Glutamate Antagonists Research Articles

Regulation of apoptosis in the ischemic penumbra in the first day post-stroke.

Regulation of apoptosis in the ischemic penumbra in the first day post-stroke.

Catatonia in Down syndrome: systematic approach to diagnosis, treatment and outcome assessment based on a case series of seven patients.

ObjectiveThe goal is to expand our knowledge of catatonia occurring in adolescents and young adults with Down syndrome (DS) by describing the first prospective, consecutive, well-characterized cohort of seven young people with DS diagnosed with catatonia and treated between 2013 and 2018, and to assess each patient’s treatment responses. Longitudinal assessment of each patient’s response to treatment is intended to provide clinicians and psychiatrists a firm foundation from which assess treatment efficacy.Study designYoung adults with Down syndrome were consecutively enrolled in the study as they were diagnosed with catatonia. A comprehensive data set included medical, laboratory, developmental, demographic, family, social and genetic data, including query into disorders for which individuals with DS are at risk. Catatonia was diagnosed based on an unequivocal history of regression, positive Bush-Francis Catatonia Rating Scale and positive response to intravenous lorazepam. Patients’ longitudinal progress was monitored using the Catatonia Impact Scale (CIS) developed for this purpose.ResultsSeven consecutive DS patients, who presented with unequivocal regression were diagnosed with catatonia and treated for 2.7–6 years using standard-of-care therapies; primarily GABA agonist, lorazepam, electroconvulsive therapy (ECT) and glutamate antagonists (dextromethorphan/quinidine, memantine, minocycline). Responses to each treatment modality were assessed at clinic visits and through weekly electronic CIS reports.ConclusionSeven young adults with DS were diagnosed with catatonia; all responded to Lorazepam and/or ECT therapy with good to very good results. Though ECT most dramatically returned patients to baseline, symptoms often returned requiring additional ECT. Dextromethorphan/quinidine, not used until mid-2017, appeared to reduce the reoccurrence of symptoms following ECT. Though all seven patients improved significantly, each continues to require some form of treatment to maintain a good level of functioning. Findings of a significant number of autoimmune disorders and laboratory markers of immune activation in this population may guide new diagnostic and treatment opportunities.

Chronic memantine decreases nicotine self-administration in rats

Neurobehavioral bases of tobacco addiction and nicotine reinforcement are complex, involving more than only nicotinic cholinergic or dopaminergic systems. Memantine is an NMDA glutamate antagonist used to improve cognitive function in people with Alzheimer's disease. Glutamate may be an important component of the reinforcing effects of nicotine, so memantine was evaluated as a potential smoking cessation aid. Two studies were conducted with adult female rats, one testing acute effects of memantine over a range of doses for changing nicotine self-administration and the other testing the chronic effects of memantine to reduce nicotine self-administration. Acute memantine injections slightly, but significantly, increased nicotine self-administration in a dose-related manner. In contrast, chronic memantine treatment significantly reduced nicotine self-administration. During the first day of memantine administration in the chronic study, nicotine self-administration was significantly elevated replicating the acute study. Starting in the second week of treatment there was a significant reduction of nicotine self-administration relative to controls. This was seen because memantine treatment prevented the increase in nicotine self-administration shown by controls. There even continued to be a memantine-induced lowered nicotine self-administration during the week after the cessation of memantine treatment. Memantine or other drugs affecting NMDA glutamate receptors may be useful aids to smoking cessation. Full efficacy for reducing nicotine self-administration was seen as the NMDA drug treatment is given chronically. Importantly, the effect persisted even after treatment is ended, indicating the high potential for NMDA glutamate receptors to impact nicotine addiction.

Electrical stimulation mPFC affects morphine addiction by changing glutamate concentration in the ventral tegmental area.

Morphine addiction is known as a serious social problem. Medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) are two important sites of the brain that contribute to this type of addiction, and a complicated relation exists in between. In addition, neurotransmitters like glutamate and γ--Amino Butyric Acid (GABA) play an important role in the formation of these relations. Thus, the present study was undertaken to investigate these relations by evaluating the level of associated changes in the indicated neurotransmitters in the VTA, using HPLC method. This was performed after electrical stimulation and inducing lesion of mPFC and through microinjections of N-Methyl-D-Aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, respectively AP5 and CNQX, into the VTA of addicted rats. Our results showed that intra-peritoneal (i.p.) administration of morphine in 9days in the morphine group, and also electrical stimulation (100μA) of mPFC, receiving (i.p.) morphine, caused an increase in the glutamate release in the VTA, compared to the control group, but the increase of glutamate levels in the VTA in the morphine-stimulation group was not significant, compared to the morphine group. Moreover, GABA release into this area was decreasing in morphine and morphine- stimulation groups, compared to the control group. Our findings also showed that electrical lesion (0.4mA) of mPFC, and also microinjection of glutamate antagonists into the VTA, receiving (i.p.) morphine in rats, caused a decrease of glutamate in the VTA. Therefore, it could be concluded that the relation between mPFC and VTA is highly effective in the formation of reward system.

Increased Levels of Kynurenic Acid in the Cerebrospinal Fluid in Patients with Hydrocephalus.

Normal pressure hydrocephalus (NPH) is a potentially reversible neurological syndrome commonly characterized by gait disturbance, urinary incontinence, and dementia. Hydrocephalus e-vacuo (He-v) is also characterized by the occurrence of dementia but does not show gait disturbance or urinary incontinence and has no evident cerebrospinal fluid (CSF) pressure elevation. Kynurenic acid (KYNA), an endogenous metabolite of the L-kynurenine (L-KYN) pathway of L-tryptophan (L-TRP) degradation, is an antagonist of glutamate N-methyl-D-aspartic acid and alpha-7 nicotinic cholinergic receptors that have been linked to dementia. We investigated KYNA, L-KYN, and L-TRP levels in human CSF and serum during the aging process in 30 healthy control individuals. In addition, clinical parameters and L-TRP metabolites in CSF and serum were evaluated in four patients with NPH and five with He-v. KYNA, L-KYN, and L-TRP levels in CSF and serum were determined using highperformance liquid chromatography. Healthy controls showed a significant decrease in serum albumin with age. Compared with their corresponding controls and unlike patients with He-v, patients with NPH (age ≤ 50 years) had significant increases in CSF protein (241%, p < 0.001), CSF albumin (246%, p < 0.001), CSF IgG (328%, p < 0.001), and CSF:serum IgG (321%, p < 0.001) and CSF:serum albumin (257%, p < 0.001) ratios. Controls had significant increases in KYNA, L-KYN, and L-TRP levels in the CSF with advancing age but not in the serum. Compared with the corresponding controls, KYNA levels were significantly increased in the CSF of patients with NPH (141%, p < 0.05) and He-v (225%; p < 0.01). Additionally, the serum levels of KYNA were increased in patients with NPH and He-v to 161% and 156% of controls, respectively (both p < 0.01). The serum levels of L-KYN and L-TRP were significantly reduced in patients with He-v but not in patients with NPH. C-reactive protein, as a marker of inflammation, was significantly increased in the serum of patients with He-v but not in patients with NPH, compared with the corresponding controls. The aging process is related to elevated CSF levels of KYNA, L-KYN, and L-TRP levels. There are significant differences in clinical parameters between the two forms of hydrocephalus and these differences might have diagnostic utility. The occurrence of dementia in patients with either form of hydrocephalus might be at least partly related to elevated KYNA levels in the CNS and/or periphery.

Vagus Nerve Stimulation as a Treatment for Catatonia: A Hypothesis.

Background: Catatonia is a syndrome comprising psychomotor, behavioral, and autonomous symptoms which may occur in the context of severe schizophrenic, affective, and other mental disorders or medical conditions. Treatment options include high dose benzodiazepines (lorazepam) and electroconvulsive therapy (ECT) with some evidence for the effectiveness of glutamate antagonists. However, due to a lack of randomized controlled studies in this severely ill population, evidence base is weak.Methods: On occasion of the case of a patient with treatment resistant catatonia in schizoaffective disorder, we developed the hypothesis of vagus nerve stimulation (VNS) being a potential therapy for treatment resistant catatonia.Results: Based on a selective literature search, we found a remarkable overlap of the pathophysiology of catatonia on the one hand and the putative mechanisms of action of VNS on the other hand in several domains: functional brain imaging, involved neurotransmitter systems, clinical, and theoretical. We thus decided to use VNS as a single subject clinical trial. During the 1-year-follow-up, we observed a fluctuating, but ultimately marked improvement of both catatonic symptoms and general psychopathology.Conclusions: We assume there is a sufficient hypothetical corroboration for the potential effectiveness of VNS as a long-term treatment in predominantly catatonic syndromes. This hypothesis could be tested in proof-of-concept clinical trials.

Developmental Changes in the Inhibition of Glycinergic Synaptic Currents by Niflumic Acid in Hypoglossal Motoneurons.

Mammalian brainstem hypoglossal motoneurones (HMs) receive powerful synaptic glycinergic inputs and are involved in a variety of motor functions, including respiration, chewing, sucking, swallowing, and phonation. During the early postnatal development, subunit composition of chloride-permeable glycine receptors (GlyRs) changes leading to a decrease of “fetal” alpha2 and elevation of “adult” alpha1 GlyR subunits. It has been recently demonstrated that niflumic acid (NFA), a member of the fenamate class of non-steroidal anti-inflammatory drugs, is an efficient subunits-specific blocker of GlyRs. At a heterologous expression of different GlyR subunits it has been shown that blocking potency of NFA is more than one order higher for alpha2 GlyRs than for receptors formed by alpha1 subunit. To reveal the action of NFA on the synaptic activity we analyzed here the effects of NFA on the glycinergic inhibitory post-synaptic currents in the HMs from mouse brainstem slices. In the whole-cell patch clamp configuration, the amplitude and the frequency of glycinergic synaptic currents from two age groups have been analyzed: “neonate” (P2–P4) and “juvenile” (P7–P12). Addition of NFA in the presence of antagonists of glutamate and GABA receptors caused a decrease in the mean amplitude and frequency of synaptic events. The degree of the inhibition induced by NFA decreased with the postnatal development, being higher on the motoneurons from “neonate” brainstem slices in comparison with the “juvenile” age group. Analysis of the pair-pulse facilitation suggests the post-synaptic origin of NFA action. These observations provide evidence on the developmental changes in the inhibition by NFA of glycinergic synaptic transmission, which reflects increase in the alpha1 and decrease in the alpha2 GlyR subunits expression in synapses to hypoglossal motoneurons during the early stages of postnatal life.

Effects of acute and chronic nicotine on catecholamine neurons of the nucleus of the solitary tract.

Nicotine is an addictive drug that has broad effects throughout the brain. One site of action is the nucleus of the solitary tract (NTS), where nicotine initiates a stress response and modulates cardiovascular and gastric function through nicotinic acetylcholine receptors (nAChRs). Catecholamine (CA) neurons in the NTS influence stress and gastric and cardiovascular reflexes, making them potential mediators of nicotine's effects; however nicotine's effect on these neurons is unknown. Here, we determined nicotine's actions on NTS-CA neurons by use of patch-clamp techniques in brain slices from transgenic mice expressing enhanced green fluorescent protein driven by the tyrosine hydroxylase promoter (TH-EGFP). Picospritzing nicotine both induced a direct inward current and increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in NTS-CA neurons, effects blocked by nonselective nAChR antagonists TMPH and MLA. The increase in sEPSC frequency was mimicked by nAChRα7 agonist AR-R17779 and blocked by nAChRα7 antagonist MG624. AR-R17779 also increased the firing of TH-EGFP neurons, an effect dependent on glutamate inputs, as it was blocked by the glutamate antagonist NBQX. In contrast, the nicotine-induced current was mimicked by nAChRα4β2 agonist RJR2403 and blocked by nAChRα4β2 antagonist DHβE. RJR2403 also increased the firing rate of TH-EGFP neurons independently of glutamate. Finally, both somatodendritic and sEPSC nicotine responses from NTS-CA neurons were larger in nicotine-dependent mice that had under gone spontaneous nicotine withdrawal. These results demonstrate that 1) nicotine activates NTS-CA neurons both directly, by inducing a direct current, and indirectly, by increasing glutamate inputs, and 2) NTS-CA nicotine responsiveness is altered during nicotine withdrawal.

Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors.

Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate of a suicide every 40 s. The weightiest concern about suicidal behavior is how difficult it is for healthcare professionals to predict. However, recent evidence in genomic studies has pointed out the essential role that genetics could play in influencing person’s suicide risk. Combining genomic and clinical risk assessment approaches, some studies have identified a number of biomarkers for suicidal ideation, which are involved in neural connectivity, neural activity, mood, as well as in immune and inflammatory response, such as the mammalian target of rapamycin (mTOR) signaling. This interesting discovery provides the neurobiological bases for the use of drugs that impact these specific signaling pathways in the treatment of suicidality, such as ketamine. Ketamine, an N-methyl-d-aspartate glutamate (NMDA) antagonist agent, has recently hit the headlines because of its rapid antidepressant and concurrent anti-suicidal action. Here we review the preclinical and clinical evidence that lay the foundations of the efficacy of ketamine in the treatment of suicidal ideation in mood disorders, thereby also approaching the essential question of the understanding of neurobiological processes of suicide and the potential therapeutics.

Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network...

Breathing responses produced by optogenetic stimulation of adrenergic C1 neurons are dependent on the connection with preBötzinger complex in rats.

Optogenetic stimulation of the adrenergic C1 neurons produces cardiorespiratory activation, and selective depletion of these cells attenuates breathing responses induced by hypoxia. The preBötzinger complex (preBötC) is a group of neurons located in the intermediate aspect of the ventrolateral medulla, critical for respiratory rhythmogenesis, and is modulated by glutamate and catecholamines. Our hypothesis is that selective activation of C1 neurons leads to breathing responses by excitatory connections with the preBötC neurons. Anatomical connection between C1 cells and preBötC was evaluated using retrograde (Cholera Toxin b; preBötC) and anterograde (LVV-PRSx8-ChR2-eYFP; C1 region) tracers. LVV-PRSx8-ChR2-eYFP (viral vector that expresses channelrhodopsin-2 (ChR2) under the control of the catecholaminergic neuron-preferring promoter (PRSx8) was also injected into the C1 region of male Wistar rats for the functional experiments. Anatomical results demonstrated that preBötC neurons receive projections from C1 cells, and these projections express tyrosine hydroxylase and vesicular glutamate transporter 2. Functional connection between C1 cells and preBötC was evaluated by photostimulation of ChR2-transduced C1 neurons before and after unilateral injection of the ionotropic glutamate antagonist, kynurenic acid (kyn), or cocktail of adrenergic antagonists in the preBötC. Kyn injection into preBötC blocked the increase in DiaEMG frequency without changing the MAP increase elicited by photostimulation of C1 neurons, while the injection of adrenergic antagonists into the preBötC did not change DiaEMG frequency and MAP increase induced by photostimulation of C1 cells. Our results suggest that the increase in breathing produced by photostimulation of C1 neurons can be caused by a direct glutamatergic activation of preBötC neurons.

Potential Future of New Glutamate Agonists and Antagonists Development.

Receptors of glutamic acid are known for over 30 years for their action and for about 20 years for their structure. Presence of at least three classes of ionotropic receptors was confirmed at the beginning of 80'. Recognition of the sequence and first cloning were done at the beginning of 90'. In 1994 ligand binding site was recognized at the junction of two subunits S1-S2 in the ligand-binding domain. Since then, many subtypes of ionotropic and metabotropic glutamate receptors were recognized, together with their localization and functions. In the meantime numerous orthosteric ligands, both agonists and antagonists were developed especially for NMDA ion channels. Their usefulness as drugs was rather low, due to the involvement in the excitatory tract. More interest was focused on metabotropic receptors, which are GPSR's and can be modulated both by orthosteric and allosteric modulators. It seems like allosterism could be considered as promising future for glutamate receptors and ion channels, especially when first allosteric negative modulators of the mGluR2 went close into the clinical trial.

In silico identification of AChE and PARP-1 dual-targeted inhibitors of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease of the elderly that seriously affects the quality of life and the life expectancy of those affected. There is, as yet, no effective drug treatment of AD, although several acetylcholinesterase (AChE) inhibitors and a glutamate antagonist can provide relief from its symptoms. Recent studies have indicated that the overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) may promote nerve cell death in the brains of AD patients, implying that PARP-1 inhibition may have therapeutic value for the treatment of AD. Therefore, it is important to investigate novel agents with both AChE- and PARP-1-inhibitory bioactivities. In this study, the structure-based virtual screening of PARP-1 inhibitors was performed to search for potential agents with high affinities for AChE. The dynamic stability of the selected AChE-ligand complexes was investigated by molecular dynamics (MD) simulation. Two compounds, CID57390505 and CID71605390, showed high affinities for and stability in complex with AChE in docking and MD simulations. Thus, our in silico research identified two compounds with AChE and PARP-1 dual-targeted activities, indicating that this technique could aid attempts to develop more potent agents against AD.

Profiling neurotransmitters in a crustacean neural circuit for locomotion.

Locomotor systems are widely used to study rhythmically active neural networks. These networks have to be coordinated in order to produce meaningful behavior. The crayfish swimmeret system is well suited to investigate such coordination of distributed neural oscillators because the neurons and their connectivity for generating and especially for coordinating the motor output are identified. The system maintains a fixed phase lag between the segmental oscillators, independent of cycle period. To further the understanding of the system’s plasticity for keeping the phase lag fixed, we profiled the neurotransmitters used by the Coordinating Neurons, which are necessary and sufficient for coordination of the segmental oscillators. We used a combination of electrophysiological, immunohistochemical, and mass spectrometric methods. This arrangement of methods ensured that we could screen for several specific neurotransmitters, since a single method is often not suitable for all neurotransmitters of interest. In a first step, to preselect neurotransmitter candidates, we investigated the effect of substances known to be present in some swimmeret system neurons on the motor output and coordination. Subsequently, we demonstrated electrophysiologically that the identified synapse between the Coordinating Neurons and their target is mainly chemical, but neither glutamate antagonist nor γ-aminobutyric acid antagonist application affected this synapse. With immunohistochemical experiments, we provide strong evidence that the Coordinating Neurons are not serotonergic. Single-cell MALDI-TOF mass spectrometry with subsequent principal component analysis identified acetylcholine as the putative neurotransmitter for both types of Coordinating Neurons.

Gamma-Decanolactone Improves Biochemical Parameters Associated with Pilocarpine-Induced Seizures in Male Mice.

Gamma-decanolactone (GD) is a monoterpene effective against seizures induced by pentylenetetrazole. The mechanism of action of GD is likely to be via glutamate antagonism. GD also inhibits intracellular reactive oxygen species (ROS) generation and the lipopolysaccharide-induced expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) in vitro. Considering the neuropharmacological profile of GD studied so far, we investigated the effect of intraperitoneal administration of GD 100 and 300 mg/kg on pilocarpine (PIL)-induced status epilepticus (SE) in mice. GD was administered 30 min before PIL. Behavioral (latency to first seizure and the percentage of clonic forelimb seizures), biochemical, and oxidative stress parameters were evaluated. DNA damage in the cerebral cortex of mice was assessed using the comet assay and mutagenic activity of GD was evaluated using Salmonella/microsome assay in TA100, TA98, TA97a, TA102, and TA1535 strains, with and without metabolic activation (S9 mix). The behavioral results showed that only the latency to the first clonic seizure increased in the groups treated with GD 300 mg/kg, but not when the animals received GD 100 mg/kg. Both GD doses were able to increase superoxide dismutase and catalase activities, inducing a decrease in ROS and nitrite production and in DNA damage in the cerebral cortex. GD was not able to induce base pair substitution and frameshift mutations in the absence or in the presence of metabolic activation. These findings demonstrate that GD does not improve behavioral parameters in the PIL model, but it was able to protect seizure-related oxidative stress and DNA damage in mice, without inducing gene mutations.

Central Nucleus of the Amygdala Mediates Sympathoinhibitory Responses to Activation of Paraventricular Nucleus of the Thalamus

The paraventricular nucleus of the thalamus (PVT) is known to relay sensory information from the brainstem, and information from limbic and cortical structures involved in visceral and homeostatic regulation, and affective behaviors. In turn, PVT relays this information to a number of forebrain structures, including the amygdala. However, whether PVT is involved in mediating cardiovascular information to other central sites is not clear. This study was done to investigate whether the cardiovascular responses elicited by PVT involved a pathway that included the central nucleus of the amygdala (ACe). In the first series of experiments, a systematic mapping of PVT was done to identify cardiovascular responsive sites using microinjection of glutamate (Glu; 10 nL, 0.25 M) in chloralose anesthetized Wistar rats. Glu injections into PVT elicited decreases in systemic mean arterial pressure (MAP, −20 ± 3 mmHg) and heart rate (HR; −15 ± 5 bpm). These depressor responses were mediated through sympathoinhibition as intravenous injections of the ganglionic blocker hexamethonium bromide prevented the responses. In the second series, iontophoretic injections of the anterograde tract tracer PHA‐L were made at PVT depressor sites in the Wistar rats. Dense PHA‐L fiber and presumptive terminal labeling was found within and around the region of the lateral ACe, while light to moderate labeling was observed within the medial ACe. Additionally, extensive labeling was observed throughout the extended amygdala, including the bed nucleus of the stria terminalis. In the final series, bilateral microinjection (100 nL) of either the synaptic blocker CoCl2, the non‐specific glutamate antagonist kynurenic acid or the specific NMDA receptor antagonists 2‐amino‐5‐phosphonovalerate or MK801 were made into ACe in the chloralose anesthetized Wistar rats. Injections of these compounds did not significantly alter the resting levels of arterial pressure (AP) or HR, but significantly attenuated (p&lt;0.01) the MAP response (mean of all injected compounds; −7 ± 5 mmHg) to activation of PVT. On the other hand, these injections into ACe did not alter the HR response (mean of all injected compounds; −12 ± 3 bpm) to PVT stimulation. These data suggest that PVT may function as a relay of sensory information that affects AP responses associated with motivated and addictive behaviors, arousal and/or stress through a sympathoinhibitory neural circuit involving ACe.Support or Funding InformationSupported in part by Heart and Stroke Foundation of Ontario.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High‐Fat Diet Induced Modulation of Glutamatergic Currents in Neurons of the Dorsal Motor Nucleus of the Vagus Increases Gastric Tone and Motility

Understanding how vagally‐mediated neurocircuits are affected by alterations in diet is crucial to addressing dysregulated feeding behaviors and energy balance, as well as their role in the development of obesity. We have demonstrated previously that acute high fat diet (HFD) exposure modulates glutamatergic neurotransmission to vagal efferent motoneurons. The purpose of this study was to test the hypothesis that acute HFD increases activation of synaptic NMDA receptors (NMDA‐R) on gastric‐projecting dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal efferent drive to the stomach.Sprague Dawley rats (4–8 weeks of age) of both sexes were fed a control diet (14% kcal from fat) throughout the study, or a HFD (60% kcal from fat) for 3–5 days prior to experimentation. Daily food intake was measured from singly‐housed rats for 4 days prior and throughout exposure to HFD. Whole cell patch clamp recordings of gastric‐projecting DMV neurons were made from thin (300μm) brainstem slices. The effects of the NMDA‐R antagonist, AP5 (25μM) on amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) as well as action potential firing (AP) firing rate were examined. In vivo recordings of gastric motility and tone were made in response to microinjection of the non‐selective ionotropic glutamate antagonist, kynurenic acid (100pmol/60nL) and AP5 (500pmol/60nL).HFD exposure had no significant effect on caloric intake (control 55±4kcal/24hr vs acute HFD 59±9kcal/24hr; p&gt;0.05) during the acute (3–5 day) period of study. After acute exposure to HFD, however, 9/15 DMV neurons responded to AP5 with a significant decrease in mEPSC amplitude and frequency (24.6±2.9pA vs 17.5±1.7pA; 1.4±0.3 pulses per second (p.p.s) vs 0.5±0.1p.p.s, respectively P&lt;0.05 for each) as compared to only 1/18 control neurons. (18.7±1.3pA vs 18.0±1.3pA, P&gt;0.05). In control conditions, AP5 had no effect on AP firing rate on 7/10 neurons (40.0±4.8 events/30sec vs 47.9±6.5 events/30sec, P&gt;0.05), however, firing rate was decreased significantly in 5/5 neurons following acute HFD exposure (27.4±4.87 events/30sec vs 21.1±13.6 events/30sec, P&lt;0.05). Brainstem microinjection of kynurenic acid had no effect on antral motility in control rats (102.5±17.6% of baseline, P&gt;0.05), but significantly reduced motility following acute HFD exposure (59.9±1.10% of baseline, P&lt;0.05).These data suggest that acute HFD exposure increases NMDA‐R activation, increases DMV neuronal excitability and, subsequently, vagal efferent control of gastric motility. Since this NMDA‐R activation is observed only during periods of caloric balance, these results suggest that plasticity within vagal neurocircuit glutamatergic signaling may be a critical homeostatic response to altered diet that helps maintain appropriate feeding behavior and caloric intake to defend against the development of obesity.Support or Funding InformationNSF IOS1148079 to Kirsteen BrowningThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release.

Excitatory and Inhibitory Neuronal Circuits in the Spinal Cord and Their Role in the Control of Motor Neuron Function and Degeneration.

The complex neuronal networks of the spinal cord coordinate a wide variety of motor functions, including walking, running, and voluntary and involuntary movements. This is accomplished by different groups of neurons, called center pattern generators, which control left-right alternation and flexor-extensor patterns. These spinal circuits, located in the ventral horns, are formed by several neuronal types, and the specific function of most of them has been identified by means of studies in vivo and in the isolated spinal cord of mice harboring genetically induced ablation of specific neuronal populations. These studies have shown that the coordinated activity of several interneuron types, mainly GABAergic and glycinergic inhibitory neurons, have a crucial role in the modulation of motor neurons activity that finally excites the corresponding muscles. A pharmacological experimental approach by administering in the spinal cord agonists and antagonists of glutamate, GABA, glycine, and acetylcholine receptors to alter their synaptic action has also produced important results, linking the deficits in the synaptic function with the resulting motor alterations. These results have also increased the knowledge of the mechanisms of motor neuron degeneration, which is characteristic of diseases such as amyotrophic lateral sclerosis, and therefore open the possibility of designing new strategies for the prevention and treatment of these diseases.

PACAP-(6-38) or kynurenate microinjections in the RVLM prevent the development of sympathetic long-term facilitation after acute intermittent hypoxia.

Intermittent hypoxia causes a persistent increase in sympathetic activity that progresses to hypertension in chronic conditions such as obstructive sleep apnea. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neurotransmitter that causes long-lasting sympathetic excitation. We aimed to determine if intermittent activation of the rostral ventrolateral medulla (RVLM) causes PACAP-mediated elevation of sympathetic nerve activity, termed sympathetic long-term facilitation (sLTF). The role of PACAP in mediating sLTF in response to intermittent activation of the RVLM was investigated in urethane-anaesthetized and artificially ventilated rats ( n = 65, Sprague-Dawley). Bilateral RVLM microinjections of the PACAP type 1 receptor/vasoactive intestinal polypeptide receptor type 2 receptor antagonist PACAP-(6-38) [ n = 6, change (Δ): -16.4 ± 6.5%) or an ionotropic glutamate antagonist, kynurenate ( n = 6, Δ:-7.2 ± 2.3%), blocked the development of acute intermittent hypoxia-induced sLTF ( n = 6, Δ: 49.2 ± 14.2%). Intermittent RVLM microinjections of glutamate caused sLTF ( n = 5, Δ: 56.9 ± 14.7%) that was abolished by PACAP-(6-38) pretreatment ( n = 5, Δ:-1.2 ± 4.7%). Conversely, intermittent microinjections of PACAP in the RVLM did not elicit sLTF. Intermittent bilateral disinhibition of the RVLM by microinjection of γ-aminobutyric acid in the caudal ventrolateral medulla did not elicit sLTF. Direct activation of RVLM neurons is crucial for the development of sLTF. PACAP and glutamate act synergistically in the RVLM, with both being necessary for the sLTF response. We found that activation of glutamate but not PACAP receptors is necessary and sufficient to generate sLTF, even in the absence of intermittent hypoxia. Our results demonstrate that PACAP within the RVLM may contribute to the development of obstructive sleep apnea -induced hypertension. NEW & NOTEWORTHY Pharmacological blockade of either pituitary adenylate cyclase-activating polypeptide (PACAP) or ionotropic glutamate receptors in the rostral ventrolateral medulla prevents development of sympathetic long-term facilitation. PACAP receptor inhibition prevents the occurrence of hypoxia-induced peripheral chemoreflex sensitization. Thus, PACAP receptors may be a potential therapeutic target serving to reduce heightened sympathetic tone and hypersensitized cardiovascular reflexes.