Browsing by Subject "NMDA RECEPTORS"

Sort by: Order: Results:

Now showing items 1-6 of 6
  • Ribeiro, Deidiane Elisa; Casarotto, Plinio Cabrera; Júnior, Ailton Spiacci; Fernandes, Gabriel Gripp; Pinheiro, Lucas César; Tanus- Santos, José Eduardo; Zangrossi Jr, Hélio; Silveira Guimarães, Francisco; Lourenço Joca, Samia Regiane; Biojone, Caroline (2019)
    Nitric oxide (NO) triggers escape reactions in the dorsal periaqueductal gray matter (dPAG), a core structure mediating panic-associated response, and decreases the release of BDNF in vitro. BDNF mediates the panicolytic effect induced by antidepressant drugs and produces these effects per se when injected into the dPAG. Based on these findings, we hypothesize that nitric oxide synthase (NOS) inhibitors would have panicolytic properties associated with increased BDNF signaling in the dPAG. We observed that the repeated (7 days), but not acute (1 day), systemic administration of the NOS inhibitor aminoguanidine (AMG; 15 mg/kg/day) increased the latency to escape from the open arm of the elevated T-maze (ETM) and inhibited the number of jumps in hypoxia-induced escape reaction in rats, suggesting a panicolytic-like effect. Repeated, but not acute, AMG administration (15 mg/kg) also decreased nitrite levels and increased TRKB phosphorylation at residues Y706/7 in the dPAG. Notwithstanding the lack of AMG effect on total BDNF levels in this structure, the microinjection of the TRK antagonist K252a into the dPAG blocked the anti-escape effect of this drug in the ETM. Taken together our data suggest that the inhibition of NO production by AMG increases the levels of pTRKB, which is required for the panicolytic-like effect observed.
  • de Miguel, Elena; Vekovischeva, Olga; Kuokkanen, Katja; Vesajoki, Marja; Paasikoski, Nelli; Kaskinoro, Janne; Myllymäki, Mikko; Lainiola, Mira; Janhunen, Sanna K.; Hyytiä, Petri; Linden, Anni-Maija; Korpi, Esa R. (2019)
    Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABA(B) receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABA(B) receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABA(B) PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [S-35] GTP gamma S binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [S-35] GTP gamma S binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABA(B) receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction.
  • Platzer, Konrad; Yuan, Hongjie; Schuetz, Hannah; Winschel, Alexander; Chen, Wenjuan; Hu, Chun; Kusumoto, Hirofumi; Heyne, Henrike O.; Helbig, Katherine L.; Tang, Sha; Willing, Marcia C.; Tinkle, Brad T.; Adams, Darius J.; Depienne, Christel; Keren, Boris; Mignot, Cyril; Frengen, Eirik; Stromme, Petter; Biskup, Saskia; Doecker, Dennis; Strom, Tim M.; Mefford, Heather C.; Myers, Candace T.; Muir, Alison M.; LaCroix, Amy; Sadleir, Lynette; Scheffer, Ingrid E.; Brilstra, Eva; van Haelst, Mieke M.; van der Smagt, Jasper J.; Bok, Levinus A.; Moller, Rikke S.; Jensen, Uffe B.; Millichap, John J.; Berg, Anne T.; Goldberg, Ethan M.; De Bie, Isabelle; Fox, Stephanie; Major, Philippe; Jones, Julie R.; Zackai, Elaine H.; Abou Jamra, Rami; Rolfs, Arndt; Leventer, Richard J.; Lawson, John A.; Roscioli, Tony; Jansen, Floor E.; Ranza, Emmanuelle; Korff, Christian M.; Lehesjoki, Anna-Elina; Courage, Carolina; Linnankivi, Tarja; Smith, Douglas R.; Stanley, Christine; Mintz, Mark; McKnight, Dianalee; Decker, Amy; Tan, Wen-Hann; Tarnopolsky, Mark A.; Brady, Lauren I.; Wolff, Markus; Dondit, Lutz; Pedro, Helio F.; Parisotto, Sarah E.; Jones, Kelly L.; Patel, Anup D.; Franz, David N.; Vanzo, Rena; Marco, Elysa; Ranells, Judith D.; Di Donato, Nataliya; Dobyns, William B.; Laube, Bodo; Traynelis, Stephen F.; Lemke, Johannes R. (2017)
    Background We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
  • Yuryev, Mikhail; Andriichuk, Liliia; Leiwe, Marcus; Jokinen, Ville; Carabalona, Aurelie; Rivera, Claudio (2018)
    Prior to sensory experience spontaneous activity appears to play a fundamental role in the correct formation of prominent functional features of different cortical regions. The use of anaesthesia during pregnancy such as ketamine is largely considered to negatively affect neuronal development by interfering with synaptic transmission. Interestingly, the characteristics of spontaneous activity as well as the acute functional effects of maternal anaesthesia remain largely untested in the embryonic cortex in vivo. In the present work, we performed in vivo imaging of spontaneous calcium activity and cell motility in the marginal zone of the cortex of E14-15 embryos connected to the mother. We made use of a preparation where the blood circulation from the mother through the umbilical cord is preserved and fluctuations in intracellular calcium in the embryonic frontal cortex are acquired using two-photon imaging. We found that spontaneous transients were either sporadic or correlated in clusters of neuronal ensembles at this age. These events were not sensitive to maternal isoflurane anaesthesia but were strongly inhibited by acute in situ or maternal application of low concentration of the anaesthetic ketamine (a non-competitive antagonist of NMDA receptors). Moreover, simultaneous imaging of cell motility revealed a correlated strong sensitivity to ketamine. These results show that anaesthetic compounds can differ significantly in their impact on spontaneous early cortical activity as well as motility of cells in the marginal zone. The effects found in this study may be relevant in the etiology of heightened vulnerability to cerebral dysfunction associated with the use of ketamine during pregnancy.
  • Lesnikova, Angelina; Casarotto, Plinio; Moliner, Rafael; Fred, Senem Merve; Biojone, Caroline; Castren, Eero (2021)
    Perineuronal nets (PNNs) have an important physiological role in the retention of learning by restricting cognitive flexibility. Their deposition peaks after developmental periods of intensive learning, usually in late childhood, and they help in long-term preservation of newly acquired skills and information. Modulation of PNN function by various techniques enhances plasticity and regulates the retention of memories, which may be beneficial when memory persistence entails negative symptoms such as post-traumatic stress disorder (PTSD). In this study, we investigated the role of PTP sigma [receptor-type tyrosine-protein phosphatase S, a phosphatase that is activated by binding of chondroitin sulfate proteoglycans (CSPGs) from PNNs] in retention of memories using Novel Object Recognition and Fear Conditioning models. We observed that mice haploinsufficient for PTPRS gene (PTP sigma(+/-)), although having improved short-term object recognition memory, display impaired long-term memory in both Novel Object Recognition and Fear Conditioning paradigm, as compared to WT littermates. However, PTP sigma(+/-) mice did not show any differences in behavioral tests that do not heavily rely on cognitive flexibility, such as Elevated Plus Maze, Open Field, Marble Burying, and Forced Swimming Test. Since PTP sigma has been shown to interact with and dephosphorylate TRKB, we investigated activation of this receptor and its downstream pathways in limbic areas known to be associated with memory. We found that phosphorylation of TRKB and PLC gamma are increased in the hippocampus, prefrontal cortex, and amygdaloid complex of PTP sigma(+/-) mice, but other TRKB-mediated signaling pathways are not affected. Our data suggest that PTP sigma downregulation promotes TRKB phosphorylation in different brain areas, improves short-term memory performance but disrupts long-term memory retention in the tested animal models. Inhibition of PTP sigma or disruption of PNN-PTP sigma-TRKB complex might be a potential target for disorders where negative modulation of the acquired memories can be beneficial.
  • Wei, Hong; Viisanen-Kuopila, Hanna; You, Hao-Jun; Pertovaara, Antti (2016)
    Here we studied whether and through which mechanisms spinal administration of histamine dihydrochloride (histamine) attenuates pain behavior in neuropathic animals. Experiments were performed in rats with spinal nerve ligation-induced neuropathy and a chronic intrathecal catheter for spinal drug delivery. Mechanical hypersensitivity was assessed with monofilaments while radiant heat was used for assessing nociception. Ongoing neuropathic pain and its attenuation by histamine was assessed using conditioned place-preference test. Following spinal administration, histamine at doses 0.1-10 mu g produced a dose-related mechanical antihypersensitivity effect. With prolonged treatment (twice daily 10 mu g for five days), the antihypersensitivity effect of spinal histamine was reduced. In place-preference test, neuropathic animals preferred the chamber paired with histamine (10 mu g). Histamine (10 mu g) failed to influence heat nociception in neuropathic animals or mechanically induced pain behavior in a group of healthy control rats. Histamine-induced mechanical antihypersensitivity effect was prevented by spinal pretreatment with zolantidine (histamine H-2 receptor antagonist), prazosine (alpha(1)-adrenoceptor antagonist) and bicuculline (gamma-aminobutyric acid subtype A, GABA(A), receptor antagonist), but not by pyrilamine (histamine H-1 receptor antagonist), atipamezole (alpha(2)-adrenoceptor antagonist), or raclopride (dopamine D-2 receptor antagonist). A-960656, a histamine H-3 receptor antagonist alone that presumably increased endogenous histamine levels reduced hypersensitivity. Additionally, histamine prevented central (presumably postsynaptically-induced) facilitation of hypersensitivity induced by N-methyl-n-aspartate. The results indicate that spinal histamine at the dose range of 0.1-10 mu g selectively attenuates mechanical hypersensitivity and ongoing pain in neuropathy. The spinal histamine-induced antihypersensitivity effect involves histamine H-2 and GABA(A) receptors and (presumably neuropathy-induced) co-activation of spinal al-adrenoceptors. (C) 2015 Elsevier B.V. All rights reserved.