Non-competitive Antagonist Research Articles

Trial protocol for a multicenter randomized controlled trial to assess the efficacy and safety of intravenous ketamine for chronic daily headaches: the “KetHead” trial

BackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to conventional medical management and/or patients cannot afford expensive treatments. It is stipulated that CDH share a mechanism of central sensitization in the trigeminocervical complex, mediated by activation of the N-methyl-d-aspartate (NMDA) receptors. Ketamine, a non-competitive NMDA antagonist, has been used in the treatment of chronic pain, but its role in CDH has not been completely established. This trial aims to evaluate the effect of high-dose IV ketamine infusions (compared to placebo) on the number of headache days at 28 days post-infusion.MethodsA multicenter, placebo-controlled, randomized controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessors. The study will include 56 adults with a CDH diagnosis as per ICHD-3 criteria. Participants will be randomized (1:1) to either ketamine (1 mg. kg−1 bolus followed by infusion of 1 mg. kg−1. h−1 for 6 h) or placebo (0.9% saline in the same volume and infusion rate as the trial medication) bolus and infusion for 6 h. The impact on the number of monthly headache days, headache intensity, physical activity, mood, sleep, quality of life, analgesic consumption, and adverse effects will be recorded at baseline, immediately post-infusion, and from 1 to 28 days, 29 to 56 days, and 57 to 84 days after the infusionDiscussionDespite advancements in treatment, many patients continue to suffer from CDH. This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion. This treatment could become a safe, affordable, and widely available option for patients living with refractory headache.Trial registrationClinicalTrials.gov NCT05306899. Registered on April 1, 2022

Effectiveness and Tolerability of Intranasal Esketamine in Treatment-Resistant Depression: Report of Two Clinical Cases

IntroductionMajor depressive disorder (MDD) is a mental health disorder characterised by persistently low mood; anhedonia; feelings of worthlessness and guilt; altered appetite, weight and sleep and suicidal ideation. About one-third of patients do not respond to available antidepressants (AD). Treatment-resistant depression (TRD) is a clinical term used to define a lack of response to two or more AD in patients with MDD that do not respond to other lines of treatment either. TRD is associated with an increased risk of relapse, hospitalisation and suicide. Esketamine is a non-competitive NMDAR antagonist that acts as an antidepressant by modulating glutamatergic neurotransmission, disturbed in MDD patients. It has recently been approved by the European Commission as a fast-acting nasal spray therapy for depression and suicidal ideation after showing effectiveness in TRD patients (Papakostas et al. JCP 2020; 81 4).ObjectivesThe aim of this study is to determine the effectiveness, safety and tolerability of intranasal esketamine in two TRD-diagnosed patients and to assess their clinical evolution.MethodsA prospective study was conducted describing the evolution of two TRD patients treated with intranasal esketamine. We used The Hamilton Depression Rating Scale (HDRS) to quantify the severity of their symptoms and assess their recovery over time, analyzing the score change from baseline to endpoint as a primary outcome of the study. We also applied the Addensbrooke Cognitive Examination (ACE-III) as a tool to establish their cognitive condition before therapy and its evolution. Changes in dosage during treatment, adverse effects, time required for onset of action, clinical outcomes and other variables were also measured.ResultsIntranasal esketamine was administered twice a week during the first 4-week induction phase and weekly during the following 6-month maintenance phase. Dosage of antidepressant was determined depending on each patient’s age and clinical evolution, being 56 mg the initial dose for case 1 (57 years old) and 28 mg for case 2 (71 years old). This antidepressant was effective in both patients in a fast-acting way, with the onset of action occuring within the first two weeks. During the course of treatment, the HDRS score significantly decreased, associated with improvement and remission of depressive symptoms. Cognitive performance got better in both cases. None of the patients discontinued treatment due to adverse effects or lack of efficacy.ConclusionsOur data suggest that intranasal esketamine therapy is a good alternative in TRD patients, being effective, fast-acting and well-tolerated, with a manageable safety profile. Clinical stability was also observed in the medium-term follow-up after the end of treatment. This presents esketamine as a promising therapeutic and effective strategy in MDD patients who are either treatment-resistant or acutely suicidal.Disclosure of InterestNone Declared

Tratamiento del deterioro cognitivo

The treatment of cognitive impairment is multidisciplinary and begins with an intervention on risk factors. Non-pharmacological treatment includes measures such as cognitive stimulation and aerobic exercise. In regard to diet, the Mediterranean diet has demonstrated cognitive improvement and only the medical nutrition product souvenaid has managed to show isolated benefits in episodic memory in initial cognitive impairment due to Alzheimer's disease. Among the pharmacological interventions on symptoms, current evidence only supports the use of acetylcholinesterase inhibitors (ACEI) such as donepezil, rivastigmine, and galantamine as well as memantine, a non-competitive NMDA antagonist of glutamate receptors, in mild to moderately-advanced Alzheimer's dementia. ACEI have also shown cognitive benefits in Lewy body dementia, but not in frontotemporal dementia. The treatment of dementia-phase behavioral symptoms improves the quality of life of patients and family members and includes addressing psychosis, agitation, depression, apathy, or sleep disorders.

EARLY ONSET AGGRESSIVE BEHAVIOR INDUCED BY PERAMPANEL IN THE TREATMENT OF CHRONIC INSOMNIA: A CASE REPORT

IntroductionChronic insomnia, resistant to different treatments (pharmacological, sleep hygiene and cognitive-behavioral therapy) remains one of the greatest challenges in our daily practice as psychiatrists. The pharmacological options include benzodiazepines and their analogues (zolpidem, zopiclone, etc.). However, when trying to treat chronic insomnia the use of off-label drugs, including antidepressants with sedative action (such as trazodone), antipsychotics or antiepiletic drugs, is not uncommon.Perampanel is a non-competitive AMPA receptor antagonist, marketed for the treatment of partial onset epilepsy and primary generalized tonic-clonic seizures. It has been used in the treatment of chronic insomnia with positive results and it has shown to improve the quality of sleep in a recent observational retrospective cohort study.The most frequent adverse effects of Perampanel include dizziness and drowsiness. Perampanel can also cause psychiatric and behavioral adverse effects, aggression and irritability in up to 10% of patients, as well as depression, and suicidal ideation, with higher rates in patients with psychiatric history.ObjectivesTo draw attention to possible adverse effects of Perampanel and to add knowledge to improve the treatment for chronic insomnia.MethodsCase report and non-systematic literature review of the current data.ResultsA 33 year old woman with Anorexia Nervosa was admitted to the psychiatric hospitalization unit due to suicidal ideation and a history of chronic insomnia. Perampanel was started at a dose of 2mg/day, progressively titrated to 6mg/day, following patient’s informed consent. A week after the initiation of treatment, her sleep pattern had improved but she became aggressive, showed low tolerability to minor frustrations and suffered from an intensification of suicidal ideation. She became extremely hostile to the personnel, had severe tantrums and deliberate self injurious behavior. Perampanel was discontinued and in less than a week her aggressive behavior succumbed. Although she was not re-exposed to Perampanel the symptoms she presented are considered a very likely adverse drug reaction. Levomepromazine 20mg/day and Lormetazepam 0.5mg/day were reinstated as a treatment for insomnia.ConclusionsPsychiatric comorbidity is known to be a risk factor for behavioral adverse effects of Perampanel. Therefore Perampanel as a treatment for chronic insomnia needs a careful individual benefit-risk assessment and monitoring for adverse effects.Disclosure of InterestNone Declared

Antidepressant-like effect of CP-101,606: Evidence of mTOR pathway activation

BackgroundAs a non-competitive N-methyl d-aspartate receptor antagonist, ketamine exerts rapid-onset and long-lasting antidepressant effects on depression, but some side effects limit its use. To identify a safer compound that may provide similar antidepressant effects, here we investigated whether CP-101,606, a selective NR2B receptor inhibitor, provides similar antidepressant effects and explored its underlying mechanisms. MethodsTo mimic depressive-like behavior, mice were subjected to chronic unpredictable mild stress (CUMS) for 21 days. Mice were treated with CP-101,606 at 10, 20, and 40 mg/kg doses for 7, 14, and 21 days, respectively, followed by a sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). Western blot analysis was performed on several targets (mTOR, p-mTOR, p70S6K, p-p70S6K, PSD-95, and GluA1), along with immunohistochemistry (GluA1) and immunofluorescence (p-mTOR) assays, using hippocampal tissue. ResultsCP-101,606 at 20 and 40 mg/kg doses for 7 and 14 days and fluoxetine 10 mg/kg and CP-101606 20 mg/kg for 21 days ameliorated depression-like behaviors in the SPT, TST, and FST. The effects of CP-101,606 were associated with a reversal of the CUMS-induced decrease in mTOR (Ser2448) and p70S6K (Thr389) phosphorylation and increasing PSD95 and GluA1 synthesis in the hippocampus. ConclusionsOur results demonstrate that CP-101,606 produces antidepressant effects in CUMS mice, which may be mediated by mTOR signaling cascade upregulation. Our findings suggest the possible utility of CP-101,606 as a treatment for depression.

Prenatal ketamine exposure impairs prepulse inhibition via arginine vasopressin receptor 1A-mediated GABAergic neuronal dysfunction in the striatum

Ketamine is a widely used anesthetic with N-methyl-D-aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis. However, the mechanism underlying the effects of ketamine on the immature brain remains unclear. In this study, NMDA receptor antagonists, ketamine and methoxetamine, were administered to pregnant F344 rats (E17). These regimens induce psychosis-like behaviors in the offspring, such as hyperlocomotion induced by MK-801, a non-competitive NMDA receptor antagonist. We also observed that prepulse inhibition (PPI) was significantly reduced. Interestingly, ketamine administration increased the arginine vasopressin receptor 1A (Avpr1a) expression levels in the striatum of offspring with abnormal behaviors. Methoxetamine, another NMDA receptor antagonist, also showed similar results. In addition, we demonstrated a viral vector-induced Avpr1a overexpression in the striatum-inhibited PPI. In the striatum of offspring, ketamine or methoxetamine treatment increased glutamate decarboxylase 67 (GAD67) and δ-aminobutyric acid (GABA) levels. These results show that prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum.

Immunomodulatory IL-23 receptor antagonist peptide nanocoatings for implant soft tissue healing.

Peri-implantitis, caused by an inflammatory response to pathogens, is the leading cause of dental implant failure. Poor soft tissue healing surrounding implants - caused by inadequate surface properties - leads to infection, inflammation, and dysregulated keratinocyte and macrophage function. One activated inflammatory response, active around peri-implantitis compared to healthy sites, is the IL-23/IL-17A cytokine axis. Implant surfaces can be synthesized with peptide nanocoatings to present immunomodulatory motifs to target peri-implant keratinocytes to control macrophage polarization and regulate inflammatory axises toward enhancing soft tissue healing. We synthesized an IL-23 receptor (IL-23R) noncompetitive antagonist peptide nanocoating using silanization and evaluated keratinocyte secretome changes and macrophage polarization (M1-like "pro-inflammatory" vs. M2-like "pro-regenerative"). IL-23R antagonist peptide nanocoatings were successfully synthesized on titanium, to model dental implant surfaces, and compared to nonfunctional nanocoatings and non-coated titanium. IL-23R antagonist nanocoatings significantly decreased keratinocyte IL-23, and downstream IL-17A, expression compared to controls. This peptide noncompetitive antagonistic function was demonstrated under lipopolysaccharide stimulation. Large scale changes in keratinocyte secretome content, toward a pro-regenerative milieu, were observed from keratinocytes cultured on the IL-23R antagonist nanocoatings compared to controls. Conditioned medium collected from keratinocytes cultured on the IL-23R antagonist nanocoatings polarized macrophages toward a M2-like phenotype, based on increased CD163 and CD206 expression and reduced iNOS expression, compared to controls. Our results support development of IL-23R noncompetitive antagonist nanocoatings to reduce the pro-inflammatory IL-23/17A pathway and augment macrophage polarization toward a pro-regenerative phenotype. Immunomodulatory implant surface engineering may promote soft tissue healing and thereby reduce rates of peri-implantitis.

Memantine as a neuroprotective agent in ischemic stroke: Preclinical and clinical analysis.

The primary mechanism for neuron death after an ischemic stroke is excitotoxic injury. Excessive depolarization leads to NMDA-mediated calcium entry to the neuron and, subsequently, cellular death. Therefore, the inhibition of the NMDA channel has been proposed as a neuroprotective measure in ischemic stroke. The high morbimortality associated with stroke warrants new therapies that can improve the functional prognosis of patients. Memantine is a non-competitive NMDA receptor antagonist which has gained attention as a potential drug for ischemic stroke. Here we analyze the available preclinical and clinical evidence concerning the use of memantine following an ischemic stroke. Preclinical evidence shows inhibition of the excitotoxic cascade, as well as improved outcomes in terms of motor and sensory function with the use of memantine. The available clinical trials of high-dose memantine in patients poststroke have found that it can improve patients' NIHSS and Barthel index and help patients with poststroke aphasia and intracranial hemorrhage. These results suggest that memantine has a clinically relevant neuroprotective effect; however, small sample sizes and other study shortcomings limit the impact of these findings. Even so, current studies show promising results that should serve as a basis to promote future research to conclusively determine if memantine does improve the outcomes of patients' post-ischemic stroke. We anticipate that future trials will fill current gaps in knowledge, and these latter results will broaden the therapeutic arsenal for clinicians looking to improve the prognosis of patients poststroke.

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective.

Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward 'non-NMDA' (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds.

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy.

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).

Dorsal hippocampal CA1 NMDA receptors mediate the interactive effects of quetiapine and lithium on memory retention in male rats.

Lithium and quetiapine are administered simultaneously as a treatment for bipolar disorder. The concurrent use of these two drugs has been observed to affect the neurobiological mechanisms underlying learning and memory. To clarify the precise mechanisms involved, we evaluated the possible role of the dorsal hippocampal CA1 NMDA receptors in the interactive effects of lithium and quetiapine in memory consolidation. The dorsal hippocampal CA1 regions of adult male Wistar rats were bilaterally cannulated, and a single-trial step-through inhibitory avoidance apparatus was used to assess memory consolidation. Post-training administration of certain doses of lithium (20, 30, and 40 mg/kg, IP) diminished memory consolidation. Post-training administration of higher doses of quetiapine (5, 10, and 20 mg/kg, IP) augmented memory consolidation. Post-training administration of certain doses of quetiapine (2.5, 5, 10, and 20 mg/kg) dose-dependently restored lithium-induced memory impairment. Post-training microinjection of ineffective doses of the NMDA (10-5 and 10-4 µg/rat, intra-CA1) plus an ineffective dose of quetiapine (2.5 mg/kg) restored the lithium-induced memory impairment. Post-training microinjection of ineffective doses of the noncompetitive NMDA receptor antagonist, MK-801 (0.0625 and 0.0125 μg/rat, intra-CA1), diminished the quetiapine-induced (10 mg/kg) memory improvement in lithium-induced memory impairment. These findings suggest a functional interaction between lithium and quetiapine through hippocampal CA1 NMDA receptor mechanisms in memory consolidation.

Multi-centre discriminating concentration determination of broflanilide and potential for cross-resistance to other public health insecticides in Anopheles vector populations

Novel insecticides are urgently needed to control insecticide-resistant populations of Anopheles malaria vectors. Broflanilide acts as a non-competitive antagonist of the gamma-aminobutyric acid receptor and has shown prolonged effectiveness as an indoor residual spraying product (VECTRON T500) in experimental hut trials against pyrethroid-resistant vector populations. This multi-centre study expanded upon initial discriminating concentration testing of broflanilide, using six Anopheles insectary colonies (An. gambiae Kisumu KCMUCo, An. gambiae Kisumu NIMR, An. arabiensis KGB, An. arabiensis SENN, An. coluzzii N’Gousso and An. stephensi SK), representing major malaria vector species, to facilitate prospective susceptibility monitoring of this new insecticide; and investigated the potential for cross-resistance to broflanilide via the A296S mutation associated with dieldrin resistance (rdl). Across all vector species tested, the discriminating concentration for broflanilide ranged between LC99 × 2 = 1.126–54.00 μg/ml or LC95 × 3 = 0.7437–17.82 μg/ml. Lower concentrations of broflanilide were required to induce complete mortality of An. arabiensis SENN (dieldrin-resistant), compared to its susceptible counterpart, An. arabiensis KGB, and there was no association between the presence of the rdl mechanism of resistance and survival in broflanilide bioassays, demonstrating a lack of cross-resistance to broflanilide. Study findings provide a benchmark for broflanilide susceptibility monitoring as part of ongoing VECTRON T500 community trials in Tanzania and Benin.

The structural patterns of the potentiation and the blockade of inhibitory <i>cys</i>-loop receptors through the transmembrane domain

Anion-conducting cys-loop receptors activated by -aminobutyric acid (GABAАRs) and glycine (GlyRs) have inhibitory activity in the brain and spinal cord. GABAАRs and GlyRs are targets for various substances that potentiate or inhibit the receptor functions. Many of these substances are clinically significant agents to treat neurological and psychiatric conditions.
 The review covers both our results and literature data on electrophysiology, mutations, and biochemistry of non-competitive antagonists, general anesthetics, barbiturates, and fenamates modulating GABAАRs and GlyRs. We focused on our own molecular modeling to determine the sites and the characteristics of binding of these substances to the GABAАR and GlyR transmembrane domain. With the structural patterns of the binding, we have identified possible molecular mechanisms of action for these substances.

Activation of basolateral amygdala to anterior cingulate cortex circuit alleviates MK-801 induced social and cognitive deficits of schizophrenia.

Schizophrenia is a severe psychiatric disorder with a high prevalence worldwide, however, its pathogenesis remains poorly understood. In this study, we used the non-competitive NMDA receptor antagonist MK-801 to induce schizophrenia-like behaviors and confirmed that mice exhibited stereotypic rotational behavior and hyperlocomotion, social interaction defects and cognitive dysfunction, similar to the clinical symptoms in patients. Here, the anterior cingulate cortex (ACC) and basolateral amygdala (BLA) were involved in the schizophrenia-like behaviors induced by MK-801. Furthermore, we confirmed BLA sent glutamatergic projection to the ACC. Chemogenetic and optogenetic regulation of BLA-ACC projecting neurons affected social and cognitive deficits but not stereotypic rotational behavior in MK-801-treated mice. Overall, our study revealed that the BLA-ACC circuit plays a major role and may be a potential target for treating schizophrenia-related symptoms.

Suppressive effects of ketamine on auditory steady-state responses in intact, awake macaques: A non-human primate model of schizophrenia

Auditory steady-state responses (ASSRs) are recurrent neural activities entrained to regular cyclic auditory stimulation. ASSRs are altered in individuals with schizophrenia, and may be related to hypofunction of the N-methyl-D-aspartate (NMDA) glutamate receptor. Noncompetitive NMDA receptor antagonists, including ketamine, have been used in ASSR studies of rodent models of schizophrenia. Although animal studies using non-human primates are required to complement rodent studies, the effects of ketamine on ASSRs are unknown in intact awake non-human primates. In this study, after administration of vehicle or ketamine, click trains at 20–83.3 Hz were presented to elicit ASSRs during recording of electroencephalograms in intact, awake macaque monkeys. The results indicated that ASSRs quantified by event-related spectral perturbation and inter-trial coherence were maximal at 83.3 Hz after vehicle administration, and that ketamine reduced ASSRs at 58.8 and 83.3 Hz, but not at 20 and 40 Hz. The present results demonstrated a reduction of ASSRs by the NMDA receptor antagonist at optimal frequencies with maximal responses in intact, awake macaques, comparable to ASSR reduction in patients with schizophrenia. These findings suggest that ASSR can be used as a neurophysiological biomarker of the disturbance of gamma-oscillatory neural circuits in this ketamine model of schizophrenia using intact, awake macaques. Thus, this model with ASSRs would be useful in the investigation of human brain pathophysiology as well as in preclinical translational research.

Non-competitive AMPA glutamate receptors antagonism by perampanel as a strategy to counteract hippocampal hyper-excitability and cognitive deficits in cerebral amyloidosis

Pathological accumulation of Aβ oligomers has been linked to neuronal networks hyperexcitability, potentially underpinned by glutamatergic AMPA receptors (AMPARs) dysfunction. We aimed to investigate whether the non-competitive block of AMPARs was able to counteract the alteration of hippocampal epileptic threshold, and of synaptic plasticity linked to Aβ oligomers accumulation, being this glutamate receptor a valuable specific therapeutic target. In this work, we showed that the non-competitive AMPARs antagonist perampanel (PER) which, per se, did not affect physiological synaptic transmission, was able to counteract Aβ-induced hyperexcitability. Moreover, AMPAR antagonism was able to counteract Aβ-induced hippocampal LTP impairment and hippocampal-based cognitive deficits in Aβ oligomers-injected mice, while retaining antiseizure efficacy. Beside this, AMPAR antagonism was also able to reduce the increased expression of proinflammatory cytokines in this mice model, also suggesting the presence of an anti-inflammatory activity. Thus, targeting AMPARs might be a valuable strategy to reduce both hippocampal networks hyperexcitability and synaptic plasticity deficits induced by Aβ oligomers accumulation.

RBIO-08. MEMANTINE INCREASES DENDRITIC ARBORIZATION OF IMMATURE NEURONS AFTER IRRADIATION WITH NO EVIDENCE OF DISRUPTION IN THE NORMAL BRAIN FUNCTION

Abstract Cranial irradiation (IR) is a cornerstone in the treatment of high-grade pediatric brain tumors. While lifesaving, it is associated with severe sequalae in 50-90 % of the survivors, as they often show disabling cognitive dysfunction, declined IQ, impaired processing speed, anxiety and posttraumatic stress symptoms, resulting in poorer academic accomplishments and social isolation. Memantine (Mem) is a non-competitive NMDA receptor antagonist and a potent enhancer of neural plasticity. While an improvement in cognition in post-IR cancer survivors and in synaptic plasticity in association to hippocampal neurogenesis have been documented, the exact mechanisms underlying Mem’s actions are poorly understood. The goal of this project is to further dissect the actions of Mem and identify factors that contribute to hippocampal neurogenesis. To this end, 20-day-old C57BL6/J mice were subjected to a single dose of 7 Gy whole brain irradiation and then supplied with Mem in the drinking water (10 mg/kg/day) to obtain a steady-state plasma concentration of the drug. Two weeks after IR, Sholl analysis of the morphology of the newborn neurons of Mem treated animals showed a statistically significant increase in coverage area (500 µm2 vs. 250 µm2, p < 0,0001) and number of dendrites (15 vs. 5, p < 0,0001) compared to non-treated individuals. Bulk-RNA sequencing analysis revealed 9 differentially expressed genes (alpha=0.1) between the hippocampal cell populations of Mem and vehicle-treated IR mice, which are related to protein folding and the programmed cell death machinery. At six weeks after IR, Mem treatment maintains the gamma oscillatory dynamics in the hippocampal CA3 region (~2x10-9 V2 in non-IR, ~1x109 V2 in IR), but with no apparent recovery to the sham levels. These results emphasize the strong neurogenic effect that Mem exerts on the surviving newborn neurons, while also highlighting Mem’s low toxicity and impact on the normal function of the brain.

The psychotomimetic ketamine disrupts the transfer of late sensory information in the corticothalamic network.

In prodromal and early schizophrenia, disorders of attention and perception are associated with structural and chemical brain abnormalities and with dysfunctional corticothalamic networks exhibiting disturbed brain rhythms. The underlying mechanisms are elusive. The non-competitive NMDA receptor antagonist ketamine simulates the symptoms of prodromal and early schizophrenia, including disturbances in ongoing and task & sensory-related broadband beta-/gamma-frequency (17-29 Hz/30-80 Hz) oscillations in corticothalamic networks. In normal healthy subjects and rodents, complex integration processes, like sensory perception, induce transient, large-scale synchronised beta/gamma oscillations in a time window of a few hundred ms (200-700 ms) after the presentation of the object of attention (e.g., sensory stimulation). Our goal was to use an electrophysiological multisite network approach to investigate, in lightly anesthetised rats, the effects of a single psychotomimetic dose (2.5mg/kg, subcutaneous) of ketamine on sensory stimulus-induced oscillations. Ketamine transiently increased the power of baseline beta/gamma oscillations and decreased sensory-induced beta/gamma oscillations. In addition, it disrupted information transferability in both the somatosensory thalamus and the related cortex and decreased the sensory-induced thalamocortical connectivity in the broadband gamma range. The present findings support the hypothesis that NMDA receptor antagonism disrupts the transfer of perceptual information in the somatosensory cortico-thalamo-cortical system.

Sustained MK-801 induced deficit in a novel probabilistic reversal learning task.

Cognitive flexibility, the ability to adapt to unexpected changes, is critical for healthy environmental and social interactions, and thus to everyday functioning. In neuropsychiatric diseases, cognitive flexibility is often impaired and treatment options are lacking. Probabilistic reversal learning (PRL) is commonly used to measure cognitive flexibility in rodents and humans. In PRL tasks, subjects must sample choice options and, from probabilistic feedback, find the current best choice which then changes without warning. However, in rodents, pharmacological models of human cognitive impairment tend to disrupt only the first (or few) of several contingency reversals, making quantitative assessment of behavioral effects difficult. To address this limitation, we developed a novel rat PRL where reversals occur at relatively long intervals in time that demonstrates increased sensitivity to the non-competitive NMDA receptor antagonist MK-801. Here, we quantitively compare behavior in time-based PRL with a widely used task where reversals occur based on choice behavior. In time-based PRL, MK-801 induced sustained reversal learning deficits both in time and across reversal blocks but, at the same dose, only transient weak effects in performance-based PRL. Moreover, time-based PRL yielded better estimates of behavior and reinforcement learning model parameters, which opens meaningful pharmacological windows to efficiently test and develop novel drugs preclinically with the goal of improving cognitive impairment in human patients.

O010 / #862 FRONTOPARIETAL TDCS DECREASES PSYCHOSIS-RELEVANT OSCILLOPATHIES: A PRECLINICAL PROOF OF THERAPEUTIC CONCEPT: TRACK 2: BRAIN STIMULATION

During the prodromal phase of schizophrenia with its complex and insidious clinical picture, EEG recordings detect widespread oscillation disturbances (or oscillopathies) during the wake-sleep cycle. Neural oscillations are electro-biomarkers of the connectivity state within systems. A single systemic psychotomimetic administration of ketamine, a non-competitive NMDA glutamate receptor antagonist, transiently reproduces the oscillopathies with a clinical picture reminiscent of the psychosis prodrome.