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1
Sheng, Hui, Yanmin Zhang, Jihu Sun, Lu Gao, Bei Ma, Jianqiang Lu, and Xin Ni. "Corticotropin-Releasing Hormone (CRH) Depresses N-Methyl-d-Aspartate Receptor-Mediated Current in Cultured Rat Hippocampal Neurons via CRH Receptor Type 1." Endocrinology 149, no. 3 (December 13, 2007): 1389–98. http://dx.doi.org/10.1210/en.2007-1378.
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CRH, the primary regulator of the neuroendocrine responses to stress, has been shown to modulate synaptic efficacy and the process of learning and memory in hippocampus. However, effects of CRH on N-methyl-d-aspartate (NMDA) receptor, the key receptor for synaptic plasticity, remain unclear. In primary cultured hippocampal neurons, using the technique of whole-cell patch-clamp recordings, we found that CRH (1 pmol/liter to 10 nmol/liter) inhibited NMDA-induced currents in a dose-dependent manner. This effect was reversed by the CRH receptor type 1 (CRHR1) antagonist antalarmin but not by the CRHR2 antagonist astressin-2B, suggesting that CRHR1 mediated the inhibitory effect of CRH. Investigations on the signaling pathways of CRH showed that CRH dose-dependently induced phosphorylated phospholipase C (PLC)-β3 expression and increased intracellular cAMP content in these cells. Blocking PLC activity with U73122 prevented CRH-induced depression of NMDA current, whereas blocking protein kinase A (H89) and adenylate cyclase (SQ22536) failed to affect the CRH-induced depression of NMDA current. Application of inositol-1,4,5-triphosphate receptor (IP3R) antagonist, Ca2+ chelators or protein kinase C (PKC) inhibitors also mainly blocked CRH-induced depression of NMDA currents, suggesting involvement of PLC/IP3R/Ca2+and PLC/PKC signaling pathways in CRH down-regulation of NMDA receptors. Our results suggest that CRH may exert neuromodulatory actions on hippocampus through regulating NMDA receptor function.
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De Bundel, Dimitri, Teresa Femenía, Caitlin M. DuPont, Åsa Konradsson-Geuken, Kritin Feltmann, Björn Schilström, and Maria Lindskog. "Hippocampal and prefrontal dopamine D1/5 receptor involvement in the memory-enhancing effect of reboxetine." International Journal of Neuropsychopharmacology 16, no. 9 (October 1, 2013): 2041–51. http://dx.doi.org/10.1017/s1461145713000370.
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Abstract Dopamine modulates cognitive functions through regulation of synaptic transmission and plasticity in the hippocampus and prefrontal cortex (PFC). Thus, dopamine dysfunction in depression may be particularly relevant for the cognitive symptoms. The norepinephrine transporter inhibitor reboxetine facilitates memory processing in both healthy volunteers and in depressed patients and increases dopamine release in both the hippocampus and PFC. We investigated the potential involvement of the hippocampal and PFC dopamine D1/5 receptors in the cognitive effects of reboxetine using the object recognition test in rats. Infusion of the D1/5 antagonist SCH23390 into the dorsal hippocampus or medial PFC prior to the exploration of the objects impaired memory. Conversely, infusion of the D1/5 agonist SKF81297 into the dorsal hippocampus or medial PFC facilitated memory. Reboxetine similarly facilitated recognition memory in healthy rats and the D1/5 antagonist SCH23390 reversed this effect when infused into the dorsal PFC, but not when infused into the hippocampus. Moreover, systemic reboxetine increased the levels of the NMDA subunit GluN2A in the PFC but not in the hippocampus. Finally, we demonstrate that a single dose of reboxetine does not affect immobility in the forced swim test but improves recognition memory in the Flinders sensitive line (FSL) rat model for depression. The present data in rats are in line with effects of reboxetine on memory formation in healthy volunteers and depressed patients and indicate the involvement of PFC dopamine D1/5 receptors.
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Sokolenko, Elysia, Matthew R. Hudson, Jess Nithianantharajah, and Nigel C. Jones. "The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice." Journal of Psychopharmacology 33, no. 12 (October 3, 2019): 1588–99. http://dx.doi.org/10.1177/0269881119875976.
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Background: Abnormalities in neural oscillations that occur in the gamma frequency range (30–80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists. Aims: We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR2/3) agonist LY379268. Methods: C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus. Results: MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130–180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment. Conclusions: NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR2/3. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.
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Bernabeu, Ramon, and Frank R. Sharp. "NMDA and AMPA/Kainate Glutamate Receptors Modulate Dentate Neurogenesis and CA3 Synapsin-I in Normal and Ischemic Hippocampus." Journal of Cerebral Blood Flow & Metabolism 20, no. 12 (December 2000): 1669–80. http://dx.doi.org/10.1097/00004647-200012000-00006.
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The effect of N-methyl-d-aspartate (NMDA) and 2-(aminomethyl)phenylacetic acid/kainate (AMPA/kainate) glutamate receptors on dentate cell proliferation and hippocampal synapsin-I induction was examined after global ischemia. Cell proliferation was assessed using BrdU labeling, and synaptic responses were assessed using synapsin-I expression, Systemic glutamate receptor antagonists (MK-801 and NBQX) increased BrdU-labeled cells in the dentate subgranular zone (SGZ) of control adult gerbils (30% to 90%, P < 0.05). After global ischemia (at 15 days after 10 minutes of ischemia), most CA1 pyramidal neurons died, whereas the numbers of BrdU-labeled cells in the SGZ increased dramatically (>1000%, P < 0,0001). Systemic injections of MK801 or NBQX, as well as intrahippocampal injections of either drug, when given at the time of ischemia completely blocked the birth of cells in the SGZ and the death of CA1 pyramidal neurons at 15 days after ischemia. Glutamate receptor antagonists had little effect on cell birth and death when administered 7 days after ischemia. The induction of synapsin-I protein in stratum moleculare of CA3 at 7 and 15 days after global ischemia was blocked by pretreatment with systemic or intrahippocampal MK-801 or NBQX. It is proposed that decreased dentate glutamate receptor activation—produced by glutamate receptor antagonists in normal animals and by chronic ischemic hippocampal injury—may trigger dentate neurogenesis and synaptogenesis. The synapsin-I induction in mossy fiber terminals most likely represents re-modeling of dentate granule cell neuron presynaptic elements in CA3 in response to the ischemia. The dentate neurogenesis and synaptogenesis that occur after ischemia may contribute to memory recovery after hippocampal injury caused by global ischemia.
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Cammarota, Martín, Daniela M. Barros, Mónica R. M. Vianna, Lia R. M. Bevilaqua, Adriana Coitinho, Germán Szapiro, Luciana A. Izquierdo, Jorge H. Medina, and Iván Izquierdo. "The transition from memory retrieval to extinction." Anais da Academia Brasileira de Ciências 76, no. 3 (September 2004): 573–82. http://dx.doi.org/10.1590/s0001-37652004000300011.
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Memory is measured by measuring retrieval. Retrieval is often triggered by the conditioned stimulus (CS); however, as known since Pavlov, presentation of the CS alone generates extinction. One-trial avoidance (IA) is a much used conditioned fear paradigm in which the CS is the safe part of a training apparatus, the unconditioned stimulus (US) is a footshock and the conditioned response is to stay in the safe area. In IA, retrieval is measured without the US, as latency to step-down from the safe area (i.e., a platform). Extinction is installed at the moment of the first unreinforced test session, as clearly shown by the fact that many drugs, including PKA, ERK and protein synthesis inhibitors as well as NMDA receptor antagonists, hinder extinction when infused into the hippocampus or the basolateral amygdala at the moment of the first test session but not later. Some, but not all the molecular systems required for extinction are also activated by retrieval, further endorsing the hypothesis that although retrieval is behaviorally and biochemically necessary for the generation of extinction, this last process constitutes a new learning secondary to the unreinforced expression of the original trace.
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Morris, R. G. M., and U. Frey. "Hippocampal synaptic plasticity: role in spatial learning or the automatic recording of attended experience?" Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 352, no. 1360 (October 29, 1997): 1489–503. http://dx.doi.org/10.1098/rstb.1997.0136.
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Allocentric spatial learning can sometimes occur in one trial. The incorporation of information into a spatial representation may, therefore, obey a one–trial correlational learning rule rather than a multi–trial error–correcting rule. It has been suggested that physiological implementation of such a rule could be mediated by N –methyl–D–aspartate (NMDA) receptor–dependent long–term potentiation (LTP) in the hippocampus, as its induction obeys a correlational type of synaptic learning rule. Support for this idea came originally from the finding that intracerebral infusion of the NMDA antagonist AP5 impairs spatial learning, but studies summarized in the first part of this paper have called it into question. First, rats previously given experience of spatial learning in a watermaze can learn a new spatial reference memory task at a normal rate despite an appreciable NMDA receptor blockade. Second, the classical phenomenon of ‘blocking’ occurs in spatial learning. The latter finding implies that spatial learning can also be sensitive to an animal's expectations about reward and so depend on more than the detection of simple spatial correlations. In this paper a new hypothesis is proposed about the function of hippocampal LTP. This hypothesis retains the idea that LTP subserves rapid one–trial memory, but abandons the notion that it serves any specific role in the geometric aspects of spatial learning. It is suggested that LTP participates in the ‘automatic recording of attended experience’: a subsystem of episodic memory in which events are temporarily remembered in association with the contexts in which they occur. An automatic correlational form of synaptic plasticity is ideally suited to the online registration of context–event associations. In support, it is reported that the ability of rats to remember the most recent place they have visited in a familiar environment is exquisitely sensitive to AP5 in a delay–dependent manner. Moreover, new studies of the lasting persistence of NMDA–dependent LTP, known to require protein synthesis, point to intracellular mechanisms that enable transient synaptic changes to be stabilized if they occur in close temporal proximity to important events. This new property of hippocampal LTP is a desirable characteristic of an event memory system.
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Liu, Zhuguo, Zheng Yu, Shuo Yu, Cui Zhu, Mingxin Dong, Wenxiang Mao, Jie Hu, Mary Prorok, Ruibin Su, and Qiuyun Dai. "A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects." Marine Drugs 19, no. 1 (January 19, 2021): 44. http://dx.doi.org/10.3390/md19010044.
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N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.
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Yu, Tzu-Ping, and Cui-Wei Xie. "Orphanin FQ/Nociceptin Inhibits Synaptic Transmission and Long-Term Potentiation in Rat Dentate Gyrus Through Postsynaptic Mechanisms." Journal of Neurophysiology 80, no. 3 (September 1, 1998): 1277–84. http://dx.doi.org/10.1152/jn.1998.80.3.1277.
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Yu, Tzu-Ping and Cui-Wei Xie. Orphanin FQ/nociceptin inhibits synaptic transmission and long-term potentiation in the rat dentate gyrus through postsynaptic mechanisms. J. Neurophysiol. 80: 1277–1284, 1998. Orphanin FQ/nociceptin (OFQ), a recently characterized natural ligand for the opioid receptor-like 1 (ORL1) receptor, shares structural similarity to the endogenous opioids. Our previous study found that OFQ, like classical opioids, modulated synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region, suggesting a modulatory role for OFQ in synaptic plasticity involved in learning and memory. In the present study we investigated the action of OFQ in the dentate gyrus and explored possible underlying cellular mechanisms. Field potential recordings showed that OFQ significantly inhibited excitatory synaptic transmission and LTP induction in the dentate lateral perforant path. In the presence of OFQ, the excitatory postsynaptic potential (EPSP) slope-population spike (E-S) curve was shifted to the right, and no significant change was found in paired-pulse facilitation, suggesting a postsynaptic mechanism responsible for the inhibition of synaptic transmission. Under whole cell voltage-clamp conditions, bath application of OFQ activated K+ currents in most granule cells tested at a holding potential of −50 mV, suggesting that OFQ could reduce the excitability of dentate granule cells by hyperpolarizing cell membranes. OFQ also inhibited the amplitude of N-methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic currents (EPSCs) without affecting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–mediated EPSCs. This inhibition was not blocked by opioid receptor antagonists. Furthermore, the inward currents evoked by focal application of NMDA to granule cells were suppressed by OFQ in a dose-dependent manner, suggesting that OFQ may suppress LTP by inhibiting the function of postsynaptic NMDA receptors. These results demonstrate that OFQ may negatively modulate synaptic transmission and plasticity in the dentate gyrus through postsynaptic mechanisms, including hyperpolarization of granule cells as well as inhibition of the function of postsynaptic NMDA receptors/channels in dentate granule cells.
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Mannara, Francesco, Marija Radosevic, Jesús Planagumà, David Soto, Esther Aguilar, Anna García-Serra, Estibaliz Maudes, et al. "Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis." Brain 143, no. 9 (August 24, 2020): 2709–20. http://dx.doi.org/10.1093/brain/awaa195.
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Abstract Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients’ NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient’s CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients’ or controls’ CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient’s CSF antibodies, but not those infused with controls’ CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.
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Hao, Xuechao, Xianlin Zhu, Ping Li, Feng Lv, and Su Min. "NMDA receptor antagonist enhances antidepressant efficacy and alleviates learning-memory function impairment induced by electroconvulsive shock with regulating glutamate receptors expression in hippocampus." Journal of Affective Disorders 190 (January 2016): 819–27. http://dx.doi.org/10.1016/j.jad.2015.11.021.
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Wyart, Claire, Simona Cocco, Laurent Bourdieu, Jean-Francois Léger, Catherine Herr, and Didier Chatenay. "Dynamics of Excitatory Synaptic Components in Sustained Firing at Low Rates." Journal of Neurophysiology 93, no. 6 (June 2005): 3370–80. http://dx.doi.org/10.1152/jn.00530.2004.
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Sustained firing is necessary for the persistent activity associated with working memory. The relative contributions of the reverberation of excitation and of the temporal dynamics of the excitatory postsynaptic potential (EPSP) to the maintenance of activity are difficult to evaluate in classical preparations. We used simplified models of synchronous excitatory networks, hippocampal autapses and pairs, to study the synaptic mechanisms underlying firing at low rates. Calcium imaging and cell attached recordings showed that these neurons spontaneously fired bursts of action potentials that lasted for seconds over a wide range of frequencies. In 2-wk-old cells, the median firing frequency was low (11 ± 8.8 Hz), whereas in 3- to 4-wk-old cells, it decreased to a very low value (2 ± 1.3 Hz). In both cases, we have shown that the slowest synaptic component supported firing. In 2-wk-old autapses, antagonists of N-methyl-d-aspartate receptors (NMDARs) induced rare isolated spikes showing that the NMDA component of the EPSP was essential for bursts at low frequency. In 3- to 4-wk-old neurons, the very low frequency firing was maintained without the NMDAR activation. However EGTA-AM or α-methyl-4-carboxyphenylglycine (MCPG) removed the very slow depolarizing component of the EPSP and prevented the sustained firing at very low rate. A metabotropic glutamate receptor (mGluR)-activated calcium sensitive conductance is therefore responsible for a very slow synaptic component associated with firing at very low rate. In addition, our observations suggested that the asynchronous release of glutamate might participate also in the recurring bursting.
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Sarker, Gitalee, and Daria Peleg-Raibstein. "Maternal Overnutrition Induces Long-Term Cognitive Deficits across Several Generations." Nutrients 11, no. 1 (December 20, 2018): 7. http://dx.doi.org/10.3390/nu11010007.
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Ample evidence from epidemiological studies has linked maternal obesity with metabolic disorders such as obesity, cardiovascular disease, and diabetes in the next generation. Recently, it was also shown that maternal obesity has long-term effects on the progeny’s central nervous system. However, very little is known regarding how maternal overnutrition may affect, in particular, the cognitive abilities of the offspring. We reported that first-generation offspring exposed to a maternal high-fat diet (MHFD) displayed age-dependent cognitive deficits. These deficits were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions of MHFD offspring. Here, we tested the hypothesis that MHFD in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the second and third generations. We found that MHFD led to cognitive disabilities and an altered response to a noncompetitive receptor antagonist of the N-Methyl-D-aspartic acid (NMDA) receptor in adult MHFD offspring in both second and third generations in a sex-specific manner. Our results suggest that maternal overnutrition leads to an increased risk of developing obesity in subsequent generations as well as to cognitive impairments, affecting learning and memory processes in adulthood. Furthermore, MHFD exposure may facilitate pathological brain aging which is not a consequence of obesity. Our findings shed light on the long-term effects of maternal overnutrition on the development of the central nervous system and the underlying mechanisms which these traits relate to disease predisposition.
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Terman, Gregory W., Clifford L. Eastman, and Charles Chavkin. "Mu Opiates Inhibit Long-Term Potentiation Induction in the Spinal Cord Slice." Journal of Neurophysiology 85, no. 2 (February 1, 2001): 485–94. http://dx.doi.org/10.1152/jn.2001.85.2.485.
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Long-term potentiation (LTP) involves a prolonged increase in neuronal excitability following repeated afferent input. This phenomenon has been extensively studied in the hippocampus as a model of learning and memory. Similar long-term increases in neuronal responses have been reported in the dorsal horn of the spinal cord following intense primary afferent stimulation. In these studies, we utilized the spinal cord slice preparation to examine effects of the potently antinociceptive mu opioids in modulating primary afferent/dorsal horn neurotransmission as well as LTP of such transmission. Transverse slices were made from the lumbar spinal cord of 10- to 17-day-old rats, placed in a recording chamber, and perfused with artificial cerebrospinal fluid also containing bicuculline (10 μM) and strychnine (1 μM). Primary afferent activation was achieved in the spinal slice by electrical stimulation of the dorsal root (DR) or the tract of Lissauer (LT) which is known to contain a high percentage of small diameter fibers likely to transmit nociception. Consistent with this anatomy, response latencies of LT-evoked field potentials in the dorsal horn were considerably slower than the response latencies of DR-evoked potentials. Only LT-evoked field potentials were found to be reliably inhibited by the mu opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly5] enkephalin-ol (DAMGO, 1 μM), although evoked potentials from both DR and LT were blocked by the AMPA/kainate glutamate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione. Moreover repeated stimulation of LT produced LTP of LT- but not DR-evoked potentials. In contrast, repeated stimulation of DR showed no reliable LTP. LTP of LT-evoked potentials depended on N-methyl-d-aspartate (NMDA) receptor activity, in that it was attenuated by the NMDA antagonist APV. Moreover, such LTP was inhibited by DAMGO interfering with LTP induction mechanisms. Finally, in whole cell voltage-clamp studies of Lamina I neurons, DAMGO inhibited excitatory postsynaptic current (EPSC) response amplitudes from LT stimulation-evoked excitatory amino acid release but not from glutamate puffed onto the cell and increased paired-pulse facilitation of EPSCs evoked by LT stimulation. These studies suggest that mu opioids exert their inhibitory effects presynaptically, likely through the inhibition of glutamate release from primary afferent terminals, and thereby inhibit the induction of LTP in the spinal dorsal horn.
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Jafari-Sabet, Majid, Hamed Mofidi, and Mohammad-Sadegh Attarian-Khosroshahi. "NMDA receptors in the dorsal hippocampal area are involved in tramadol state-dependent memory of passive avoidance learning in mice." Canadian Journal of Physiology and Pharmacology 96, no. 1 (January 2018): 45–50. http://dx.doi.org/10.1139/cjpp-2017-0228.
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The precise neurobiological mechanisms of tramadol abuse underlying the cognitive function are still unknown. The aim of the present study was to examine the possible effects of intra-CA1 injections of N-methyl-d-aspartate (NMDA), a glutamate NMDA receptor (NMDAR) agonist, and d,l-2-amino-5-phosphonopentanoic acid (DL-AP5), a competitive NMDAR antagonist, on tramadol state-dependent memory. A single-trial step-down passive avoidance task was used for the assessment of memory retrieval in adult male NMRI mice. Post-training i.p. administration of an atypical μ-opioid receptor agonist, tramadol (2.5 and 5 mg/kg), dose-dependently induced impairment of memory retention. Pre-test injection of tramadol (2.5 and 5 mg/kg) induced state-dependent retrieval of the memory acquired under post-training administration of tramadol (5 mg/kg) influence. Pre-test intra-CA1 injection of NMDA (10−5 and 10−4 μg/mouse) 5 min before the administration of tramadol (5 mg/kg, i.p.) dose-dependently inhibited tramadol state-dependent memory. Pre-test intra-CA1 injection of DL-AP5 (0.25 and 0.5 μg/mouse) reversed the memory impairment induced by post-training administration of tramadol (5 mg/kg). Pre-test administration of DL-AP5 (0.25 and 0.5 μg/mouse) with an ineffective dose of tramadol (1.25 mg/kg) restored the retrieval and induced tramadol state-dependent memory. It can be concluded that dorsal hippocampal NMDAR mechanisms play an important role in the modulation of tramadol state-dependent memory.
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Vickery, R. M., Shanida H. Morris, and Lynn J. Bindman. "Metabotropic Glutamate Receptors Are Involved in Long-Term Potentiation in Isolated Slices of Rat Medial Frontal Cortex." Journal of Neurophysiology 78, no. 6 (December 1, 1997): 3039–46. http://dx.doi.org/10.1152/jn.1997.78.6.3039.
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Vickery, R. M., Shanida H. Morris, and Lynn J. Bindman. Metabotropic glutamate receptors are involved in long-term potentiation in isolated slices of rat medial frontal cortex. J. Neurophysiol. 78: 3039–3046, 1997. The prelimbic region of medial frontal cortex in the rat receives a direct input from the hippocampus and this functional connection is essential for aspects of spatial memory. Activity-dependent changes in the effectiveness of synaptic transmission in the medial frontal cortex, namely long-term potentiation (LTP) and long-term depression (LTD) can persist for tens of minutes or hours and may be the basis of learning and memory storage. Glutamatergic activation of ionotropic receptors is required to induce both LTP and LTD. We now present evidence of the involvement of metabotropic glutamate receptors in LTP in isolated slices of frontal cortex. Repetitive bursts of stimulation at theta frequencies (TBS) were applied to layer II, and monosynaptic EPSPs were monitored in layer V neurons of the prelimbic area. TBS was found to be more effective at inducing LTP than tetanic stimulation at 100 Hz and produced LTP that lasted >30 min in 8 out of 14 neurons. Tetanic stimulation at 100 Hz in the presence of the N-methyl-d-aspartate (NMDA)-antagonist 2-amino-5-phosphonopentanoate (AP5) was reported to be a reliable method of inducing LTD in prelimbic cortex ( Hirsch and Crépel 1991 ). However we found that this protocol did not facilitate the induction of LTD. The role of metabotropic glutamate receptors (mGluR) in LTP was assessed by using the selective, broad-spectrum antagonist (R, S)-α-methyl-4- carboxyphenylglycine (MCPG). This drug significantly reduced the incidence of LTP after TBS to only 1 of 14 neurons ( P < 0.02, χ2 test). The pooled responses to TBS in MCPG showed significantly reduced potentiation [( P < 0.02, analysis of variance (ANOVA)]. The broad-spectrum mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and the selective group I agonist S-3 hydroxyphenylglycine(S-3HPG) both produced membrane depolarization, an increase in number of spikes evoked by depolarizing current pulses, and a reduction in the afterhyperpolarization. Similar effects were produced by these agonists even when synaptic transmission was blocked by use of the γ-aminobutyric acid-B (GABAB) receptor agonist, 200 μM baclofen, which suggests that group I mGluRs are present on layer V neurons. We conclude that mGluRs participate in the production of LTP in prelimbic cortex, and that this excitatory effect could be mediated by the postsynaptic group I mGluRs.
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Ferragud, Antonio, Clara Velázquez-Sánchez, Ali Al Abdullatif, Valentina Sabino, and Pietro Cottone. "Withdrawal from Extended, Intermittent Access to A Highly Palatable Diet Impairs Hippocampal Memory Function and Neurogenesis: Effects of Memantine." Nutrients 12, no. 5 (May 23, 2020): 1520. http://dx.doi.org/10.3390/nu12051520.
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Background: Compulsive eating can be promoted by intermittent access to palatable food and is often accompanied by cognitive deficits and reduction in hippocampal plasticity. Here, we investigated the effects of intermittent access to palatable food on hippocampal function and neurogenesis. Methods: Male Wistar rats were either fed chow for 7 days/week (Chow/Chow group), or fed chow intermittently for 5 days/week followed by a palatable diet for 2 days/week (Chow/Palatable group). Hippocampal function and neurogenesis were assessed either during withdrawal or following renewed access to palatable food. Furthermore, the ability of the uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist memantine to prevent the diet-induced memory deficits and block the maladaptive feeding was tested. Results: Palatable food withdrawn Chow/Palatable rats showed both a weakened ability for contextual spatial processing and a bias in their preference for a “novel cue” over a “novel place,” compared to controls. They also showed reduced expression of immature neurons in the dentate gyrus of the hippocampus as well as a withdrawal-dependent decrease of proliferating cells. Memantine treatment was able both to reverse the memory deficits and to reduce the excessive intake of palatable diet and the withdrawal-induced hypophagia in food cycling rats. Conclusions: In summary, our results provide evidence that withdrawal from highly palatable food produces NMDAR-dependent deficits in hippocampal function and a reduction in hippocampal neurogenesis.
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Kourrich, Saı̈d, and C. Andrew Chapman. "NMDA Receptor-Dependent Long-Term Synaptic Depression in the Entorhinal Cortex In Vitro." Journal of Neurophysiology 89, no. 4 (April 1, 2003): 2112–19. http://dx.doi.org/10.1152/jn.00714.2002.
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The entorhinal cortex receives a large projection from the piriform (primary olfactory) cortex and, in turn, provides the hippocampal formation with most of its cortical sensory input. Synaptic plasticity in this pathway may therefore affect the processing of olfactory information and memory encoding. We have recently found that long-term synaptic depression (LTD) can be induced in this pathway in vivo by repetitive paired-pulse stimulation but not by low-frequency (1 Hz) stimulation with single pulses. Here, we have used field potential recordings to investigate the stimulation parameters and transmitter receptors required for the induction of LTD in the rat entorhinal cortex in vitro. The effectiveness of low-frequency stimulation (900 pulses at 1 or 5 Hz) and repeated delivery of pairs of stimulation pulses (30-ms interpulse interval) was assessed. Only repeated paired-pulse stimulation resulted in lasting LTD, and a low-intensity paired-pulse stimulation protocol that induces LTD in vivo was only effective in the presence of the GABAA receptor antagonist bicuculline (50 μM). LTD could also be induced in normal ACSF, however, by increasing the number of pulse-pairs delivered and by increasing the stimulation intensity during LTD induction. The induction of LTD was blocked by constant bath application of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2-amino-5-phosphonovalerate (50 μM), indicating that LTD is dependent on NMDA receptor activation. However, LTD was not blocked by the group I/II mGluR antagonist (RS)-α-ethyl-4-carboxyphenylglycine (500 μM) or by bicuculline (50 μM). The induction of LTD in the entorhinal cortex in vitro is therefore dependent on intense stimulation that recruits activation of NMDA receptors, but does not require concurrent activation of mGluRs or inhibitory synaptic inputs.
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Toda, Alyssa M. A., and Richard L. Huganir. "Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38." Proceedings of the National Academy of Sciences 112, no. 21 (May 11, 2015): 6712–17. http://dx.doi.org/10.1073/pnas.1507229112.
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Dynamic changes in synaptic strength are thought to be critical for higher brain function such as learning and memory. Alterations in synaptic strength can result from modulation of AMPA receptor (AMPAR) function and trafficking to synaptic sites. The phosphorylation state of AMPAR subunits is one mechanism by which cells regulate receptor function and trafficking. Receptor phosphorylation is in turn regulated by extracellular signals; these include neuronal activity, neuropeptides, and neuromodulators such as dopamine and norepinephrine (NE). Although numerous studies have reported that the neuropeptide pituitary adenylate cyclase activating polypeptide 38 (PACAP38) alters hippocampal CA1 synaptic strength and GluA1 synaptic localization, its effect on AMPAR phosphorylation state has not been explored. We determined that PACAP38 stimulation of hippocampal cultures increased phosphorylation of S845, and decreased phosphorylation of T840 on the GluA1 AMPAR subunit. Increases in GluA1 S845 phosphorylation primarily occurred via PAC1 and VPAC2 receptor activation, whereas a reduction in GluA1 T840 phosphorylation was largely driven by PAC1 receptor activation and to a lesser extent by VPAC1 and VPAC2 receptor activation. GluA1 S845 phosphorylation could be blocked by a PKA inhibitor, and GluA1 T840 dephosphorylation could be blocked by a protein phosphatase 1/2A (PP1/PP2A) inhibitor and was partly blocked by a NMDA receptor (NMDAR) antagonist. These results demonstrate that the neuropeptide PACAP38 inversely regulates the phosphorylation of two distinct sites on GluA1 and may play an important role modulating AMPAR function and synaptic plasticity in the brain.
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Ahnaou, Abdallah, Kobe Heleven, Ria Biermans, Nikolay V. Manyakov, and Wilhelmus H. Drinkenburg. "NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats." International Journal of Molecular Sciences 22, no. 16 (August 12, 2021): 8672. http://dx.doi.org/10.3390/ijms22168672.
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Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.
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Stazi, Martina, and Oliver Wirths. "Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease." Molecular Neurobiology 58, no. 1 (September 10, 2020): 204–16. http://dx.doi.org/10.1007/s12035-020-02120-z.
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AbstractMemantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer’s disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.
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Grover, Lawrence M., and Chen Yan. "Evidence for Involvement of Group II/III Metabotropic Glutamate Receptors in NMDA Receptor–Independent Long-Term Potentiation in Area CA1 of Rat Hippocampus." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 2956–69. http://dx.doi.org/10.1152/jn.1999.82.6.2956.
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Previous studies implicated metabotropic glutamate receptors (mGluRs) in N-methyl-d-aspartate (NMDA) receptor–independent long-term potentiation (LTP) in area CA1 of the rat hippocampus. To learn more about the specific roles played by mGluRs in NMDA receptor–independent LTP, we used whole cell recordings to load individual CA1 pyramidal neurons with a G-protein inhibitor [guanosine-5′-O-(2-thiodiphosphate), GDPβS]. Although loading postsynaptic CA1 pyramidal neurons with GDPβS significantly reduced G-protein dependent postsynaptic potentials, GDPβS failed to prevent NMDA receptor– independent LTP, suggesting that postsynaptic G-protein–dependent mGluRs are not required. We also performed a series of extracellular field potential experiments in which we applied group-selective mGluR antagonists. We had previously determined that paired-pulse facilitation (PPF) was decreased during the first 30–45 min of NMDA receptor–independent LTP. To determine if mGluRs might be involved in these PPF changes, we used a twin-pulse stimulation protocol to measure PPF in field potential experiments. NMDA receptor–independent LTP was prevented by a group II mGluR antagonist [(2S)-α-ethylglutamic acid] and a group III mGluR antagonist [(RS)-α-cyclopropyl-4-phosphonophenylglycine], but was not prevented by other group II and III mGluR antagonists [(RS)-α-methylserine-O-phosphate monophenyl ester or (RS)-α-methylserine-O-phosphate]. NMDA receptor–independent LTP was not prevented by either of the group I mGluR antagonists we examined, (RS)-1-aminoindan-1,5-dicarboxylic acid and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester. The PPF changes which accompany NMDA receptor–independent LTP were not prevented by any of the group-selective mGluR antagonists we examined, even when the LTP itself was blocked. Finally, we found that tetanic stimulation in the presence of group III mGluR antagonists lead to nonspecific potentiation in control (nontetanized) input pathways. Taken together, our results argue against the involvement of postsynaptic group I mGluRs in NMDA receptor–independent LTP. Group II and/or group III mGluRs are required, but the specific details of the roles played by these mGluRs in NMDA receptor–independent LTP are uncertain. Based on the pattern of results we obtained, we suggest that group II mGluRs are required for induction of NMDA receptor–independent LTP, and that group III mGluRs are involved in determining the input specificity of NMDA receptor–independent LTP by suppressing potentiation of nearby, nontetanized synapses.
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Simpson, Louise H., Howard V. Wheal, and Robert Williamson. "The contribution of non-NMDA and NMDA receptors to graded bursting activity in the CA1 region of the hippocampus in a chronic model of epilepsy." Canadian Journal of Physiology and Pharmacology 69, no. 7 (July 1, 1991): 1091–98. http://dx.doi.org/10.1139/y91-161.
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The selective excitatory amino acid receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonovalerate (D-APV), have been used to investigate the identity of the receptors involved in evoked epileptiform bursting activity in the chronic kainic acid lesioned hippocampus. Comparisons have been made with the acute bursting activity induced by bicuculline. Presented data suggest there are two possible mechanisms contributing to epileptiform bursting activity in the kainic acid lesioned hippocampus. One of these is probably a product of disinhibition, and generates a predominantly non-NMDA receptor mediated burst which is blocked by CNQX (2 μM). The second synaptic mechanism involves a major (or total) contribution by NMDA receptors to the epileptiform burst, and is blocked by D-APV (10 μM).Key words: hippocampus, CNQX, synapses, epileptiform, NMDA.
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Radenovic, Lidija, Vesna Selakovic, Branka Janac, and Dajana Todorovic. "Effect of glutamate antagonists on nitric oxide production in rat brain following intrahippocampal injection." Archives of Biological Sciences 59, no. 1 (2007): 29–36. http://dx.doi.org/10.2298/abs0701029r.
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Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. The involvement of ionotropic glutamate NMDA and AMPA/kainate receptors in induction of NO production in the rat brain was examined after injection of kainate, a non-NMDA receptor agonist; kainate plus 6-cyano- 7-nitroquinoxaline-2,3-dione (CNQX), a selective AMPA/kainate receptor antagonist; or kainate plus 2-amino-5-phosphonopentanoic acid (APV), a selective NMDA receptor antagonist. Competitive glutamate receptor antagonists were injected with kainate unilaterally into the CA3 region of the rat hippocampus. The accumulation of nitrite, the stable metabolite of NO, was measured by the Griess reaction at different times (5 min, 15 min, 2 h, 48 h, and 7 days) in hippocampus, forebrain cortex, striatum, and cerebellum homogenates. The used glutamate antagonists APV and CNQX both provided sufficient neuroprotection in the sense of reducing nitrite concentrations, but with different mechanisms and time dynamics. Our findings suggest that NMDA and AMPA/kainate receptors are differentially involved in nitric oxide production. <br><br><font color="red"><b> This article has been retracted. Link to the retraction <u><a href="http://dx.doi.org/10.2298/ABS150319031E">10.2298/ABS150319031E</a><u></b></font>
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Roberts, Michael, and Matthew Shapiro. "NMDA receptor antagonists impair memory for nonspatial, socially transmitted food preference." Behavioral Neuroscience 116, no. 6 (2002): 1059–69. http://dx.doi.org/10.1037/0735-7044.116.6.1059.
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Meltzer, Herbert Y., Lakshmi Rajagopal, Mei Huang, Yoshihiro Oyamada, Sunoh Kwon, and Masakuni Horiguchi. "Translating the N-methyl-d-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia." International Journal of Neuropsychopharmacology 16, no. 10 (November 1, 2013): 2181–94. http://dx.doi.org/10.1017/s1461145713000928.
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Abstract The N-methyl-d-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT1A, and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT1A partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5–10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.
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Kabir, Md Tanvir, Mohammad A. Sufian, Md Sahab Uddin, Mst Marium Begum, Shammi Akhter, Ariful Islam, Bijo Mathew, Md Siddiqul Islam, Md Shah Amran, and Ghulam Md. Ashraf. "NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy." Current Pharmaceutical Design 25, no. 33 (November 19, 2019): 3506–18. http://dx.doi.org/10.2174/1381612825666191011102444.
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: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes problems with memory, thinking, and behavior. Currently, there is no drug that can reduce the pathological events of this degenerative disease but symptomatic relief is possible that can abate the disease condition. N-methyl-D-aspartate (NMDA) receptors exert a critical role for synaptic plasticity as well as transmission. Overstimulation of glutamate receptors, predominantly NMDA type, may cause excitotoxic effects on neurons and is recommended as a mechanism for neurodegeneration. Atypical activation of the NMDA receptor has been suggested for AD by synaptic dysfunction. NMDA receptor antagonists especially memantine block the NMDA receptor and can reduce the influx of calcium (Ca2+) ions into neuron, thus, toxic intracellular events are not activated. This review represents the role of NMDA receptors antagonists as potential therapeutic agents to reduce AD. Moreover, this review highlights the repositioning of memantine as a potential novel therapeutic multitargeting agent for AD.
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Izumi, Yukitoshi, Hiroshi Katsuki, Ann M. Benz, and Charles F. Zorumski. "Oxygen Deprivation Produces Delayed Inhibition of Long-Term Potentiation by Activation of NMDA Receptors and Nitric Oxide Synthase." Journal of Cerebral Blood Flow & Metabolism 18, no. 1 (January 1998): 97–108. http://dx.doi.org/10.1097/00004647-199801000-00010.
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The acute and delayed effects of anoxia on synaptic transmission and long-term potentiation (LTP) were examined in the CA1 region of rat hippocampal slices. Oxygen deprivation for 20 minutes completely but reversibly depressed excitatory postsynaptic potentials mediated by both N-methyl-d-aspartate receptors (NMDAR) and non-NMDAR. Although LTP was reliably produced by a single tetanus delivered 30 minutes after reoxygenation, LTP could not be induced when a tetanus was delivered 70 to 100 minutes after reoxygenation. A tetanus delivered 100 minutes after reoxygenation produced lasting synaptic enhancement when 100 μmol/L d,l-amino-phosphonovaleric acid (APV), a competitive NMDAR antagonist, was administered during the period of oxygen deprivation. The delayed effects of oxygen deprivation were not blocked when APV was administered after oxygen deprivation. Similarly, the delayed effects on LTP induction were overcome by inhibitors of nitric oxide synthase when the nitric oxide synthase inhibitors were administered during anoxia, but not when administered after oxygen deprivation. These results suggest that untimely activation of NMDAR and nitric oxide release during anoxia produce delayed inhibition of LTP induction and may be involved in the memory defects that occur subsequent to cerebral hypoxia.
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Kishida, Kenneth T., Charles A. Hoeffer, Daoying Hu, Maryland Pao, Steven M. Holland, and Eric Klann. "Synaptic Plasticity Deficits and Mild Memory Impairments in Mouse Models of Chronic Granulomatous Disease." Molecular and Cellular Biology 26, no. 15 (August 1, 2006): 5908–20. http://dx.doi.org/10.1128/mcb.00269-06.
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ABSTRACT Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-d-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91 phox and p47 phox , both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91 phox and p47 phox mutant mice have mild impairments in hippocampus-dependent memory. The gp91 phox mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47 phox mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD.
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Warner, Michael A., Kenneth H. Neill, J. Victor Nadler, and Barbara J. Crain. "Regionally Selective Effects of NMDA Receptor Antagonists against Ischemic Brain Damage in the Gerbil." Journal of Cerebral Blood Flow & Metabolism 11, no. 4 (July 1991): 600–610. http://dx.doi.org/10.1038/jcbfm.1991.110.
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This study compared the ability of three N-methyl-D-aspartate (NMDA) receptor antagonists to prevent neuronal degeneration in an animal model of global cerebral ischemia. The model employed is characterized by damage to the striatum, hippocampus, and neocortex. Antagonists were administered to gerbils either before or after a 5-min bilateral carotid occlusion. The intraischemic rectal temperature was either maintained at 36–37°C or allowed to fall passively to 28–32°C. Antagonists and doses tested were 1 and 10 mg/kg of MK-801 (pre- or postischemia), 30 mg/kg of CGS 19755 preischemia, four 25 mg/kg doses of CGS 19755 administered between 0.5 and 6.5 h postischemia, and 40 mg/kg of MDL 27,266 (pre- or postischemia). All three NMDA receptor antagonists exhibited some degree of neuroprotective activity when the carotid occlusion was performed under normothermic conditions. Most of the treatments with antagonist markedly reduced striatal damage. CA1 hippocampal and neocortical pyramidal cells were spared by only three of the treatments, however, and the extent of neuroprotection varied widely from case to case. Toxic doses of antagonist were required to protect CA1 pyramidal cells from ischemic damage. Ischemic damage to hippocampal areas CA2–CA3a and CA4 appeared to be resistant to all of these treatments. Most CA1 pyramidal cells that were protected from degeneration by an NMDA receptor antagonist were histologically abnormal. The neuroprotective effects of MK-801 and intraischemic hypothermia appeared to be additive. MK-801 (10 mg/kg) consistently reduced the postischemic brain temperature, but only the magnitude of hypothermia produced soon after reperfusion correlated with its neuroprotective action. These results suggest that NMDA receptor antagonists are relatively poor neuroprotective agents against a moderately severe ischemic insult.
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Radenovic, Lidija, and Vesna Selakovic. "Mitochondrial superoxide production and MnSOD activity following exposure to an agonist and antagonists of ionotropic receptors in rat brain." Archives of Biological Sciences 57, no. 1 (2005): 1–10. http://dx.doi.org/10.2298/abs0501001r.
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The involvement of NMDA and AMPA/kainate receptors in the induction of superoxide production in the rat brain was examined after intrahippocampal injection of kainate, a non-NMDA receptor agonist; kainate plus CNQX, a selective AMPA/kainate receptor antagonist; or kainate plus APV, a selective NMDA receptor antagonist. The measurements took place at different times in the ipsi- and contralateral hippocampus, forebrain cortex, striatum, and cerebellum homogenates. The used glutamate antagonists both ensured sufficient neuroprotection in the sense of lowering superoxide production and raising MnSOD levels, but in the mechanisms and time dynamics of their effects were different. Our findings suggest that NMDA and AMPA/kainate receptors are differentially involved in superoxide production. <br><br><font color="red"><b> This article has been retracted. Link to the retraction <u><a href="http://dx.doi.org/10.2298/ABS150318026E">10.2298/ABS150318026E</a><u></b></font>
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Villarreal, Desiree M., Viet Do, Evelyn Haddad, and Brian E. Derrick. "NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay." Nature Neuroscience 5, no. 1 (December 10, 2001): 48–52. http://dx.doi.org/10.1038/nn776.
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Lord, Brian, Cindy Wintmolders, Xavier Langlois, Leslie Nguyen, Tim Lovenberg, and Pascal Bonaventure. "Comparison of the ex vivo receptor occupancy profile of ketamine to several NMDA receptor antagonists in mouse hippocampus." European Journal of Pharmacology 715, no. 1-3 (September 2013): 21–25. http://dx.doi.org/10.1016/j.ejphar.2013.06.028.
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Egorov, Alexei V., Tengis Gloveli, and Wolfgang Müller. "Muscarinic Control of Dendritic Excitability and Ca2+Signaling in CA1 Pyramidal Neurons in Rat Hippocampal Slice." Journal of Neurophysiology 82, no. 4 (October 1, 1999): 1909–15. http://dx.doi.org/10.1152/jn.1999.82.4.1909.
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The cholinergic system is critically involved in synaptic models of learning and memory by enhancing dendritic [Ca2+]i signals. Diffuse cholinergic innervation suggests subcellular modulation of membrane currents and Ca2+ signals. Here we use ion-selective microelectrodes to study spread of carbachol (CCh) after focal application into brain slice and subcellular muscarinic modulation of synaptic responses in CA1 pyramidal neurons. Proximal application of CCh rapidly blocked the somatic slow afterhyperpolarization (sAHP) following repetitive stimulation. In contrast, the time course of potentiation of the slow tetanic depolarization (STD) during synaptic input was slower and followed the time course of spread of CCh to the dendritic tree. With distal application, augmentation of the somatic STD and of dendritic Ca2+ responses followed spread of CCh to the entire apical dendritic tree, whereas the sAHP was blocked only after spread of CCh to the proximal dendritic segment. In dendritic recordings, CCh blocked a small sAHP, augmented the STD, and rather reduced dendritic action potentials. Augmentation of dendritic Ca2+ signals was highly correlated to augmentation of the STD. The NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV) blocked ∼55% of the STD in control and during CCh application. In conclusion, muscarinic suppression of the proximal sAHP can augment firing and thereby Ca2+ responses. Dendritic augmentation of the STD by blockade of the sAHP and direct enhancement of N-methyl-d-aspartate (NMDA) receptor–mediated currents potentiates Ca2+ signals even when firing is not affected due to suprathreshold input. In this way, subcellular muscarinic modulation may contribute to parallel information processing and storage by dendritic synapses of CA1 pyramidal neurons.
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Zhang, Danshen, Leiming Ren, and Li Zhang. "P3-297 Both adenosine A1 receptor and NMDA receptor co-regulated learning and memory in hippocampus." Neurobiology of Aging 25 (July 2004): S439. http://dx.doi.org/10.1016/s0197-4580(04)81447-7.
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Kapsali, F., C. Tsopelas, I. Kamilaris, M. Dimitraka, and A. Sardis. "Glutamate and Depression." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70883-1.
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Glutamate is the principal excitatory neurotransmitter in the cerebral cortex and it is implicated in the pathophysiology of depression and antidepressant activity.Aim:Aim of this study is to review recent studies and examine the physiology of glutamate and its receptors, pathophysiology of NMDA, effects of stress on glial cells and glutamate neurotransmission and explore the antidepressant properties of NMDA antagonists.Method:Review of recent pharmacological, imaging and genetic studies.Results:Increasing evidence supports a tight relationship between stress, the glutamatergic system and depression. Extracellular glutamate concentrations are increased in several brain regions including prefrontal cortex and hippocampus after exposure to stress. Interactions between glutamate and other neurotransmitters are discussed, as are possible mechanisms by which such altered receptor activity might result in the clinical expression of depression.A variety of NMDA antagonists, group I metabotropic glutamate receptor antagonists, as well as positive modulators of AMPA receptors, demonstrate efficacy in various preclinical modelsConclusions:It seems that a breakthrough in the therapy of depression will require going beyond monoamine-based theory of depression. Evidence indicates that the glutaminergic system might be a promising target fir novel antidepressant therapy.
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Kim, Ji-Eun, Duk-Shin Lee, Hana Park, and Tae-Cheon Kang. "Src/CK2/PTEN-Mediated GluN2B and CREB Dephosphorylations Regulate the Responsiveness to AMPA Receptor Antagonists in Chronic Epilepsy Rats." International Journal of Molecular Sciences 21, no. 24 (December 17, 2020): 9633. http://dx.doi.org/10.3390/ijms21249633.
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Both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) have been reported as targets for treatment of epilepsy. To investigate the roles and interactions of AMPAR and NMDAR in ictogenesis of epileptic hippocampus, we analyzed AMPAR antagonists (perampanel and GYKI 52466)-mediated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulation and glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) tyrosine (Y) 1472 phosphorylation in epilepsy rats. Both perampanel and GYKI 52466 increased PTEN expression and its activity (reduced phosphorylation), concomitant with decreased activities (phosphorylations) of Src family-casein kinase 2 (CK2) signaling pathway. Compatible with these, they also restored the upregulated GluN2B Y1472 and Ca2+/cAMP response element-binding protein (CREB) serine (S) 133 phosphorylations and surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) to basal level in the epileptic hippocampus. These effects of perampanel and GYKI 52466 are observed in responders (whose seizure activities are responsive to AMPAR antagonists), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). Therefore, our findings suggest that Src/CK2/PTEN-mediated GluN2B Y1472 and CREB S133 regulations may be one of the responsible signaling pathways for the generation of refractory seizures in non-responders to AMPAR antagonists.
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Zapukhliak, Olha, Olga Netsyk, Artur Romanov, Oleksandr Maximyuk, Murat Oz, Gregory L. Holmes, Oleg Krishtal, and Dmytro Isaev. "Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors." PLOS ONE 16, no. 3 (March 12, 2021): e0240074. http://dx.doi.org/10.1371/journal.pone.0240074.
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Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
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Kim, Eunyoung, Lawrence M. Grover, Don Bertolotti, and Todd L. Green. "Growth hormone rescues hippocampal synaptic function after sleep deprivation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 298, no. 6 (June 2010): R1588—R1596. http://dx.doi.org/10.1152/ajpregu.00580.2009.
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Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-d-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone links sleep to hippocampal function, then restoration of growth hormone during sleep deprivation should prevent adverse consequences of sleep loss. To test this hypothesis, we examined rat hippocampus for spontaneous excitatory synaptic currents in CA1 pyramidal neurons, long-term potentiation in area CA1, and NMDA receptor subunit proteins in synaptic membranes. Three days of sleep deprivation caused a significant reduction in NMDA receptor-mediated synaptic currents compared with control treatments. When rats were injected with growth hormone once per day during sleep deprivation, the loss of NMDA receptor-mediated synaptic currents was prevented. Growth hormone injections also prevented the impairment of long-term potentiation that normally follows sleep deprivation. In addition, sleep deprivation led to a selective loss of NMDA receptor 2B (NR2B) from hippocampal synaptic membranes, but normal NR2B expression was restored by growth hormone injection. Our results identify growth hormone as a critical mediator linking sleep to normal synaptic function of the hippocampus.
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Xing, Hang, Sihan Xu, Xin’e Xie, Yuan Wang, Chengbiao Lu, and Xiong Han. "Levetiracetam induction of theta frequency oscillations in rodent hippocampus in vitro." Canadian Journal of Physiology and Pharmacology 98, no. 10 (October 2020): 725–32. http://dx.doi.org/10.1139/cjpp-2019-0727.
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Levetiracetam (LEV) has been demonstrated to improve cognitive function. Hippocampal theta rhythm (4–12 Hz) is associated with a variety of cognitively related behaviors, such as exploration in both humans and animal models. We investigated the effects of LEV on the theta rhythm in the rat hippocampal CA3 in hippocampal slices in vitro. We found that LEV increased the theta power in a dose-dependent manner. The increase in theta power can be blocked by GABAA receptor (GABAAR) or NMDA receptor (NMDAR) antagonists but not by AMPA receptor antagonist, indicating the involvement of GABAAR and NMDAR in the induction of theta activity. Interestingly, LEV enhancement of theta power can be also blocked by taurine or GABA-A agonist THIP, indicating that LEV induction of theta may be related to the indirect boosting of GABA action via reduction of extrasynaptic GABAAR activation. Furthermore, the increased theta power can be partially reduced by the mACh receptor (mAChR) antagonist atropine but not by nACh receptor antagonists, suggesting that mAChR activation provides excitatory input into local network responsible for LEV-induced theta. Our study demonstrated that LEV induced a novel theta oscillation in vitro, which may have implications in the treatment of the neuronal disorders with impaired theta oscillation and cognitive function.
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Nishijima, Takeshi, Masahiro Okamoto, Takashi Matsui, Ichiro Kita, and Hideaki Soya. "Hippocampal functional hyperemia mediated by NMDA receptor/NO signaling in rats during mild exercise." Journal of Applied Physiology 112, no. 1 (January 1, 2012): 197–203. http://dx.doi.org/10.1152/japplphysiol.00763.2011.
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Current studies have demonstrated that exercise increases regional cerebral blood flow (rCBF), an index of neuronal activity. However, neuronal regulation of the increased rCBF in the brain parenchyma is poorly understood. We developed a running model with rats for monitoring hippocampal cerebral blood flow (Hip-CBF) and found that mild treadmill running increases Hip-CBF in a tetrodotoxin-dependent manner, suggesting that functional hyperemia, an increase in rCBF in response to neuronal activation, occurs in the running rat's hippocampus (Nishijima T and Soya H. Neurosci Res 54: 186–191, 2006). To further support our hypothesis, it was important to discover the neurogenic pathways behind the increase in Hip-CBF that occurred during running. Here, we examine the possible role of N-methyl-d-aspartate (NMDA) receptor/nitric oxide (NO) signaling and group I metabotropic glutamate receptors in mediating the Hip-CBF increase. Hip-CBF during running was measured by laser-Doppler flowmetry. Intrahippocampal drug administration was performed by microdialysis. Mild treadmill running (10 m/min) increased Hip-CBF, which was remarkably attenuated by either NMDA receptor antagonists (1 mM MK-801) or NO synthase inhibitors (2 mM NG-nitro-l-arginine methyl ester). However, group I metabotropic glutamate receptor antagonists {1 mM 7-(hydroxyimino)cyclopropa[ b]chromen-1a-carboxylate ethyl ester + 1 mM 2-methyl-6-(phenylethynyl)pyridine hydrochloride} augmented the running-induced Hip-CBF increase. We also found that rCBF in the olfactory bulb was unchanged with running. These results strongly suggest that Hip-CBF during mild exercise is regulated locally under hippocampal neuronal activity, mediated mainly through NMDA receptor/NO signaling. Collectively, these results, together with our previous findings, support our hypothesis that mild exercise elicits neuronal activation, which then triggers functional hyperemia in the rat hippocampus.
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Grochecki, Pawel, Irena Smaga, Malgorzata Lopatynska-Mazurek, Ewa Gibula-Tarlowska, Ewa Kedzierska, Joanna Listos, Sylwia Talarek, et al. "Effects of Mephedrone and Amphetamine Exposure during Adolescence on Spatial Memory in Adulthood: Behavioral and Neurochemical Analysis." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 589. http://dx.doi.org/10.3390/ijms22020589.
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A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71–84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone—but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.
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Grochecki, Pawel, Irena Smaga, Malgorzata Lopatynska-Mazurek, Ewa Gibula-Tarlowska, Ewa Kedzierska, Joanna Listos, Sylwia Talarek, et al. "Effects of Mephedrone and Amphetamine Exposure during Adolescence on Spatial Memory in Adulthood: Behavioral and Neurochemical Analysis." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 589. http://dx.doi.org/10.3390/ijms22020589.
Full textAbstract:
A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71–84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone—but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.
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Perouansky, Misha, Dimitri Baranov, Michael Salman, and Yoel Yaari. "Effects of Halothane on Glutamate Receptor-mediated Excitatory Postsynaptic Currents." Anesthesiology 83, no. 1 (July 1, 1995): 109–19. http://dx.doi.org/10.1097/00000542-199507000-00014.
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Background The effects of halothane on excitatory synaptic transmission in the central nervous system of mammals have been studied in vivo and in vitro in several investigations with partially contradicting results. Direct measurements of the effects of halothane on isolated glutamate receptor-mediated (glutamatergic) excitatory postsynaptic currents (EPSCs), however, have not been reported to date. Methods The effects of halothane on glutamatergic EPSCs were studied in vitro by using tight-seal, whole-cell recordings from CA1 pyramidal cells in thin slices from the adult mouse hippocampus. The EPSCs were pharmacologically isolated into their non-N-methyl-D-aspartate (non-NMDA) and NMDA receptor-mediated components by using selective antagonists. The effects of halothane on EPSC amplitude and kinetics were analyzed at various membrane potentials and were compared with its effects on currents evoked by exogenously applied glutamatergic agonists. Results Halothane (0.2-5.1%; 0.37-2.78 mM) reversibly blocked non-NMDA and NMDA EPSCs. This effect was voltage independent; concentrations producing 50% inhibition were 0.87% (0.66 mM) and 0.69% (0.57 mM), respectively. Currents induced by bath-applied glutamatergic agonists were not affected even by the high concentrations of halothane. Conclusions Halothane depresses glutamatergic EPSCs irrespective of receptor subtype, most likely by inhibition of glutamate release.
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Nellgård, B., and T. Wieloch. "Postischemic Blockade of AMPA but Not NMDA Receptors Mitigates Neuronal Damage in the Rat Brain following Transient Severe Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 12, no. 1 (January 1992): 2–11. http://dx.doi.org/10.1038/jcbfm.1992.2.
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Glutamatergic transmission is an important factor in the development of neuronal death following transient cerebral ischemia. In this investigation the effects of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists on neuronal damage were studied in rats exposed to 10 min of transient cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension. The animals were treated with a blocker of the ionotropic quisqualate or α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor, 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinoxaline (NBQX), given postischemia as an intraperitoneal bolus dose of 30 mg kg−1 followed by an intravenous infusion of 75 μg min−1 for 6 h, or with the noncompetitive NMDA receptor blocker dizocilpine(MK-801) given 1 mg kg−1 i.p. at recirculation and 3 h postischemia, or with the competitive NMDA receptor antagonist dl-( E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), 5 mg kg−1, given intraperitoneally at recirculation. Treatment with NBQX provided a significant reduction of neuronal damage in the hippocampal CA1 area by 44–69%, with the largest relative decrease in the temporal part of the hippocampus. In neocortex a significant decrease in the number of necrotic neurons was also noted. No protection could be seen following postischemic treatment with dizocilpine or CGP 40116. Our data demonstrate that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult. We propose that the AMPA receptor–mediated neurotoxicity could be due to ischemia-induced changes in the control mechanisms of AMPA receptor–coupled processes or to changes of AMPA receptor characteristics.
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Sung, Pi-Shan, Pei-Wen Chen, Chia-Jui Yen, Meng-Ru Shen, Chih-Hung Chen, Kuen-Jer Tsai, and Chou-Ching K. Lin. "Memantine Protects against Paclitaxel-Induced Cognitive Impairment through Modulation of Neurogenesis and Inflammation in Mice." Cancers 13, no. 16 (August 19, 2021): 4177. http://dx.doi.org/10.3390/cancers13164177.
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Chemotherapy-induced cognitive impairment (CICI) is an adverse side effect of cancer treatment with increasing awareness. Hippocampal damage and related neurocognitive impairment may mediate the development of CICI, in which altered neurogenesis may play a role. In addition, increased inflammation may be related to chemotherapy-induced hippocampal damage. Memantine, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that may enhance neurogenesis and modulate inflammation, may be useful for treating CICI. To test this hypothesis, paclitaxel was administered to eight-week-old male B6 mice to demonstrate the relationship between CICI and impaired neurogenesis, and then, we evaluated the impact of different memantine regimens on neurogenesis and inflammation in this CICI model. The results demonstrated that both the pretreatment and cotreatment regimens with memantine successfully reversed impaired neurogenesis and spatial memory impairment in behavior tests. The pretreatment regimen unsuccessfully inhibited the expression of peripheral and central TNF-α and IL-1β and did not improve the mood alterations following paclitaxel treatment. However, the cotreatment regimen led to a better modulatory effect on inflammation and restoration of mood disturbance. In conclusion, this study illustrated that impaired neurogenesis is one of the mechanisms of paclitaxel-induced CICI. Memantine may serve as a potential treatment for paclitaxel-induced CICI, but different treatment strategies may lead to variations in the treatment efficacy.
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Dani, John A. "Nicotinic Receptor Activity Alters Synaptic Plasticity." Scientific World JOURNAL 1 (2001): 393–95. http://dx.doi.org/10.1100/tsw.2001.74.
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Studies using specific agonists, antagonists, and lesions have shown that nicotinic cholinergic systems participate in attention, learning, and memory[1,2]. The nicotinic manipulations usually have the greatest influence on difficult tasks or on cognitively impaired subjects[2]. For example, Alzheimer's disease is characterized by a loss of cholinergic projections and nicotinic acetylcholine receptors (nAChRs) in the cortex and hippocampus[3]. Nicotine skin patches can improve learning rates and attention in Alzheimer's patients[4].
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Zhang, Hongmiao, Guifen Chen, Hui Kuang, and Joe Z. Tsien. "Mapping and Deciphering Neural Codes of NMDA Receptor-Dependent Fear Memory Engrams in the Hippocampus." PLoS ONE 8, no. 11 (November 26, 2013): e79454. http://dx.doi.org/10.1371/journal.pone.0079454.
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Fox, Kevin, and Nigel Daw. "A Model for the Action of NMDA Conductances in the Visual Cortex." Neural Computation 4, no. 1 (January 1992): 59–83. http://dx.doi.org/10.1162/neco.1992.4.1.59.
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A model is presented for the behavior of N-methyl-D-aspartate (NMDA) receptors during neuronal responses to visual stimuli in visual cortex based on classical steady-state equations for membrane conductance, and for binding of transmitter with NMDA and non-NMDA receptors. Constraints in the equations and the equation for voltage dependency of the NMDA receptors come from measurements in hippocampus, embryonic CNS neurons, and cortex. An excitatory amino acid transmitter released from terminals in the visual cortex is assumed to be related to the contrast of the stimulus by a hyperbolic tangent formula. The transmitter is assumed to be glutamate. The model is a two compartment representation of a single neuron at steady state. The model fits results obtained from contrast-response curves measured in the visual cortex in control conditions and with iontophoresis of NMDA and non-NMDA agonists or antagonists. The model shows how NMDA receptors contribute to the visual response in a graded multiplicative fashion at all levels of contrast. NMDA receptors do not show switch behavior, that is, they are not turned on at high levels of stimulation only. The difference in NMDA receptor current between low and high levels of stimulation cannot be accounted for solely by the voltage dependency of the NMDA receptor. One needs, in addition, another factor, such as a difference in the Hill coefficient for binding of glutamate at the NMDA receptor.
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Cao, Guan, and Kristen M. Harris. "Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice." Journal of Neurophysiology 112, no. 8 (October 15, 2014): 1916–24. http://dx.doi.org/10.1152/jn.00297.2014.
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Hippocampal long-term potentiation (LTP) is a model system for studying cellular mechanisms of learning and memory. Recent interest in mechanisms underlying the advantage of spaced over massed learning has prompted investigation into the effects of distributed episodes of LTP induction. The amount of LTP induced in hippocampal area CA1 by one train (1T) of theta-burst stimulation (TBS) in young Sprague-Dawley rats was further enhanced by additional bouts of 1T given at 1-h intervals. However, in young Long-Evans (LE) rats, 1T did not initially saturate LTP. Instead, a stronger LTP induction paradigm using eight trains of TBS (8T) induced saturated LTP in hippocampal slices from both young and adult LE rats as well as adult mice. The saturated LTP induced by 8T could be augmented by another episode of 8T following an interval of at least 90 min. The success rate across animals and slices in augmenting LTP by an additional episode of 8T increased significantly with longer intervals between the first and last episodes, ranging from 0% at 30- and 60-min intervals to 13–66% at 90- to 180-min intervals to 90–100% at 240-min intervals. Augmentation above initially saturated LTP was blocked by the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2-amino-5-phosphonovaleric acid (d-APV). These findings suggest that the strength of induction and interval between episodes of TBS, as well as the strain and age of the animal, are important components in the augmentation of LTP.
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Si, Aung, Paul Helliwell, and Ryszard Maleszka. "Effects of NMDA receptor antagonists on olfactory learning and memory in the honeybee (Apis mellifera)." Pharmacology Biochemistry and Behavior 77, no. 2 (February 2004): 191–97. http://dx.doi.org/10.1016/j.pbb.2003.09.023.
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