NMDA Receptor Antagonist Ketamine Research Articles

Is anti-NMDA receptor encephalitis real? II. Therapeutic challenges

The first part of the review challenges the diagnostic concept of anti-NMDA receptor encephalitis (ANMDARE). The second part focuses on analyzing current therapeutic approaches. It is demonstrated that the use of antipsychotics or immunosuppressants poses the risk of severe complications, potentially leading to fatal outcomes, in the near or distant future. Comparing clinical and neurobiological effects associated with antibodies to the GluN1 subunit of the glutamate N-methyl-D-aspartate receptors (NMDAR1-AB) and the administration of subanesthetic doses of the non-competitive NMDA receptor antagonist Ketamine highly suggests a neuroprotective, health-promoting role of NMDAR1-AB, which should not be suppressed but rather potentiated. Benzodiazepines and electroconvulsive therapy (ECT) remain the treatment of choice for acute polymorphic hyperkinetic psychoses.

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

Acute administration of the NMDA receptor antagonists ketamine and MK-801 reveals dysregulation of glutamatergic signalling and sensorimotor gating in the Sapap3 knockout mouse model of compulsive-like behaviour

Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours. Firstly, we investigated whether administration of the NMDA receptor (NMDAR) antagonist ketamine (30 mg/kg), would reduce anxiety and grooming behaviour in Sapap3 KO mice. Anxiety-like behaviour was measured via time spent in the light component of the light-dark box test. Grooming behaviour was recorded and scored in freely moving mice. In line with previous works conducted in older animals (i.e. typically between 6 and 9 months of age), we confirmed here that Sapap3 KO mice exhibit an anxious, compulsive grooming, hypolocomotive and reduced body weight phenotype even at a younger age (i.e., 2-3 months of age). However, we found that acute administration of ketamine did not cause a reduction in anxiety or grooming behaviour. We then investigated in vivo glutamatergic function via the administration of a different NMDAR antagonist, MK-801 (0.25 mg/kg), prior to locomotion and prepulse inhibition assays. We found evidence of altered functional NMDAR activity, as well as sexually dimorphic prepulse inhibition, a measure of sensorimotor gating, in Sapap3 KO mice. These results are suggestive of in vivo glutamatergic dysfunction and their functional consequences, enabling future research to further investigate novel treatments for OCD.

248. Effects of NMDA Receptor Antagonist Ketamine on Neural Tuning

248. Effects of NMDA Receptor Antagonist Ketamine on Neural Tuning

The NMDA receptor antagonists memantine and ketamine as anti-migraine agents.

Migraine is a debilitating disorder affecting females more frequently than males. There is some evidence that drugs targeting glutamate receptors: memantine and ketamine might be beneficial in the therapy of this entity. Therefore, the purpose of this work is to present NMDA receptor antagonists, memantine and ketamine, as potential anti-migraine agents. We searched PubMed/MEDLINE, Embase, and clinical trials submitted to ClinicalTrials.gov to find publications describing eligible trials published between database inception and December 31, 2021. This comprehensive literature review summarizes data on the use of the NMDA receptor antagonists memantine and ketamine in the pharmacotherapy of migraine. Results from 20 previous and recent preclinical experiments are discussed and correlated with 19 clinical trials (including case series, open-label, and randomized placebo-controlled trials). For the purposes of this review, the authors hypothesized that the propagation of SD is a major mechanism in the pathophysiology of migraine. In several animal studies and in vitro studies, memantine and ketamine inhibited or reduced propagation of the SD. In addition, the results of clinical trials suggest that memantine or ketamine may be an effective treatment option for migraine. However, most studies on these agents lack control group. Although further clinical trials are needed, the results suggest that ketamine or memantine may be promising molecules for the treatment of severe migraine. Particular attention should be paid to people who have a treatment-resistant form of migraine with aura or have exhausted existing treatment options. For them, the drugs under discussion could represent an interesting alternative in the future.

Some theoretical models of addictive disorder are used for behavioral transformation

Existential, neurobiological and cognitive models of addictive behavior are considered as a theoretical basis for transformational therapy of addictive disorders. The NMDA receptor antagonist ketamine, which has neurotrophic, modulatory and psychedelic effects, demonstrates the universal properties of a transforming agent for any of the presented concepts of addictive behavior. Since persistent mental and behavioral changes essentially are psychobiological changes, the substrate that determines the effectiveness of the intervention is synaptic plasticity and neural network remodeling.

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.

Ketamine Pharmacodynamics Entangled: Reply

We thank Bowdle et al.1 for their interest in our article,2 and for the important issue they raise, paraphrased as follows: what is the best anthropocentric description of the “mind-altering” effects of a heterogeneous group of compounds and drugs that act at the brain and cause significant changes in mental state. The group of drugs that we are referring to includes N-methyl-d-aspartate (NMDA) receptor antagonists (ketamine, nitrous oxide, xenon), serotonergic psychedelics (5-HT2a receptor agonists psilocybin and lysergic acid diethylamide and serotonin-releasing 3,4-methylenedioxymethamphetamine), ayahuasca, cannabinoids (CB-1 receptor agonists), and κ-opioid receptor agonists Salvinorin A and B; this list is certainly not complete (see List of Psychedelic Drugs3). During the past two decades we studied ketamine, cannabis, and recently also psilocybin in patients and healthy volunteers and observed several similarities in the subjective expression of feelings and emotions during and after treatment. One important commonality is that these drug consumers display a certain disconnection or dissociation from reality. In this sense, the word “dissociation” and “dissociative drug” have a different meaning than described by Bowdle et al.1 It may indeed not be the correct wording because dissociation does not encompass all of the symptoms experienced and expressed by the users of these drugs (not all symptoms relate to a disconnect with reality). Moreover, there are clear distinctions in symptomatology between these different drugs. For example, the hallucinogenic effects of cannabinoids are very different from those of ketamine or ayahuasca. Hence, it may just not be possible to have one denominator that describes the mind-altering effects of these drugs. The conclusion of Bowdle et al.1 is that it is best to describe the anesthetic drugs that have psychedelic effects by their mechanism of action, for example, the NMDA-receptor antagonist ketamine. However, there is ample evidence that many of the ketamine effects are non-NMDA related. For example, acute pain relief may be related to the μ-opioid receptor and/or specific background potassium channels.4,5 Therefore, we argue that we need another approach. One term that describes both the NMDA-receptor antagonists and serotonergic psychedelics is psychoplastogen. Psychoplastogens are molecules that have a neurotrophic effect and promote rapid neural plasticity in the cortex (rewiring of pathologic neurocircuitry).6 Although this term does not describe the subjective experiences caused by these drugs, it does describe the mechanisms associated with their healing effects, whether it be antidepression or pain relief. Hence, in future studies we will refer to ketamine as a psychoplastogen. We thank Dr. Bowdle et al. for this mental exercise that we hope will result in an improved description of the behavioral effects of psychedelic drugs.The Anesthesia & Pain Research Unit of the Department of Anesthesiology, Leiden University Medical Center (Leiden, The Netherlands), received/receives funding from AMO Pharma Ltd. (Leeds, United Kingdom), Bedrocan BV (Veendam, the Netherlands), Grünenthal GmbH (Aachen, Germany), Medtronic (Minneapolis, Minnesota), MSD Nederland BV (Haarlem, the Netherlands), LTS Lohmann Therapie Systeme AG (Andernach, Germany), and Trevena Inc. (Chesterbrook, Pennsylvania). Dr. Dahan received consultancy and/or speaker fees from Enalare Therapeutics Inc. (Princeton, New Jersey), Grünenthal BV (Woerden, the Netherlands), Medasense Biometrics Ltd. (Ramat Gan, Israel). Dr. Dahan received grants/awards from ZonMW (The Hague, the Netherlands) and US Food and Drug Administration (Silver Spring, Maryland).

The NMDA receptor antagonist ketamine impairs and delays context-dependent decision making in the parietal cortex

Flexible decision making is an indispensable ability for humans. A subanesthetic dose of ketamine, an N-methyl-D-aspartate receptor antagonist, impairs this flexibility in a manner that is similar to patients with schizophrenia; however how it affects neural processes related to decision making remains unclear. Here, we report that ketamine administration impairs neural processing related to context-dependent decision making, and delays the onset of decision making. We recorded single unit activity in the lateral intraparietal area (LIP) while monkeys switched between a direction-discrimination task and a depth-discrimination task. Ketamine impaired choice accuracy for incongruent stimuli that required different decisions depending on the task, for the direction-discrimination task. Neural sensitivity to irrelevant depth information increased with ketamine during direction discrimination in LIP, indicating impaired processing of irrelevant information. Furthermore, the onset of decision-related neural activity was delayed in conjunction with an increased reaction time irrespective of task and stimulus congruency. Neural sensitivity and response onset of the middle temporal area (MT) were not modulated by ketamine, indicating that ketamine worked on neural decision processes downstream of MT. These results suggest that ketamine administration may impair what information to process and when to process it for the purpose of achieving flexible decision making.

The novel dehydroepiandrosterone derivative BNN27 counteracts the impairing effects of anesthetic ketamine on rats’ non-spatial and spatial recognition memory

Conspicuous experimental evidence indicates that anesthetic doses of the non-competitive NMDA receptor antagonist ketamine disrupt memory abilities in rodents. BNN27 is a synthetic analogue of dehydroepiandrosterone (DHEA) with potent antioxidant properties and its involvement in cognition has recently been shown. It is not yet clarified whether BNN27 can attenuate the cognition deficits induced by anesthetic ketamine. The present study was designed to elucidate this issue in the rat. For this purpose, the object recognition and the object location tests which are behavioral procedures evaluating non-spatial and spatial recognition memory respectively in rodents were used. The effects of compounds on motility were also tested utilizing a motor activity cage. Post-training administration of BNN27 (3 and 6 mg/kg, intraperitoneally) counteracted anesthetic ketamine (100 mg/kg, intraperitoneally)-induced non-spatial and spatial recognition memory deficits. Further, these effects cannot be attributed to changes to locomotor activity. Our findings clearly show the protective role of BNN27, on recognition memory impairment induced by anesthetic ketamine, indicating a functional interaction following co-administration of synthetic microneurotrophins and ketamine.

Antinociceptive Effects of Morphine:Ketamine Mixtures in Rats

Chronic pain is a serious public health concern with an economic burden of $600 million annually and personal burden for approximately 100 million Americans. Prescription opioids (mu opioid receptor agonists) are the “gold standard” for treating moderate to severe pain despite their well‐documented adverse effects (dependence, respiratory depression, constipation). Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. Thus, there is a dire need for safer, more effective treatments for pain. One strategy for improving the margin of safety of opioids is combining them with other analgesic drugs to decrease the opioid dose needed for pain relief, thereby avoiding adverse effects that occur with larger doses. The NMDA receptor antagonist ketamine has been used safely and effectively to treat pain, but only under a narrow range of conditions (in emergency departments, post‐operative recovery, and combat casualty). The current studies used a model of acute pain (warm water tail withdrawal) and a model of chronic inflammatory pain (Von Frey paw withdrawal) to determine the antinociceptive effects of morphine and ketamine alone and in mixtures (in 3:1, 1:1, and 1:3 ratios) in 16 male Sprague Dawley rats. Given alone, both morphine (1‐10 mg/kg) and ketamine (3.2‐32 mg/kg) dose‐dependently increased tail withdrawal latency, with morphine having greater potency and efficacy as compared to ketamine. Similarly, given alone, both morphine (0.56‐5.6 mg/kg) and ketamine (3.2‐32 mg/kg) dose‐dependency increased force required to elicit a paw withdrawal response, with morphine having greater potency as compared to ketamine. ED50 values were used to determine the doses for mixtures. In mixtures, the potency of morphine or ketamine to produce antinociception was enhanced by 2‐3 fold as compared to either drug given alone. Dose‐equivalence and dose‐additivity analyses showed that the effects of morphine:ketamine mixtures were additive. Furthermore, morphine:ketamine mixtures that relieved pain also were tested in an assay of constipation in a separate group of 8 rats. While both morphine (1‐10 mg/kg) alone and ketamine (3.2‐32 mg/kg) alone dose‐dependently decreased fecal output, morphine:ketamine mixtures did not enhance constipation. Therefore, morphine:ketamine mixtures appear to selectively enhance antinociception. It remains unknown whether morphine:ketamine mixtures have other adverse effects (abuse, physical dependence, respiratory depression) and whether interactions between morphine and ketamine on these outcomes might be related to the ratio of each drug in mixtures. Morphine:ketamine mixtures might have greater therapeutic potential than mu opioids alone for treating moderate to severe pain, but only if adverse effects of each drug are not enhanced.

Sex- and estrous-cycle dependent dorsal hippocampal phosphoproteomic changes induced by low-dose ketamine

Numerous emotional and cognitive processes mediated by the hippocampus present differences between sexes and can be markedly influenced by hormonal status in males and females of several species. In rodents, the dorsal hippocampus (dHPC) is known to contribute to the rapid antidepressant actions of the NMDA receptor antagonist ketamine. We and others have demonstrated a greater sensitivity to the fast-acting antidepressant ketamine in female versus male rats that is estrogen- and progesterone-dependent. However, the underlying mechanisms remain unclear. Using an acute low dose (2.5 mg/kg) of ketamine that is behaviorally effective in female but not male rats, a label-free phosphoproteomics approach was employed to identify ketamine-induced changes in signaling pathway activation and phosphoprotein abundance within the dHPC of intact adult male rats and female rats in either diestrus or proestrus. At baseline, males and females showed striking dissimilarities in the dHPC proteome and phosphoproteome related to synaptic signaling and mitochondrial function—differences also strongly influenced by cycle stage in female rats. Notably, phosphoproteins enriched in PKA signaling emerged as being both significantly sex-dependent at baseline and also the primary target of ketamine-induced protein phosphorylation selectively in female rats, regardless of cycle stage. Reduced phosphoprotein abundance within this pathway was observed in males, suggesting bi-directional effects of low-dose ketamine between sexes. These findings present biological sex and hormonal milieu as critical modulators of ketamine’s rapid actions within this brain region and provide greater insight into potential translational and post-translational processes underlying sex- and hormone-dependent modulation of ketamine’s therapeutic effects.

Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study.

Background: Cognitive disorders associated with schizophrenia are closely linked to prefrontal cortex (PFC) dysfunction. Administration of the non-competitive NMDA receptor antagonist ketamine (KET) induces cognitive impairment in animals, producing effects similar to those observed in schizophrenic patients. In a previous study, we showed that KET (20 mg/kg) induces cognitive deficits in mice and that administration of clozapine (CLZ) reverses this effect. To identify biochemical mechanisms related to CLZ actions in the context of KET-induced impairment, we performed a biochemical analysis using the same experimental paradigm—acute and sub-chronic administration of these drugs (0.3 and 1 mg/kg). Methods: Since the effect of CLZ mainly depends on G-protein-related receptors, we used the Signaling PathwayFinder Kit to identify 84 genes involved in GPCR-related signal transduction and then verified the genes that were statistically significantly different on a larger group of mice using RT-PCR and Western blot analyses after the administration of acute and sub-chronic drugs. Results: Of the 84 genes involved in GPCR-related signal transduction, the expression of six, βarrestin1, βarrestin2, galanin receptor 2 (GalR2), dopamine receptor 2 (DRD2), metabotropic glutamate receptor 1 (mGluR1), and metabotropic glutamate receptor 5 (mGluR5), was significantly altered. Since these genes affect the levels of other signaling proteins, e.g., extracellular signal-regulated kinase 1/2 (ERK1/2), G protein-coupled receptor kinase 2 (Grk2), and G protein-gated inwardly rectifying potassium 3 (Girk3), we determined their levels in PFC using Western blot. Most of the observed changes occurred after acute treatment with 0.3 mg/kg CLZ. We showed that acute treatment with CLZ at a lower dose significantly increased βarrestin1 and ERK1/2. KET treatment induced the upregulation of βarrestin1. Joint administration of these drugs had no effect on the βarrestin1 level. Conclusion: The screening kit we used to study the expression of GPCR-related signal transduction allowed us to select several important genes affected by CLZ. However, the obtained data do not explain the mechanism of action of CLZ that is responsible for reversing KET-induced cognitive impairment.

Perioperative analgesia for the prolepsis of persistence of post-thoracotomy chronic neuropathic pain

Abstract: Proper perioperative analgesic management of Thoracic surgery cases constitutes a primary factor for the successful outcome of the surgery, having created the ideal conditions for both the thoracic surgeon and the anesthesiologist, but mainly for the avoidance of postoperative pain for the patient. 5%-67% of thoracic surgery cases reports post thoracotomy pain syndrome that can persist for up to 20 years. Purpose: To give prominence to the benefits of analgesics for the patient undergoing thoracic surgery after having received appropriate perioperative treatment and starts analgesic protection from the time preceding surgical incision to the patient’s complete recovery, as far as prevention of chronic neuropathic pain is concerned. Complete analgesic protection presupposes the interdisciplinary collaboration of the surgeon and the anesthesiologist with the patient. Materials & methods: Thorough review of scientific literature in scientific databases (PubMed, Scopus, SignaVitae) concerning perioperative analgesia in thoracotomies. Results: In our effort to prevent the persistence of Chronic Neuropathic Pain, we always take into consideration the fact that thoracotomy patients suffer from respiratory complications/uneasy breathing with invasive analgesia techniques. Therefore, we remain alert to reduce the use of opioids and their adverse effects on those patients. Major analgesic outcomes and avoidance of persistence of chronic neuropathic pain can be achieved with the following procedure: (1) Intravenous administration of non-steroidal anti-inflammatories, paracetamol, dexamethasone 8 mg, NMDA receptor antagonist (Ketamine 30 mg) before incision as well as local infusion of Ropivacaine 2% solution. (2) Intravenous infusion of lidocaine, fentanyl, remifentanil, morphine, tramadol, Mg, ketamine, during surgery by adjusting doses per patient and operative time. (3) Particular caution is suggested in the immediate postoperative period so as to avoid transition from acute postoperative pain to chronic neuropathic pain. Our armamentarium includes paracetamol, tramadol, dexketoprofen, oxycodone per os, PCA morphine, pain busters (paired drainage catheters with elastomeric pumps) of ropivacaine 2%, patch lidocaine and thoracic epidural analgesia with ropivacaine pumps and intercostal block nerve conduction. A medical record of the postoperative analgesic course of our patients is kept and completed by our medical and nursing staff. Conclusions: Perioperative analgesia is our key concern in all thoracic surgeries, so as to prevent post thoracotomy pain syndrome. For the purpose of this concern, we administer analgesic treatment on all surgery stages as well as keep postoperative analgesic record.

Perioperative Analgesia in Major Oncology operations for the prolepsis of persistence of Chronic Neuropathic Pain

Abstract: Perioperative Analgesia in Major Oncology operations for the prolepsis of persistence of Chronic Neuropathic Pain might include intravenous infusion of analgesics, concomitant drugs as well as invasive techniques in all surgical stages. Achieving highly effective analgesia presupposes the interdisciplinary collaboration of the surgeon and the anesthesiologist with the patient. Purpose: To give prominence to the benefits of analgetics for the oncology patient undergoing surgery after having received appropriate perioperative treatment and starts analgesic protection from the time preceding surgical incision to the patient’s complete recovery, as far as prevention of chronic neuropathic pain is concerned. Materials & methods: Thorough review of scientific literature in scientific databases (PubMed, Scopus, hesmo.org, uicc.org, Signa Vitae) which are consistent with the way our department functions and in compliance with the protocols concerning the prolepsis of persistence of Chronic Neuropathic Pain in major oncology operation patients. Results: Major analgesic outcomes and avoidance of persistence of chronic neuropathic pain, by taking into consideration the fact that postoperative oncology patients suffer from respiratory depression after invasive analgesia techniques. Also, we are prepared to reduce the use of opioids and their adverse effects, following the procedure below: (1) Choose, when allowed, a combination of general and epidural anesthesia to achieve maximum intraoperative and postoperative analgesia. (2) Intravenous administration of non-steroidal anti-inflammatories, paracetamol, dexamethasone 8mg, NMDA receptor antagonist (Ketamine 30 mg) before incision as well as local infusion of Ropivacaine 2% solution. (3) Intravenous infusion of lidocaine, fentanyl, remifentanil, morphine, tramadol, Mg, ketamine, during surgery by adjusting doses per patient and operative time. (4) Particular caution is suggested in the immediate postoperative period so as to avoid transition from acute postoperative pain to chronic neuropathic pain. Continue drop by drop administration of ropivacaine 2% from epidural catheter. Our armamentarium includes paracetamol, tramadol, dexketoprofen, oxycodone per os, PCA morphine, pain busters (paired drainage catheters with elastomeric pumps) of ropivacaine 2%, patch lidocaine and block nerve conduction. A medical record of the postoperative analgesic course of our patients is kept and completed by our medical and nursing staff.Conclusions: Perioperative analgesia is our key concern in all oncology patients undergoing major surgeries, so as to prevent persistence of chronic neuropathic pain, taking into consideration the impaired health status of patients with acute pain conditions.

The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain.

Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances, or psychosis, such as Alzheimer's disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI), and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally active dose of the M1/M4-preferring muscarinic agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high-frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high-frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.

A circuit mechanism for decision-making biases and NMDA receptor hypofunction.

Decision-making biases can be features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases during evidence integration. Monkeys showed a pro-variance bias (PVB): a preference to choose options with more variable evidence. The PVB was also present in a spiking circuit model, revealing a potential neural mechanism for this behaviour. To model possible effects of NMDA receptor (NMDA-R) antagonism on this behaviour, we simulated the effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were then tested experimentally using the NMDA-R antagonist ketamine, a pharmacological model of schizophrenia. Ketamine yielded an increase in subjects' PVB, consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction predominantly onto excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making biases are prominent.

Postnatal functional inactivation of the ventral subiculum enhances dopaminergic responses in the core part of the nucleus accumbens following ketamine injection in adult rats

For almost two decades schizophrenia has been considered to be a functional disconnection disorder. This functional disconnectivity between several brain regions could have a neurodevelopmental origin. Various approaches suggest the ventral subiculum (SUB) is a particular target region for neurodevelopemental disturbances in schizophrenia. It is also commonly acknowledged that there is a striatal dopaminergic (DA) dysregulation in schizophrenia which may depend on a subiculo-striatal disconnection involving glutamatergic NMDA receptors.The present study was designed to investigate, in adult rats, the effects of the non-competitive NMDA receptor antagonist ketamine on DA responses in the ventral striatum, or, more specifically, the core part of the nucleus accumbens (Nacc), following postnatal functional inactivation of the SUB. Functional inactivation of the left SUB was carried out by local tetrodotoxin (TTX) microinjection at postnatal day 8 (PND8), i.e. at a critical point in the neurodevelopmental period. DA variations were recorded using in vivo voltammetry in freely moving adult rats (11 weeks). Locomotor activity was recorded simultaneously with the extracellular levels of DA in the core part of the Nacc. Data obtained during the present study showed that after administration of ketamine, the two indexes were higher in TTX animals than PBS animals, the suggestion being that animals microinjected with TTX in the left SUB at PND8 present greater reactivity to ketamine than animals microinjected with PBS. These findings could provide new information regarding the involvement of NMDA glutamatergic receptors in the core part of the Nacc in the pathophysiology of schizophrenia.

Spreading Depolarizations and Subarachnoid Hemorrhage.

Cortical spreading depolarizations (SD) are strongly associated with worse tissue injury and clinical outcomes in the setting of aneurysmal subarachnoid hemorrhage (SAH). Animal studies have suggested a causal relationship, and new therapies to target SDs are starting to be tested in clinical studies. A recent set of single-center randomized trials assessed the effect of the phosphodiesterase inhibitor cilostazol in patients with SAH. Cilostazol led to improved functional outcomes and SD-related metrics in treated patients through a putative mechanism of improved cerebral blood flow. Another promising therapeutic approach includes attempts to block SDs with, for example, the NMDA receptor antagonist ketamine. SDs have emerged not only as a therapeutic target but also as a potentially useful biomarker for brain injury following SAH. Additional clinical and preclinical experimental work is greatly needed to assess the generalizability of existing therapeutic trials and to better delineate the relationship between SDs, SAH, and functional outcome.

Resolvins as novel targets for rapid-acting antidepressants

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.