, mechanism.

Gender dimorphic effect of dopamine D2 and muscarinic cholinergic receptors on memory retrieval.

Episodic memory retrieval is fundamental for daily activities of humans and animals. Muscarinic cholinergic signaling is important for memory functioning and shows gender-dependent response in episodic memory retrieval. Dopamine D2 receptors influence memory formation and retrieval by influencing cholinergic signaling in the brain. This study aimed to determine the gender-dependent effects of D2 and muscarinic activity on memory retrieval. Male and female mice were trained for Morris water maze test and contextual fear conditioning. Memory retrieval was assessed following sub-chronic treatment (for 5days) with D2 antagonist (risperidone 2.5mg/kg) alone or in combination with scopolamine (1mg/kg) or donepezil (1mg/kg). Open field test was performed prior to the retrieval test to evaluate effects of risperidone treatment on locomotor activity and exploratory behavior. Risperidone co-treatment with donepezil impaired spatial memory retrieval in males only. Muscarinic and D2 simultaneous antagonism tend to impair fear retrieval in males but significantly enhanced retrieval of fear memories in female mice. These results suggest that D2 signaling influence muscarinic receptor activity during memory retrieval in gender-dependent manner.

Aripiprazole-induced rosacea. Case report and literature review

IntroductionSkin and subcutaneus tissue disorders are common type of adverse drug reactions reported with a wide variety of both typical and atypical antipsychotics. Aripiprazole is a quinolinone antipsychotic that is a partial agonist at the D2 and 5-HT1A receptors and antagonist at the 5-HT2A receptors. We report a case of rosacea that developed after starting aripiprazole in a patient with schizophrenia and which remitted after the drug was stopped.ObjectivesTo present a case of rosacea that developed in a schizophrenic patient after starting aripiprazole. Review of literature and search for the total number of cases reported in the european database of suspected adverse drug reactions (EudraVigilance).MethodsWe carried out a literature review in Pubmed electing those articles focused on skin ad subcutaneous skin disorders in those patients that have been taking aripiprazole. Review number of cases of skin reactions reported by the European database of suspected adverse drug reactions.ResultsA 43-year-old man previously diagnosed with schizophrenia with low adherence to different treatments. He came to our service seeking for help in order to decrease delusions with a treatment with minimun adverse reactions. We started aripirazole 10 mg every day and, after 7 days appeared signs of rosacea in his face. After discontinuation of aripiprazol, after 5 days, rosacea remitted.ConclusionsRosacea in our case posibly point aripiprazole as the agent that produced the skin reaction. After stopping the treatment the signs disapeared. Awareness of skins manifestations produced by aripiprazole is essential to prevents worse skin reactions.

The effect of risperidone on reward-related brain activity is robust to drug-induced vascular changes.

Dopamine (DA) mediated brain activity is intimately linked to reward‐driven cerebral responses, while aberrant reward processing has been implicated in several psychiatric disorders. fMRI has been a valuable tool in understanding the mechanism by which DA modulators alter reward‐driven responses and how they may exert their therapeutic effect. However, the potential effects of a pharmacological compound on aspects of neurovascular coupling may cloud the interpretability of the BOLD contrast. Here, we assess the effects of risperidone on reward driven BOLD signals produced by reward anticipation and outcome, while attempting to control for potential drug effects on regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Healthy male volunteers (n = 21) each received a single oral dose of either 0.5 mg, 2 mg of risperidone or placebo in a double‐blind, placebo‐controlled, randomised, three‐period cross‐over study design. Participants underwent fMRI scanning while performing the widely used Monetary Incentive Delay (MID) task to assess drug impact on reward function. Measures of CBF (Arterial Spin Labelling) and breath‐hold challenge induced BOLD signal changes (as a proxy for CVR) were also acquired and included as covariates. Risperidone produced divergent, dose‐dependent effects on separate phases of reward processing, even after controlling for potential nonneuronal influences on the BOLD signal. These data suggest the D2 antagonist risperidone has a wide‐ranging influence on DA‐mediated reward function independent of nonneuronal factors. We also illustrate that assessment of potential vascular confounds on the BOLD signal may be advantageous when investigating CNS drug action and advocate for the inclusion of these additional measures into future study designs.

Mediatory role of the dopaminergic system through D1 receptor on glycine-induced hypophagia in neonatal broiler-type chickens.

The present study aimed to examine the mediatory role of the dopaminergic system in the food intake induced by intracerebroventricular (ICV) injection of glycine in neonatal 3-h feed-deprived (FD3) meat-type chickens. In the first and second experiments, birds were ICV injected using low and high doses of glycine (50, 100 and 200nmol) and strychnine (50, 100 and 200nmol), respectively. In experiments 3-9, the behaviorally subeffective doses of dopamine (10nmol), 6-OHDA (2.5nmol), SCH 23,390 (D1 antagonist; 5nmol), AMI-193 (D2 antagonist; 5nmol), NGB2904 (D3 antagonist; 6.4nmol) and L-741,742 (D4 antagonist; 6nmol) were, respectively, co-administrated with glycine (200nmol) in FD3 5-day-old chicks to investigate possible interplay of dopamine receptors in glycine-induced feeding behavior. Then, cumulative food intake based on body weight percentage (%BW) was determined at 30, 60 and 120min after the injection. According to the results, dopamine significantly boosted the hypophagia induced by glycine at all-time intervals (p ≤ 0.001). These results combined with the previous findings suggest an interplay between dopamine and glycine in chicken's brain in which D1 receptor-mediated food intake induced by glycine.

Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists.

The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.

The critical role of hippocampal dopamine in the pathogenesis of hepatic encephalopathy.

The pathogenesis of hepatic encephalopathy (HE) has been generally linked to blood ammonia, gamma-aminobutyric acid and serotonin. However, the exact mechanism remains unclear. In the present study, we aimed to explore the role of hippocampal dopamine (DA) and its receptors in the pathogenesis of HE through the use of behavioral testing, western blotting, and immunofluorescence staining in normal rats, HE model rats and rats treated with the DA precursor-levodopa (L-DOPA). HE model rats manifested fibrotic livers and showed serious behavioral disorders. They also had significantly lower hippocampal DA content and increased expression of both D1 and D2 receptors relative to normal rats. After treatment with L-DOPA, the HE model rats showed normal behavior and expression of D1 returned to normal levels. Furthermore, pretreatment with the D1 antagonist SCH23390 blocked the therapeutic effect of L-DOPA on behavior in HE model rats. Taken together, these results clarify that the decrease in hippocampal DA plays a role in the pathogenesis of HE and that this effect is mediated by D1. These findings provide new evidence for the pathogenesis of HE.

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

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

Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2′-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D1 and D2 receptors and GABAA receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

BackgroundONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.MethodsCell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer.ResultsIncreasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice.ConclusionONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

Abstract PO044: A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer

Abstract Objectives: Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for patients with homologous recombination (HR) deficient tumors. While HR mutations are rare in endometrial cancers (ECs), emerging data suggests that loss of function of the tumor suppressor gene PTEN, which is mutated in 80% of endometrioid ECs, may also sensitize tumors to PARP inhibition. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist that has anti-tumorigenic effects in EC via induction of apoptosis, activation of the integrated stress response and modulation of Akt signaling. Both PARP inhibitors and imipridones are being evaluated in EC clinical trials, but have yet to be explored in combination. We sought to examine the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid EC cell lines and in a mouse model of endometrioid EC. Methods: The ECC-1 and HEC-1 EC cell lines were used. Cell proliferation was assessed after exposure to varying doses of olaparib (MedChemExpress) and ONC206 (Oncoceutics) via the MTT assay. Synergy between olaparib and ONC206 was assessed by the combination index (CI) method of Chou-Talalay. Cellular stress was evaluated using the DCFH-DA assay. Apoptosis was assessed using the cleaved caspase-3 assay. Western immunoblotting was performed to determine effects of olaparib and ONC206 on apoptosis and the mTOR pathway. LKB1fl/flp53fl/fl mice were fed either a low-fat diet (10% of calories from fat, lean) or high-fat diet (60% of calories from fat, obese). Following EC onset, the mice were treated with ONC206 (100 mg/kg weekly orally), olaparib (25 mg/kg daily orally), or the combination for 4 weeks. Immunohistochemistry was used to assess Ki-67 expression in EC. Results: Both drugs inhibited cell proliferation in a dose-dependent manner (IC50 for olaparib of 15 µM for ECC-1 and 25 µM for HEC-1; IC50 for ONC206 of 3.3 µM for ECC-1 and 0.9 µM for HEC-1). Simultaneous exposure of EC cells to ONC206 and olaparib resulted in synergistic anti-proliferative effects (CI<1). Combination treatment with ONC206 and olaparib increased cellular stress and apoptosis in both cell lines (p=0.05-0.001), compared to either drug alone. Dual therapy with olaparib and ONC206 decreased expression of the anti-apoptotic protein Bcl-2 and decreased phosphorylation of S6, a downstream target of the mTOR pathway, with greater effects compared to either drug alone. The combination of ONC206 and olaparib led to a greater reduction in EC tumor weight in obese (91%) and lean (85%) mice compared to ONC 206 alone (obese 84% and lean 77%) or olaparib alone (obese 83% and lean 65%) (p<.05). ONC206 and olaparib significantly reduced Ki-67 expression in obese and lean mice, with more potent effects for the combination treatment. Conclusions: Olaparib and ONC206 had synergistic anti-tumorigenic effects in human endometrioid EC cell lines and in a mouse model of endometrioid EC, suggesting that this novel dual therapy may be worthy of further exploration in clinical trials in EC. Citation Format: Sarah E. Paraghamian, Gabrielle M. Hawkins, Wenchuan Sun, Yali Fan, Xin Zhang, Hongyan Suo, Varun Vijay Prabhu, Joshua E. Allen, Chunxiao Zhou, Victoria Bae-Jump. A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO044.

PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?

PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.

Medial orbitofrontal cortex dopamine D1/D2 receptors differentially modulate distinct forms of probabilistic decision-making.

Efficient decision-making involves weighing the costs and benefits associated with different actions and outcomes to maximize long-term utility. The medial orbitofrontal cortex (mOFC) has been implicated in guiding choice in situations involving reward uncertainty, as inactivation in rats alters choice involving probabilistic rewards. The mOFC receives considerable dopaminergic input, yet how dopamine (DA) modulates mOFC function has been virtually unexplored. Here, we assessed how mOFC D1 and D2 receptors modulate two forms of reward seeking mediated by this region, probabilistic reversal learning and probabilistic discounting. Separate groups of well-trained rats received intra-mOFC microinfusions of selective D1 or D2 antagonists or agonists prior to task performance. mOFC D1 and D2 blockade had opposing effects on performance during probabilistic reversal learning and probabilistic discounting. D1 blockade impaired, while D2 blockade increased the number of reversals completed, both mediated by changes in errors and negative feedback sensitivity apparent during the initial discrimination of the task, which suggests changes in probabilistic reinforcement learning rather than flexibility. Similarly, D1 blockade reduced, while D2 blockade increased preference for larger/risky rewards. Excess D1 stimulation had no effect on either task, while excessive D2 stimulation impaired probabilistic reversal performance, and reduced both profitable risky choice and overall task engagement. These findings highlight a previously uncharacterized role for mOFC DA, showing that D1 and D2 receptors play dissociable and opposing roles in different forms of reward-related action selection. Elucidating how DA biases behavior in these situations will expand our understanding of the mechanisms regulating optimal and aberrant decision-making.

Medicinal chemistry strategies for the development of phosphodiesterase 10A (PDE10A) inhibitors - An update of recent progress

Phosphodiesterase 10A is a member of Phosphodiesterase (PDE)-superfamily of the enzyme which is responsible for hydrolysis of cAMP and cGMP to their inactive forms 5'-AMP and 5'-GMP, respectively. PDE10A is highly expressed in the brain, particularly in the putamen and caudate nucleus. PDE10A plays an important role in the regulation of localization, duration, and amplitude of the cyclic nucleotide signalling within the subcellular domain of these regions, and thereby modulation of PDE10A enzyme can give rise to a new therapeutic approach in the treatment of schizophrenia and other neurodegenerative disorders. Limitation of the conventional therapy of schizophrenia forced the pharmaceutical industry to move their efforts to develop a novel treatment approach with reduced side effects. In the past decade, considerable developments have been made in pursuit of PDE10A centric antipsychotic agents by several pharmaceutical industries due to the distribution of PDE10A in the brain and the ability of PDE10A inhibitors to mimic the effect of D2 antagonists and D1 agonists. However, no selective PDE10A inhibitor is currently available in the market for the treatment of schizophrenia. The present compilation concisely describes the role of PDE10A inhibitors in the therapy of neurodegenerative disorders mainly in psychosis, the structure of PDE10A enzyme, key interaction of different PDE10A inhibitors with human PDE10A enzyme and recent medicinal chemistry developments in designing of safe and effective PDE10A inhibitors for the treatment of schizophrenia. The present compilation also provides useful information and future direction to bring further improvements in the discovery of PDE10A inhibitors.

Antidepressant-like effects of a new dihydro isoquinoline and its chemical precursors in mice: involvement of serotonin and dopaminergic systems

This study was aimed to synthesize novel 2-(2-bromophenyl)-N-phenethylacetamides and benzylisoquinoline (BIQ) derivatives to be evaluated as antidepressant-like agents in mice. The phenethylacetamides derivatives were synthesized by coupling aromatic amides to the backbone of 2-bromophenylacetyl chloride. The synthesis of BIQ was achieved by the reaction between synthesized phenethylacetamides and 2-chloropyridine. The structures of compounds were established mainly by 1D and 2D NMR spectra. Those compounds obtained with moderate to good yields were evaluated as antidepressant-like agents in the forced swim test and the open field paradigms in mice. The possible mechanism of those active derivatives was explored by antagonist experiments in combination with p-chloro-phenylalanine methyl ester, reserpine, sulpiride, and dopamine D1 antagonist SCH23390. Also, MAO A and B inhibition assays were performed. Docking studies between the human dopamine D3 receptor and the higher active compound were performed. The results showed that the (2-bromophenyl)-(3,4-dihydroisoquinoline-1-yl)methanone (4a) presented the most potent antidepressant-like effects without modifying the ambulatory activity of experimental mice. Antagonist experiments showed that 4a acted on the serotonergic and dopaminergic receptors. Docking studies indicated a strong affinity between the human dopamine D3 receptor and 4a. Our results showed that BIQ 4a has an antidepressant-like effect that is possibly mediated by an interaction with the presynaptic serotonin receptors and dopaminergic, D1, D2, and D3, receptors. This study highlights the pharmacological potential of halogenated BIQs in the treatment of some depressive disorders.

D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

Levodopa is the standard-of-care for Parkinson's disease, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral “dopamine agonist” matches the efficacy of levodopa. There are consistent data in both primate models and in Parkinson's disease showing that selective high intrinsic activity D1 agonists can equal levodopa in efficacy. There are, however, no data on whether such compounds would be effective in severe disease when levodopa efficacy is low or absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernible improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson's patients.

Ring Finger Protein 11 (RNF11) Modulates Dopamine Release in Drosophila

Recent work indicates a role for RING finger protein 11 (RNF11) in Parkinson disease (PD) pathology, which involves the loss of dopaminergic neurons. However, the role of RNF11 in regulating dopamine neurotransmission has not been studied. In this work, we tested the effect of RNF11 RNAi knockdown or overexpression on stimulated dopamine release in the larval Drosophila central nervous system. Dopamine release was stimulated using optogenetics and monitored in real-time using fast-scan cyclic voltammetry at an electrode implanted in an isolated ventral nerve cord. RNF11 knockdown doubled dopamine release, but there was no decrease in dopamine from RNF11 overexpression. RNF11 knockdown did not significantly increase stimulated serotonin or octopamine release, indicating the effect is dopamine specific. Dopamine clearance was also changed, as RNF11 RNAi flies had a higher Vmax and RNF11 overexpressing flies had a lower Vmax than control flies. RNF11 RNAi flies had increased mRNA levels of dopamine transporter (DAT) in RNF11, confirming changes in DAT. In RNF11 RNAi flies, release was maintained better for stimulations repeated at short intervals, indicating increases in the recycled releasable pool of dopamine. Nisoxetine, a DAT inhibitor, and flupenthixol, a D2 antagonist, did not affect RNF11 RNAi or overexpressing flies differently than control. Thus, RNF11 knockdown causes early changes in dopamine neurotransmission, and this is the first work to demonstrate that RNF11 affects both dopamine release and uptake. RNF11 expression decreases in human dopaminergic neurons during PD, and that decrease may be protective by increasing dopamine neurotransmission in the surviving dopaminergic neurons.