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CNS Neuroscience & Therapeutics Apr 2024As a phencyclidine (PCP) analog, ketamine can generate rapid-onset and substantial anesthetic effects. Contrary to traditional anesthetics, ketamine is a dissociative... (Review)
Review
BACKGROUND
As a phencyclidine (PCP) analog, ketamine can generate rapid-onset and substantial anesthetic effects. Contrary to traditional anesthetics, ketamine is a dissociative anesthetic and can induce loss of consciousness in patients. Recently, the subanaesthetic dose of ketamine was found to produce rapid-onset and lasting antidepressant effects.
AIM
However, how different concentrations of ketamine can induce diverse actions remains unclear. Furthermore, the molecular mechanisms underlying the NMDAR-mediated anesthetic and antidepressant effects of ketamine are not fully understood.
METHOD
In this review, we have introduced ketamine and its metabolism, summarized recent advances in the molecular mechanisms underlying NMDAR inhibition in the anesthetic and antidepressant effects of ketamine, explored the possible functions of NMDAR subunits in the effects of ketamine, and discussed the future directions of ketamine-based anesthetic and antidepressant drugs.
RESULT
Both the anesthetic and antidepressant effects of ketamine were thought to be mediated by N-methyl-D-aspartate receptor (NMDAR) inhibition.
CONCLUSION
The roles of NMDARs have been extensively studied in the anaesthetic effects of ketamine. However, the roles of NMDARs in antidepressant effects of ketamine are complicated and controversial.
Topics: Humans; Ketamine; Receptors, N-Methyl-D-Aspartate; Antidepressive Agents; Anesthetics
PubMed: 37680076
DOI: 10.1111/cns.14464 -
IScience Sep 2023ATP-gated P2X7 receptors (P2X7Rs) play a crucial role in brain disorders. However, how they affect normal and pathological synaptic transmission is still largely...
ATP-gated P2X7 receptors (P2X7Rs) play a crucial role in brain disorders. However, how they affect normal and pathological synaptic transmission is still largely unclear. Here, by using whole-cell patch-clamp technique to record AMPA- and NMDA receptor-mediated excitatory postsynaptic currents (s/mEPSCs) in dentate gyrus granule cells (DG GCs), we revealed a modulation by P2X7Rs of presynaptic sites, especially originated from entorhinal cortex (EC)-GC path but not the mossy cell (MC)-GC path. The involvement of P2X7Rs was confirmed using a pharmacological approach. Additionally, the acute activation of P2X7Rs directly elevated calcium influx from EC-GC terminals. In postnatal phencyclidine (PCP)-induced mouse model of schizophrenia, we observed that P2X7R deficiency restored the EC-GC synapse alteration and alleviated PCP-induced symptoms. To summarize, P2X7Rs participate in the modulation of GC excitatory neurotransmission in the DG via EC-GC pathway, contributing to pathological alterations of neuronal functions leading to neurodevelopmental disorders.
PubMed: 37649698
DOI: 10.1016/j.isci.2023.107560 -
Radiology Case Reports Oct 2023Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a constellation of specific imaging findings characterized by...
Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a constellation of specific imaging findings characterized by cytotoxic edema in the bilateral hippocampi, cerebellar cortices, and basal ganglia in patients presenting with altered mental status in the setting of substance intoxication. Previous case reports have demonstrated a strong correlation between CHANTER syndrome and polysubstance abuse, particularly with opioid intoxication. The patient we present in this case was found unresponsive following opioid use and demonstrated a constellation of findings on initial and follow-up imaging, consistent with CHANTER syndrome. While cases of irreversible brain damage or death during hospitalization have been reported in the literature, our patient demonstrated near-full recovery a few days after admission to the hospital. We aim to highlight the presentation and progression of CHANTER syndrome and alert clinicians and radiologists to include this entity in their diagnostic checklist for patients with polysubstance abuse and altered mental status.
PubMed: 37554665
DOI: 10.1016/j.radcr.2023.07.015 -
Current Neuropharmacology 2024The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present...
The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.
Topics: Rats; Mice; Animals; Antipsychotic Agents; Schizophrenia; Apomorphine; Hydroxybenzoate Ethers; Disease Models, Animal; Cognition
PubMed: 37475559
DOI: 10.2174/1570159X21666230720122354 -
Case Reports in Psychiatry 2023Venlafaxine is an antidepressant belonging to the class of serotonin-norepinephrine reuptake inhibitors that are US Food and Drug Administration-approved to treat and...
Venlafaxine is an antidepressant belonging to the class of serotonin-norepinephrine reuptake inhibitors that are US Food and Drug Administration-approved to treat and manage symptoms of depression, anxiety, and other mood disorders in adults. We describe an adolescent patient who likely had a false-positive phencyclidine result detected with an 11-panel urine drug screen in an outpatient setting of long-term use of therapeutic venlafaxine extended release for the treatment of recurrent major depressive disorder and generalized anxiety disorder. We believe that this may be the first published case report to characterize this phenomenon in a young patient in the absence of an acute overdose.
PubMed: 37404674
DOI: 10.1155/2023/6666197 -
Brain Sciences May 2023Schizophrenia is a debilitating psychiatric disorder comprising positive, negative, and cognitive impairments. Most of the animal models developed to understand the... (Review)
Review
Investigating the Robustness of a Rodent "Double Hit" (Post-Weaning Social Isolation and NMDA Receptor Antagonist) Model as an Animal Model for Schizophrenia: A Systematic Review.
Schizophrenia is a debilitating psychiatric disorder comprising positive, negative, and cognitive impairments. Most of the animal models developed to understand the neurobiology and mechanism of schizophrenia do not produce all the symptoms of the disease. Therefore, researchers need to develop new animal models with greater translational reliability, and the ability to produce most if not all symptoms of schizophrenia. This review aimed to evaluate the effectiveness of the rodent "double hit" (post-weaning social isolation and N-methyl-D-aspartate (NMDA) receptor antagonist) model to produce symptoms of schizophrenia. This systematic review was developed according to the 2020 PRISMA guidelines and checklist. The MEDLINE (PubMed) and Ebscohost databases were used to search for studies. The systematic review is based on quantitative animal studies. Studies in languages other than English that could be translated sufficiently using Google translate were also included. Data extraction was performed individually by two independent reviewers and discrepancies between them were resolved by a third reviewer. SYRCLE's risk-of-bias tool was used to test the quality and biases of included studies. Our primary search yielded a total of 47 articles, through different study selection processes. Seventeen articles met the inclusion criteria for this systematic review. Ten of the seventeen studies found that the "double hit" model was more effective in developing various symptoms of schizophrenia. Most studies showed that the "double hit" model is robust and capable of inducing cognitive impairments and positive symptoms of schizophrenia.
PubMed: 37371328
DOI: 10.3390/brainsci13060848 -
Cureus May 2023Recreational drug use is a significant public health concern in various countries. It is well understood that usage of psychedelics/hallucinogens, such as lysergic acid...
Recreational drug use is a significant public health concern in various countries. It is well understood that usage of psychedelics/hallucinogens, such as lysergic acid diethylamide (LSD), ecstasy, phencyclidine (PCP), and psilocybin-containing mushrooms, has increased significantly over the last few decades, particularly in adolescents and young adults, yet the effects of these recreational drugs are poorly understood. Psilocybin has recently been studied as an alternative to traditional antidepressant therapies with potentially benign side effects. Here, we present the case of a 48-year-old male with a past medical history of attention-deficit/hyperactivity disorder on lisdexamfetamine who presented after a syncopal episode witnessed by his wife at home. He was found to be in ventricular fibrillation and subsequently had an extensive workup with cardiac magnetic resonance imaging (MRI), ischemic evaluation, and electrophysiology, which were unrevealing. He then received an automatic implantable cardiac defibrillator and was incidentally found to have hereditary hemochromatosis on outpatient follow-up. His polypharmacy may have potentially led to catecholamine release, leading to ventricular arrhythmia.
PubMed: 37288212
DOI: 10.7759/cureus.38669 -
Frontiers in Cellular Neuroscience 2023N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist...
N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.
PubMed: 37066076
DOI: 10.3389/fncel.2023.1152248