Subtle Alterations in Glutamatergic Synapses Underlie the Aging-Related Decline in Hippocampal Function
David R. Riddle in Brain Aging, 2007
The hippocampal levels of NMDA/AMPA receptors also have been correlated directly with cognitive performance, particularly on spatial learning and memory tasks [88, 107]. For example, experimental reduction of NMDA or AMPA receptors or of their specific subunits using transgenic rodent models has resulted in deficits in spatial learning and memory [63, 64, 78, 88, 108–110]. Similarly, spatial learning and memory were impaired by administration of NMDA receptor antagonists [111–113]. Moreover, in aged animals with impaired MWM performance, both decreased levels of NMDA and AMPA receptor subunits and impaired synaptic transmission via those receptors have been reported [88, 89, 91, 96, 97]. Finally, even in the absence of a global aging-related decrease in hippocampal glutamate receptors, glutamate receptor subunits levels are correlated with cognitive performance. For example, although neither Western blot analysis nor confocal immunocy-tochemistry revealed an overall or region-specific difference in hippocampal NR1 levels between young and aged animals [107], individual spatial learning performance correlated with NR1 immunofluorescence levels in hippocampal CA3 neurons. These findings suggest that dendritic NR1 is generally preserved in the hippocampus of aged rats but the levels of this receptor subunit in selective elements of hippocampal circuitry are linked to spatial learning.
Nonopiate Analgesics and Adjuvants
Gary W. Jay in Practical Guide to Chronic Pain Syndromes, 2016
Other possible forms of adjunctive medications include NMDA receptor antagonists. There are no NMDA receptor antagonists approved for the treatment of pain; Memantine is approved for treatment of Alzheimer's disease. The NMDA receptor antagonists include ketamine, dextromethorphan, amantadine, magnesium, and methadone, an opiate which is considered to have a 10% NMDA receptor antagonism. These medications may, in the future, be very beneficial; particularly antagonists at the glycine-site NR2B sites, at which weak-binding channel blockers have shown an improved side effect profile in animal models of pain (33). Ketamine is used as an adjunctive therapy in the hospice setting when opioid therapy is not sufficient (34). Ketamine alone, or with midazolam, have long been used for sedating children undergoing minor operative procedures or painful procedures such as changing dressings for burn patients (35, 36).
Nonopiate Analgesics and Adjuvants
Gary W. Jay in Clinician’s Guide to Chronic Headache and Facial Pain, 2016
Other possible forms of adjunctive medications include NMDA receptor antagonists. There are no NMDA receptor antagonists approved for the treatment of pain; Memantine is approved for treatment of Alzheimer’s disease. The NMDA receptor antagonists include ketamine, dextromethorphan, amantadine, magnesium, and methadone, an opiate which is considered to have a 10% NMDA receptor antagonism. These medications may, in the future, be very beneficial; particularly antagonists at the glycine-site NR2B sites, at which weak-binding channel blockers have shown an improved side effect profile in animal models of pain (33). Ketamine is used as an adjunctive therapy in the hospice setting when opioid therapy is not sufficient (34). Ketamine alone, or with midazolam, have long been used for sedating children undergoing minor operative procedures or painful procedures such as changing dressings for burn patients (35, 36).
Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status
Published in Expert Opinion on Therapeutic Targets, 2019
Roberta Celli, Ines Santolini, Gilles Van Luijtelaar, Richard T Ngomba, Valeria Bruno, Ferdinando Nicoletti
Although glutamate is a main player of over-excitation in epilepsy, glutamate receptor antagonists were not successfully developed as antiepileptic drugs, with the notable exception of perampanel. One of the reasons is that iGlu receptor antagonists are not disease-dependent and cause a widespread inhibition of excitatory synaptic transmission in the CNS. In addition, NMDA receptor antagonists impair mechanisms of activity-dependent synaptic plasticity and may cause psychotomimetic effects. Targeting mGlu receptors with subtype-selective ligands (particularly, PAMs and NAMs) might offer a more favorable outcome in the treatment of epilepsy because mGlu receptors do not mediate, but rather modulate, synaptic transmission. Using these drugs, we expect a greater selectivity for overexcited neuronal networks (for example, the action of PAMs is activity-dependent), and a better profile of safety and tolerability.
A-582941, cholinergic alpha 7 nicotinic receptor agonist, improved cognitive and negative symptoms of the sub-chronic MK-801 model of schizophrenia in rats
Published in Psychiatry and Clinical Psychopharmacology, 2018
Gokhan Unal, Feyza Aricioglu
Visual learning and memory deficits are one of the main cognitive dysfunctions in schizophrenic patients. To research the cognitive dysfunction of schizophrenia, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Unit for Research on Neurocognition and Schizophrenia (TURNS) initiatives recommend NORT as a translational preclinical paradigm to investigate procognitive effect of different therapeutics [24]. NORT is a cognitive test which evaluates non-spatial visual episodic memory and is based on the spontaneous exploratory behaviour of rodents. It has been thought that perirhinal cortex and hippocampus are involved in visual recognition memory in both rodents and human [24]. It has been well confirmed that acute and chronic administration of the glutamatergic NMDA receptor antagonists impaired the recognition memory in rodents. This cognitive deficit induced by NMDA receptor antagonists reversed by second-generation antipsychotics but not first-generation antipsychotics [30]. In many studies, it was reported that NAChR agonists have a cognitive enhancer effect in not only the schizophrenia model but also in the Alzheimer model or without any model of rodents. Potasiewicz and colleagues indicated that A-582941 had procognitive activity at recognition memory on natural forgetting of rats [31], while another study demonstrated that A-582941 ameliorated ketamine-induced cognitive dysfunction in NORT in rats [32]. In our study, it was shown that A-582941 and Clozapine enhanced MK-801-induced recognition memory deficit in rats.
The neurochemistry of hypnotic suggestion
Published in American Journal of Clinical Hypnosis, 2021
David J. Acunzo, David A. Oakley, Devin B. Terhune
The various neurochemical agents reviewed here have been shown to have complex effects and this complicates our understanding of the precise neurochemical loci of observed changes in suggestibility. Classic psychedelics have downstream effects on glutamate (De Gregorio, Enns, Nuñez, Posa, & Gobbi, 2018) that somewhat mirror the effects of NMDA receptor antagonists. In addition, research in non-human animals suggests biphasic neurochemical effects of LSD such that it acts as a dopamine agonist at a late phase (Marona-Lewicka, Thisted, & Nichols, 2005). There is also evidence that NMDA receptor antagonists increase synaptic activity in GABAergic neurons and trigger striatal dopamine release (Gupta, Emmanouil, & Sethi, 2020). The glutamate and GABA results could potentially be reconciled by recourse to the notion of excitation–inhibition balance (Cavanagh, Lam, Murray, Hunt, & Kennerley, 2020) such that brain states characterized by a relative lower excitation–inhibition balance may be conducive to hypnotic responding. By contrast, benzodiazepines, which seem to enhance suggestibility, also reduce 5-HT neurotransmission (Nutt & Cowen, 1987) and dissociative states (Gitlin et al., 2020). This suggests potential points of conflict between the effects of these agents, independent pathways, or complex interactions for suggestibility enhancement. A similar limitation applies to the anatomical specificity of these effects: to our knowledge, only one study has identified neurochemical-suggestibility associations in a particular brain region (DeSouza et al., 2020), albeit without a control site.
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