Glutamate activates the NMDARs, significantly affecting multiple processes such as learning, memory, synaptic integration, and excitatory transmission in the central nervous system. Uncontrolled activation of NMDARs is a significant contributor to synaptic dysfunction. Having a properly functioning NMDAR and synapse is crucial for maintaining neuronal communication. In addition, the dysfunction of NMDAR and synapse function could contribute to the development of neurological disorders at the neuronal level; hence, targeting NMDARs with antagonists in the fight against neurological disorders is a promising route. Recently published results from the animal study on different kinds of brain diseases like stroke, epilepsy, tinnitus, ataxia, Alzheimer\'s disease, Parkinson\'s disease, and spinal cord injury have demonstrated promising therapeutic scopes. Several NMDA receptor antagonists, such as memantine, MK801, ketamine, ifenprodil, gacyclidine, amantadine, agmatine, etc., showed encouraging results against different brain disease mouse models. Given the unique expression of different subunits of the well-organized NMDA receptor system by neurons. It could potentially lead to the development of medications specifically targeting certain receptor subtypes. For a future researcher, conducting more targeted research and trials is crucial to fully understand and develop highly specific medications with good clinical effects and potential neuroprotective properties.

Ketamine is an NMDA (N-methyl-d-aspartate) glutamate receptor antagonist, which has a myriad of dose-dependent pharmacological and behavioral effects, including anesthetic, sedative, amnestic, analgesic, and anti-inflammatory properties. Intriguingly, ketamine at subanesthetic doses displays a relevant profile both in mimicking symptoms of schizophrenia and also as the first fast-acting treatment for depression. Here, we present an overview of the state-of-the-art knowledge about ketamine as an antidepressant as well as a pharmacological model of schizophrenia in animal models and human participants. Ketamine\'s dual effect appears to arise from its mechanism of action involving NMDA receptors, with both immediate and downstream consequences being triggered as a result. Finally, we discuss the feasibility of a unified approach linking the glutamatergic hypothesis of schizophrenia to the promising preclinical and clinical success of ketamine in the treatment of refractory depression.

Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the in vivo firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer\'s disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.

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Recent studies have shown that the 5-HT1a receptor (5-HT1aR) in the central 5-HT (Serotonergic) system is involved in the pathophysiology of schizophrenia through its various receptors, and the dysfunction of the ventral hippocampus may be a key causative factor in schizophrenia. To date, whether the 5-HT1a receptor is involved in ventral hippocampal dysfunction and its internal mechanism remain unclear. In this study, schizophrenia-like animal model was induced by intraperitoneal injection of aspartate receptor antagonist MK-801 in male Sprague Dawley rats, and the role of 5-HT1aR in this animal model was investigated by bilaterally micro-infusing the 5-HT1aR antagonist WAY100635 into the ventral subiculum (vSub) of the hippocampus of rats. Behavioral experiments such as open field test (OFT) and prepulse inhibition (PPI) were performed. The results showed that MK-801 induced hyperactivity and impaired prepulse inhibition in rats, whereas, micro-infusion of 5-HT1aR antagonist WAY100635 into the vSub ameliorated these phenomena. Immunofluorescence analysis revealed that WAY100635 significantly increased the c-Fos expression in vSub. Western blot and immunohistochemical analysis showed that MK-801 induced up-regulation of 5-HT1aR and phospho-extracellular regulated protein kinase (p-ERK) pathway, while micro-infusion of the WAY100635 down-regulated 5-HT1aR and p-ERK in the vSub. Therefore, the results of the present study suggested that in vSub, the 5-HT1aR antagonist WAY100635 may attenuate MK-801-induced schizophrenia-like activity by modulating excitatory neurons and downregulating p-ERK.

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.

Auditory neural networks in the brain naturally entrain to rhythmic stimuli. Such synchronization is an accessible index of local network performance as captured by EEG. Across species, click trains delivered ∼ 40 Hz show strong entrainment with primary auditory cortex (Actx) being a principal source. Imaging studies have revealed additional cortical sources, but it is unclear if they are functionally distinct. Since auditory processing evolves hierarchically, we hypothesized that local synchrony would differ between between primary and association cortices. In female SD rats (N = 12), we recorded 40 Hz click train-elicited gamma oscillations using epidural electrodes situated at two distinct sites; one above the prefrontal cortex (PFC) and another above the Actx, after dosing with saline (1 ml/kg, sc) or the NMDA antagonist, MK801 (0.025, 0.05 or 0.1 mpk), in a blocked crossover design. Post-saline, both regions showed a strong 40 Hz auditory steady state response (ASSR). The latencies for the N1 response were ∼ 16 ms (Actx) and ∼ 34 ms (PFC). Narrow band (38-42 Hz) gamma oscillations appeared rapidly (<40 ms from stim onset at Actx but in a more delayed fashion (∼200 ms) at PFC. MK801 augmented gamma synchrony at Actx while dose-dependently disrupting at the PFC. Event-related gamma (but not beta) coherence, an index of long-distance connectivity, was disrupted by MK801. In conclusion, local network gamma synchrony in a higher order association cortex performs differently from that of the primary auditory cortex. We discuss these findings in the context of evolving sound processing across the cortical hierarchy.

Neuroimaging studies have identified the anterior cingulate cortex (ACC) as one of the major targets of ketamine in the human brain, which may be related to ketamine\'s antidepressant (AD) mechanisms of action. However, due to different methodological approaches, different investigated populations, and varying measurement timepoints, results are not consistent, and the functional significance of the observed brain changes remains a matter of open debate. Inhibition of glutamate release during acute ketamine administration by lamotrigine provides the opportunity to gain additional insight into the functional significance of ketamine-induced brain changes. Furthermore, the assessment of trait negative emotionality holds promise to link findings in healthy participants to potential AD mechanisms of ketamine. In this double-blind, placebo-controlled, randomized, single dose, parallel-group study, we collected resting-state fMRI data before, during, and 24 h after ketamine administration in a sample of 75 healthy male and female participants who were randomly allocated to one of three treatment conditions (ketamine, ketamine with lamotrigine pre- treatment, placebo). Spontaneous brain activity was extracted from two ventral and one dorsal subregions of the ACC. Our results showed activity decreases during the administration of ketamine in all three ACC subregions. However, only in the ventral subregions of the ACC this effect was attenuated by lamotrigine. 24 h after administration, ACC activity returned to baseline levels, but group differences were observed between the lamotrigine and the ketamine group. Trait negative emotionality was closely linked to activity changes in the subgenual ACC after ketamine administration. These results contribute to an understanding of the functional significance of ketamine effects in different subregions of the ACC by combining an approach to modulate glutamate release with the assessment of multiple timepoints and associations with trait negative emotionality in healthy participants.

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Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.