GABA Agonist Research Articles

New Therapeutic Targets and Drugs for Schizophrenia Beyond Dopamine D2 Receptor Antagonists.

Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field.

Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

STRESS-INDUCED HYPERTHERMIA (LITERATURE REVIEW)

Stress-induced hyperthermia (SIH) is a physiological response of the body to psychological stress. Currently, 88 % of the population is in a state of chronic stress. Psychogenic hyperthermia is more common in young women. Psychogenic fever is not associated with an immunological inflammatory process, there is no increase in inflammatory mediators. The mechanism of the development of stress-induced hyperthermia is the activation of the sympathoadrenal system, vasoconstriction, an increase in the level of corticosterone and the thermogenesis of brown fat. Constant sympathetic stimulation leads to the formation of thermogenin-expressing loci in white adipose tissue. Dopaminergic and noradrenergic compounds do not affect the intensity of hyperthermia. Taking nonsteroidal analgesics does not affect this type of hyperthermia. Antipsychotics are ineffective for psychogenic hyperthermia. Effective drugs that have anxiolytic properties, which significantly reduce the basal body temperature when the dose is increased. Serotonergic receptors play a key role in modulating behavioural, autonomic, and endocrine responses to stress. Effective GABA agonists and antidepressants. For the treatment of the chronic variant of SIH, the use of fluoxetine is recommended. Psychoeducation is used as non-medicinal methods of treating functional fever; psychotherapy with an adjustment environment (verbal or non-verbal release of unreacted negative emotions and conflicts); cognitive-behavioral or other psychological therapy, meditation, relaxation training; yoga and practices aimed at reducing stress and mental disorders.

Cellular Mechanisms Associated with Neurodevelopmental Alterations Produced by General Anesthetics

: There is concern about neurodevelopmental disturbances associated with exposure to general anesthesia during early childhood. In 2016, the U.S. Food and Drug Administration released a safety alert regarding the use of gamma-aminobutyric acid (GABA) agonists and N-methyl-D-aspartate (NMDA) receptor antagonists in pediatric anesthesia, warning about the risks of their use during the last trimester of pregnancy and in children under 3 years for neurodevelopment. Animal and in vitro studies demonstrate worrisome morphological and functional alterations in young neurons and glia induced by different anesthetic drugs. These drugs can induce changes in various neuronal transmission systems, alter dendritic growth and brain connectivity, and initiate processes leading to cell demise, such as aberrant cell cycle reentry, mitochondrial dysfunction, excitotoxicity, neuroapoptosis, disruption of cytoskeletal assembly, and dysregulation of brain-derived neurotrophic factor (BNDF). Additionally, they can generate epigenetic changes that can be transmitted intergenerationally. These effects are related to age, dose, number of anesthetics received, and duration of exposure to said drugs and can be reversible or permanent, caused by direct or indirect perturbations on neurons. These disturbances may manifest as neurodevelopmental disorders later in life. This work aimed to review the cellular mechanisms involved in these alterations.

A neurophysiological basis for aperiodic EEG and the background spectral trend

Electroencephalograms (EEGs) display a mixture of rhythmic and broadband fluctuations, the latter manifesting as an apparent 1/f spectral trend. While network oscillations are known to generate rhythmic EEG, the neural basis of broadband EEG remains unexplained. Here, we use biophysical modelling to show that aperiodic neural activity can generate detectable scalp potentials and shape broadband EEG features, but that these aperiodic signals do not significantly perturb brain rhythm quantification. Further model analysis demonstrated that rhythmic EEG signals are profoundly corrupted by shifts in synapse properties. To examine this scenario, we recorded EEGs of human subjects being administered propofol, a general anesthetic and GABA receptor agonist. Drug administration caused broadband EEG changes that quantitatively matched propofol’s known effects on GABA receptors. We used our model to correct for these confounding broadband changes, which revealed that delta power, uniquely, increased within seconds of individuals losing consciousness. Altogether, this work details how EEG signals are shaped by neurophysiological factors other than brain rhythms and elucidates how these signals can undermine traditional EEG interpretation.

Exploring the Roles of Vitamins C and D and Etifoxine in Combination with Citalopram in Depression/Anxiety Model: A Focus on ICAM-1, SIRT1 and Nitric Oxide.

The study of intercellular adhesion molecule-1 (ICAM-1) and SIRT1, a member of the sirtuin family with nitric oxide (NO), is emerging in depression and anxiety. As with all antidepressants, the efficacy is delayed and inconsistent. Ascorbic acid (AA) and vitamin D (D) showed antidepressant properties, while etifoxine (Etx), a GABAA agonist, alleviates anxiety symptoms. The present study aimed to investigate the potential augmentation of citalopram using AA, D and Etx and related the antidepressant effect to brain and serum ICAM-1, SIRT1 and NO in an animal model. BALB/c mice were divided into naive, control, citalopram, citalopram + etx, citalopram + AA, citalopram + D and citalopram + etx + AA + D for 7 days. On the 8th day, the mice were restrained for 8 h, followed by a forced swim test and marble burying test before scarification. Whole-brain and serum expression of ICAM-1, Sirt1 and NO were determined. Citalopram's antidepressant and sedative effects were potentiated by ascorbic acid, vitamin D and etifoxine alone and in combination (p < 0.05), as shown by the decreased floating time and rearing frequency. Brain NO increased significantly (p < 0.05) in depression and anxiety and was associated with an ICAM-1 increase versus naive (p < 0.05) and a Sirt1 decrease (p < 0.05) versus naive. Both ICAM-1 and Sirt1 were modulated by antidepressants through a non-NO-dependent pathway. Serum NO expression was unrelated to serum ICAM-1 and Sirt1. Brain ICAM-1, Sirt1 and NO are implicated in depression and are modulated by antidepressants.

REMIMAZOLAM IMPROVES THE MARKERS OF POSTRESUSCITATION CEREBRAL INJURY IN A SWINE MODEL OF CARDIAC ARREST.

Introduction: Previous studies have manifested that those sedatives acting on γ-aminobutyric acid A (GABAa) receptor could produce effective brain protection against regional and global ischemic stimulation. The present study was designed to investigate the effect of a novel GABAa receptor agonist, remimazolam postconditioning (RP) on cerebral outcome after global ischemic stimulation induced by cardiac arrest and resuscitation in swine. Methods: A total of 24 swine were used in this study, in which the animals were randomly divided into the following three groups: sham group (n = 6), cardiopulmonary resuscitation (CPR) group (n = 9), and CPR + RP group (n = 9). The experimental model was established by the procedure of 10 min of cardiac arrest and 5 min of CPR. Those resuscitated swine in the CPR + RP group received an intravenous infusion of 2.5 mg/kg of remimazolam within 60 min. Postresuscitation cerebral injury biomarkers and neurological function were evaluated for a total of 24 h. At 24 h after resuscitation, brain cortex was harvested to evaluate the severity of pathologic damage, including tissue inflammation, oxidative stress, apoptosis, and necroptosis. Results: Baseline characteristics and CPR outcomes were not significantly different between the CPR and CPR + RP groups. After resuscitation, significantly greater cerebral injury and neurological dysfunction were observed in the CPR and CPR + RP groups than in the sham group. However, remimazolam postconditioning significantly alleviated cerebral injury and improved neurological dysfunction after resuscitation when compared with the CPR group. At 24 h after resuscitation, tissue inflammation, oxidative stress, and cell apoptosis and necroptosis were significantly increased in the CPR and CPR + RP groups when compared with the sham group. Nevertheless, the severity of pathologic damage mentioned previously were significantly milder in those swine treated with the remimazolam when compared with the CPR group. Conclusions: In a swine model of cardiac arrest and resuscitation, the remimazolam administered after resuscitation significantly improved the markers of postresuscitation cerebral injury and therefore protected the brain against global ischemic stimulation.

Negative emotionality downregulation affects moral choice but not moral judgement of harm: a pharmacological study

Previous neuroscientific research has expounded on the fundamental role played by emotion during moral decision-making. Negative emotionality has been observed to exert a general inhibitory effect towards harmful behaviors against others. Nevertheless, the downregulation of negative affects at different levels of moral processing (e.g. impersonal versus personal moral dilemmas) alongside its possible interactions with other factors (e.g. perspective taking) hasn’t been directly assessed; both of which can assist in predicting future moral decision-making. In the present research, we empirically test (Study 1, N = 41) whether downregulating negative emotionality through pharmacological interventions using lorazepam (a GABA receptor agonist), modulate the permissibility of harm to others –i.e. if participants find it more morally permissible to harm others when harm is unavoidable (inevitable harm moral dilemmas), than when it may be avoided (evitable harm moral dilemmas). Furthermore, using another sample (Study 2, N = 31), we assess whether lorazepam’s effect is modulated by different perspective-taking conditions during a moral dilemma task –e.g. “is it morally permissible for you to […]?” (1st person perspective), relative to “is it morally permissible for [x individual] to […]?” (3rd person perspective)–, where the outcome of the different scenarios is controlled. The results of both studies converge, revealing an emotion-dependent, rather than an outcome-dependent, pharmacological modulation. Lorazepam only influenced interpersonal moral judgments when not modulated by the evitable/inevitable condition. Furthermore, there was a significant interaction between perspective-taking and drug administration, as lorazepam exerted a larger effect in modulating moral choices rather than moral judgements.

Enhancing GABAergic Tonic Inhibition Reduces Seizure-Like Activity in the Neonatal Mouse Hippocampus and Neocortex.

Approximately one-third of neonatal seizures do not respond to first-line anticonvulsants, including phenobarbital, which enhances phasic inhibition. Whether enhancing tonic inhibition decreases seizure-like activity in the neonate when GABA is mainly depolarizing at this age is unknown. We evaluated if increasing tonic inhibition using THIP [4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, gaboxadol], a δ-subunit-selective GABAA receptor agonist, decreases seizure-like activity in neonatal C57BL/6J mice (postnatal day P5-8, both sexes) using acute brain slices. Whole-cell patch-clamp recordings showed that THIP enhanced GABAergic tonic inhibitory conductances in layer V neocortical and CA1 pyramidal neurons and increased their rheobase without altering sEPSC characteristics. Two-photon calcium imaging demonstrated that enhancing the activity of extrasynaptic GABAARs decreased neuronal firing in both brain regions. In the 4-aminopyridine and the low-Mg2+ model of pharmacoresistant seizures, THIP reduced epileptiform activity in the neocortex and CA1 hippocampal region of neonatal and adult brain slices in a dose-dependent manner. We conclude that neocortical layer V and CA1 pyramidal neurons have tonic inhibitory conductances, and when enhanced, they reduce neuronal firing and decrease seizure-like activity. Therefore, augmenting tonic inhibition could be a viable approach for treating neonatal seizures.

Application of ensemble learning for predicting GABAA receptor agonists

BackgroundOver the past few decades, agonists binding to the benzodiazepine site of the GABAA receptor have been successfully developed as clinical drugs. Different modulators (agonist, antagonist, and reverse agonist) bound to benzodiazepine sites exhibit different or even opposite pharmacological effects, however, their structures are so similar that it is difficult to distinguish them based solely on molecular skeleton. This study aims to develop classification models for predicting the agonists. Methods306 agonists or non-agonists were collected from literature. Six machine learning algorithms including RF, XGBoost, AdaBoost, GBoost, SVM, and ANN algorithms were employed for model development. Using six descriptors including 1D/2D Descriptors, ECFP4, 2D-Pharmacophore, MACCS, PubChem, and Estate fingerprint to characterize chemical structures. The model interpretability was explored by SHAP method. ResultsThe best model demonstrated an AUC value of 0.905 and an MCC value of 0.808 for the test set. The PubMac-based model (PubMac-GB) achieved best AUC values of 0.935 for test set. The SHAP analysis results emphasized that MaccsFP62, ECFP_624, ECFP_724, and PubchemFP213 were the crucial molecular features. Applicability domain analysis was also performed to determine reliable prediction boundaries for the model. The PubMac-GB model was applied to virtual screening for potential GABAA agonists and the top 100 compounds were given. ConclusionOverall, our ensemble learning-based model (PubMac-GB) achieved comparable performance and would be helpful in effectively identifying agonists of GABAA receptors.

The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats.

In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for threehours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors.

Activation of 5-HT5A receptor in the ventrolateral orbital cortex produces antinociceptive effects in rat models of neuropathic and inflammatory pain

The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT5A receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT5A receptor activation. We found an upregulation of 5-HT5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT5A receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT5A receptor antagonist SB-699551. Moreover, application of the GABAA receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABAA receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT5A receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level.

A novel combination treatment for fragile X syndrome predicted using computational methods.

Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx's data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABAA receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.

Glutamate Spillover Dynamically Strengthens Gabaergic Synaptic Inhibition of the Hypothalamic Paraventricular Nucleus.

The hypothalamic paraventricular nucleus (PVN) is strongly inhibited by γ-aminobutyric acid (GABA) from the surrounding peri-nuclear zone (PNZ). Because glutamate mediates fast excitatory transmission and is substrate for GABA synthesis, we tested its capacity to dynamically strengthen GABA inhibition. In PVN slices from male mice, bath glutamate applied during ionotropic glutamate receptor blockade increased PNZ-evoked inhibitory postsynaptic currents (eIPSCs) without affecting GABA-A receptor agonist currents or single-channel conductance, implicating a presynaptic mechanism(s). Consistent with this interpretation, bath glutamate failed to strengthen IPSCs during pharmacological saturation of GABA-A receptors. Presynaptic analyses revealed that glutamate did not affect paired-pulse ratio, peak eIPSC variability, GABA vesicle recycling speed, or readily releasable pool (RRP) size. Notably, glutamate-GABA strengthening (GGS) was unaffected by metabotropic glutamate receptor blockade and graded external Ca2+ when normalized to baseline amplitude. GGS was prevented by pan- but not glial-specific inhibition of glutamate uptake and by inhibition of glutamic acid decarboxylase (GAD), indicating reliance on glutamate uptake by neuronal excitatory amino acid transporter 3 (EAAT3) and enzymatic conversion of glutamate to GABA. EAAT3 immunoreactivity was strongly localized to presumptive PVN GABA terminals. High bath K+ also induced GGS, which was prevented by glutamate vesicle depletion, indicating that synaptic glutamate release strengthens PVN GABA inhibition. GGS suppressed PVN cell firing, indicating its functional significance. In sum, PVN GGS buffers neuronal excitation by apparent "over-filling" of vesicles with GABA synthesized from synaptically released glutamate. We posit that GGS protects against sustained PVN excitation and excitotoxicity while potentially aiding stress adaptation and habituation.

GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions.

Dementia and autoimmune diseases are prevalent conditions with limited treatment options. Taurine and homotaurine (HT) are naturally occurring sulfonate amino acids, with taurine being highly abundant in animal tissues, but declining with age in the blood. HT is a blood-brain barrier permeable drug under investigation for Alzheimer's disease. HT also has beneficial effects in a mouse model of multiple sclerosis likely through an anti-inflammatory mechanism mediated by GABAA receptor (GABAAR) agonism in immune cells. While both taurine and HT are structural GABA analogs and thought to be GABA mimetics at GABAARs, there is uncertainty concerning their potency as GABA mimetics on native GABAARs. We show that HT is a very potent GABA mimetic, as it evokes GABAAR-mediated currents with an EC50 of 0.4μM (vs. 3.7μM for GABA and 116µM for taurine) in murine cerebellar granule cells in brain slices, with both taurine and HT having similar efficacy in activating native GABAARs. Furthermore, HT displaces the high affinity GABAAR ligand [3H]muscimol at similarly low concentrations (HT IC50 of 0.16μM vs. 125μM for taurine) in mouse brain homogenates. The potency of taurine and HT as GABAAR agonists aligns with endogenous concentrations of taurine in the blood and with HT concentrations achieved in the brain following oral administration of HT or the HT pro-drug ALZ-801. Consequently, we discuss that GABAARs subtypes, similar to the ones we studied here in neurons, are plausible targets for mediating the potential beneficial effects of taurine in health and life-span extension and the beneficial HT effects in dementia and autoimmune conditions.

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology.

Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication. Benzodiazepines are the currently accepted treatment for OP-induced convulsions, but the convulsions become refractory to these GABAA agonists and repeated dosing has diminishing effectiveness. As such, adjunct anticonvulsant treatments are needed to provide improved protection against recurrent and prolonged convulsions and the associated excitotoxic CNS damage that results from them. Previously we have shown that brief, 4-min administration of 3%-5% isoflurane in 100% oxygen has profound anticonvulsant and CNS protective effects when administered 30min after a lethal dose of paraoxon. In this report we provide an extended time course of the effectiveness of 5% isoflurane delivered for 5min, ranging from 60 to 180min after a lethal dose of paraoxon in rats. We observed substantial effectiveness in preventing neuronal loss as shown by Fluoro-Jade B staining when isoflurane was administered 1h after paraoxon, with diminishing effectiveness at 90, 120 and 180min. In vivo magnetic resonance imaging (MRI) derived T2 and mean diffusivity (MD) values showed that 5-min isoflurane administration at a concentration of 5% prevents brain edema and tissue damage when administered 1h after a lethal dose of paraoxon. We also observed reduced astrogliosis as shown by GFAP immunohistochemistry. Studies with continuous EEG monitoring are ongoing to demonstrate effectiveness in animal models of soman poisoning.

The pre-Bötzinger complex is necessary for the expression of inspiratory and post-inspiratory motor discharge of the vagus

The mammalian three-phase respiratory motor pattern of inspiration, post-inspiration and expiration is expressed in spinal and cranial motor nerve discharge and is generated by a distributed ponto-medullary respiratory pattern generating network. Respiratory motor pattern generation depends on a rhythmogenic kernel located within the pre-Bötzinger complex (pre-BötC). In the present study, we tested the effect of unilateral and bilateral inactivation of the pre-BötC after local microinjection of the GABAA receptor agonist isoguvacine (10 mM, 50 nl) on phrenic (PNA), hypoglossal (HNA) and vagal nerve (VNA) respiratory motor activities in an in situ perfused brainstem preparation of rats. Bilateral inactivation of the pre-BötC triggered cessation of phrenic (PNA), hypoglossal (HNA) and vagal (VNA) nerve activities for 15–20 min. Ipsilateral isoguvacine injections into the pre-BötC triggered transient (6–8 min) cessation of inspiratory and post-inspiratory VNA (p < 0.001) and suppressed inspiratory HNA by − 70 ± 15% (p < 0.01), while inspiratory PNA burst frequency increased by 46 ± 30% (p < 0.01). Taken together, these observations confirm the role of the pre-BötC as the rhythmogenic kernel of the mammalian respiratory network in situ and highlight a significant role for the pre-BötC in the transmission of vagal inspiratory and post-inspiratory pre-motor drive to the nucleus ambiguus.

Dissociable role of the basolateral complex of the amygdala in the acquisition and extinction of conditioned fear following reproductive experience in female rats

In female rats and humans, reproductive experience (i.e., pregnancy) alters the behavioral, hormonal and molecular substrates of fear extinction. Here, we assessed whether the role of a central neural substrate of fear extinction, the basolateral amygdala (BLA), also changes following reproductive experience. Nulliparous (virgin) and primiparous (one prior pregnancy) female rats received infusions of the GABAA agonist, muscimol, to temporarily inactivate the BLA prior to fear conditioning or extinction training. In follow up experiments, the BLA was also inactivated immediately after extinction training. BLA inactivation impaired the acquisition and expression of conditioned fear in both nulliparous and primiparous rats. In nulliparous rats, BLA inactivation prior to or immediately after extinction training impaired extinction retention. In contrast, in primiparous rats, BLA inactivation prior to or immediately after extinction training did not impair extinction retention, despite suppressing freezing during extinction training. These results suggest that, consistent with past findings in males, the BLA is a central component of the neural circuitry of fear acquisition and its extinction in virgin female rats. However, after pregnancy, female rats no longer depend on the BLA to extinguish fear, despite requiring the BLA to acquire conditioned fear. Given that fear extinction forms the basis of exposure therapy for anxiety disorders in humans, the present findings may have clinical implications. To improve the efficacy of exposure therapy for anxiety disorders, we may need to target different mechanisms in females dependent on their reproductive history.

A Comprehensive Review of Gastroesophageal Reflux Disease (GERD) Treatment and its Clinical Perspectives

Gastroesophageal reflux disease (GERD) occurs by regurgitation of food in the stomach. Aggressive factors increase GERD whereas defensive factors decrease GERD progression. GERD if mild can be put under control by lifestyle modification and giving non-pharmacological treatment methods to patients however if the disease progresses non-pharmacological methods are ineffective. Drugs reduce GERD progression and also maintain the pH of the stomach to a normal level and prevent abnormal acid exposure to the oesophagus. Antacids and alginate protect oesophagus by reducing acidity and increasing viscosity. Proton pump inhibitors and histamine 2 receptor antagonists reduce acid secretion by inhibiting its secretion. Prokinetic agents increase the motility of the stomach and reduce obesity. Metabotropic glutamate receptors, gamma-aminobutyric acid receptor agonists, and cannabinoid receptors are receptor-specific drugs that act on receptors underlying the gastrointestinal tract and alter the function of receptors which increases reflux disease. Combination of antacid and alginate, domperidone and omeprazole, omeprazole and baclofen, aluminum hydroxide, magnesium, and simethicone are frequently given in GERD to expedite the healing rate and reduce acid secretion. Combinations of suitable medications reduce the adverse effects of a single medication and also make it therapeutically more effective than using monotherapy drugs. The pharmacological method is safe and effective and treats GERD completely.

CNSC-12. PATHOLOGY SPECIFIC, PHARMACOLOGICALLY REVERSIBLE LOSS OF NEURONAL FUNCTION IN HUMAN GLIOMAS

Abstract Prior evidence has demonstrated that neuronal activity is preserved within glioma-infiltrated cortex and maintains the ability to engage in task specific computations albeit with information loss. These findings support a potential therapeutic target to rescue cognitive impairments seen in nearly all afflicted patients if neuronal activity can be recovered. We developed an in vivo human behavioral and electrophysiological model to assess neuronal population tuning responses within primary sensory cortex including the decodability of stimuli and task-related changes in population spiking in a cohort of 14 human patients undergoing awake resection. We placed high-density electrode arrays to record human local field potentials from gliomas projecting to the cortical surface. We next designed a static sensory detection threshold task, stimulating with a tachometer at two different face and hand sites totaling 11,200 trials while recording from macroelectrode cortical contacts over both tumor-infiltrated (50 electrodes) and normal appearing cortex (52 electrodes). In tumor-infiltrated cortex, the ability to decode the site of stimulation using the oscillatory power in both theta (4-8 Hz) and gamma (32-70 Hz) bands was reduced compared to normal appearing cortex. However, tumor-infiltrated cortex-maintained selectivity between hand and face stimulation. Targeted next-generation tumor sequencing uncovered novel molecular targets of glioma-neuronal integration. The degree of loss of selectivity correlated with WHO grade and pathology. WHO grade 4 tumors and oligodendrogliomas compared to astrocytomas demonstrating greater loss of selectivity. Gabaergic agonist has been postulated to restore neuronal selectivity in aging and neurodegenerative disease. Therefore, we next computed GABA agonist dose (estimated by time off Propofol and beginning of behavioral testing). Higher concentrations of GABA agonist correlated with improved theta band selectivity and decodability. These results suggest that loss of neuronal computations in glioma-infiltrated cortex is caused by loss of neuronal selectivity and is both tumor selective and pharmacologically reversible.