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P.1.g.067 The GalR1–GalR2 heteroreceptor complex can be the receptor for galanin fragment 1–15
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P.1.g. Basic and clinical neuroscience − Neuropharmacology
P.1.g.066 Altered presynaptic and postsynaptic transmission in dorsal raphe neurons of GIRK2 knockout mice Llamosas1 ° ,
Ugedo1 ,
Torrecilla1
1 University
N. L. M. of the Basque Country, pharmacology, Leioa − Bizkaia, Spain It is well known that G protein-coupled inwardly rectifying K+ (GIRK) channels containing GIRK2 subunit play an important role controlling excitability of several brain areas. On the postsynaptic side, these K+ channels can be activated by different G protein-coupled receptors and mediate the slow inhibitory effects of many neurotransmitters. However, on the presynaptic side, controversial results have been obtained from studies assessing the contribution of GIRK channels in the presynaptic inhibition of neurotransmitter release in different brain areas. In this context, we studied the involvement of GIRK channels in 5-HT, GABAergic and glutamatergic synaptic activity in Dorsal Raphe (DR) neurons in mice lacking Girk2 gene. For this purpose, whole-cell patchclamp experiments were performed in slices containing DR. Outward currents evoked by agonists for 5-HT1A receptors (5-CT) and GABAB receptors (baclofen) were examined, as well as the spontaneous and evoked excitatory and inhibitory postsynaptic currents (sEPSC/eEPSC and sIPSC/eIPSC, respectively). In wild-type mice, application of 5-CT (100 nM) and baclofen (30mM) onto DR slices elicited outward currents that were largely diminished in GIRK2 knockout mice (p < 0.001). This great reduction in the amplitude of the currents suggests the involvement of GIRK2 subunit in the postsynaptic currents induced by 5-HT1A and GABAB receptors. Moreover, significant changes were observed in the GABAergic presynaptic activity in GIRK2 knockout mice. Thus, frequency and amplitude of sIPSC were significantly decreased in GIRK2 knockout mice compared to wild-type mice (p < 0.01 and p < 0.001, respectively). Furthermore, the study of the GABAergic synaptic plasticity revealed that compared to wildtype mice, GIRK2 knockout mice had a significant increase in the number of neurons which showed paired-pulse facilitation. Altogether, this results suggest a reduced presynaptic GABA release compared to wild-type mice. Next, we investigated whether this difference in GABA release could be due to an alteration of 5-HT transmission in GIRK2 knockout mice. The application of the 5-HT1A receptor antagonist, WAY100635 (1 mM) produced an increase in the frequency of sIPSC in wild-type mice, but this effect was significantly smaller in GIRK2 knockout group (p < 0.05). Presynaptic release of glutamate remained unaltered, as no significant changes were found in the frequency and amplitude of sEPSC or in the AMPA/NMDA ratio of eEPSC in DR neurones of GIRK2 knockout group compared to wild-type mice. Overall, this study demonstrates that in DR, GIRK2 subunit containing GIRK channels are the main inhibitory effectors of the postsynaptic actions of 5-HT1A and GABAB receptors, shown by almost absent agonist-induced outward currents in GIRK2 knockout mice. Regarding presynaptic transmission, these results indicate that Girk2 gene deletion reduces GABA release at least in part by affecting 5-HT transmission in DR neurons. Disclosure statement: Supported by Saiotek S-PE11UN055, FIS PI12/00613, Basque Government IT747−13 and University of the Basque Country UFI 11/12. N Llamosas has a grant from UPV/EHU.
P.1.g.067 The GalR1–GalR2 heteroreceptor complex can be the receptor for galanin fragment 1−15 D.O. Borroto Escuela1 ° , F. Calvo1 , M. Narvaez2 , W. RomeroFernandez1 , C. Millon2 , M. Di Palma1 , M. P´erez-Alea3 , M. Tena4 , L.F. Agnati1 , A.O. Tarakanov5 , P. Garriga4 , Z. D´ıazCabiale2 , K. Fuxe1 1 Karolinska Institutet, Division of Cellular and Molecular Neurochemistry. Department of Neuroscience, Stockholm, Sweden; 2 Universidad de M´alaga, Facultad de Medicina Departamento de Fisiolog´ıa, M´alaga, Spain; 3 Institut de Recerca Vall d’Hebron, Lab Animal Models and Cancer, Barcelona, Spain; 4 Universitat Polit`ecnica de Catalunya, Departament d’Engieneria Qu´ımica, Barcelona, Spain; 5 Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, Saint Petersburg, Russia In the last decade the importance of the role of neuropeptides, including Galanin, and its receptors in the treatment of stressrelated mood disorder is becoming increasingly apparent. Galanin receptor (GalR) subtypes linked to central galanin neurons may form heteromers with each other and other types of GPCRs in the CNS [1]. Previous work has established homodimerization and internalization of GalR1 in living CHO cells using FRET and time lapse confocal imaging [2]. Thus, GalR1 can exist as a dimer in the plasma membrane which may undergo desensitization and internalization upon agonist activation with Gal1−29. Furthermore, we have examined the possible existence of GalR-5-HT1A heteromers in HEK-293 cells using a proximitybased FRET assay [3]. Using CRE-luciferase and SRE-luciferase reporter assays it was found that signaling either the mitogenactivated protein kinase (MAPK) or of adenylyl cyclase (AC) pathways by these heteromers results in a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of Gi/o linked to each of the receptors followed by an exaggerated inhibition of AC or stimulation of MAPK activity [3]. These receptor heteromers may exist in the ascending raphe 5-HT pathways in view of the demonstration of antagonistic GalR-5-HT1A receptor interactions in the limbic regions and in the raphe reducing the affinity of the 5-HT1A receptors. GalR1 and GalR2 in particular are found in many regions of the CNS as demonstrated with in situ hybridization, radioligand binding and immunohistochemical studies and have all a high affinity for galanin. By means of Bioluminescence Resonance energy transfer (BRET2) evidence has for the first time been obtained for the existence of GalR1– GalR2 heteromers in living HEK293T cells. Through confocal laser microscopy the GalR1YFP and GalR2GFP2 were also shown to be colocated in the plasma membrane of these cells. Furthermore, in situ Proximity Ligation Assay indicated the existence of the GalR1–GalR2 heteroreceptor complexes in discrete areas of the brain. Signaling by either the MAPK, AC or PLC/PKC pathways initiated from these heteromers indicated preferential binding of the N-terminal galanin fragment 1−15 versus galanin 1−29 to the GalR1–GalR2 heteromer. A bioinformatic analysis suggested the existence of a basic set of three homology amino acid protriplets in the two participating receptors which may contribute to the formation of the GalR1–GalR2 heteromer by participating in guide-clasp interactions in the receptor interface. These current observation can explain the differential effects previously observed of N-terminal galanin fragment 1−15 versus galanin 1−29 in the central cardiovascular function. Thus, galanin fragment binding sites were in the 1990ies inter alia discovered in the
P.1.g. Basic and clinical neuroscience − Neuropharmacology hippocampus, striatum and cerebral cortex by radioligand biding and may thus reflect the presence of GalR1–GalR2 heteroreceptor complexes. The presence of these complexes in discrete brain regions that preferentially bind the N-terminal galanin fragment, introduces novel therapeutic strategies for treatment of depression by targeting the GalR1–GalR2 heteroreceptor complexes which can be linked to limbic 5-HT1A receptors. References [1] Fuxe K, Borroto-Escuela DO, Romero-Fernandez W et al., 2012 On the existence and function of galanin receptor heteromers in the central nervous system. Frontiers in endocrinology 3, 127. [2] Wirz SA, Davis CN, Lu X, Zal T, Bartfai T. 2005 Homodimerization and internalization of galanin type 1 receptor in living CHO cells. Neuropeptides 39, 535–546. [3] Borroto-Escuela DO, Narvaez M, Marcellino D et al., 2010 Galanin receptor-1 modulates 5-hydroxtryptamine-1A signaling via heterodimerization. Biochem Biophys Res Commun 393, 767–772.
P.1.g.068 Effect of L-valine peptidomimetics on cognition and neurotransmission in the hippocampus of socially isolated rats E.N. Encheva1 ° , L.P. Tancheva2 , L. Alova2 , L. Shikova2 , M. Kaneva2 , R. Klisurov3 , D. Tsekova4 1 Medical University of Sofia, Dept. of Physiology, Sofia, Bulgaria; 2 Bulgarian Academy of Sciences, Institute of Neurobiology, Sofia, Bulgaria; 3 Medical University of Sofia, Dept. of Pharmacology, Sofia, Bulgaria; 4 University of Chemical Technology and Metallurgy, Dept. of Organic Chemistry, Sofia, Bulgaria Introduction: New functional peptidomimetics were synthesized on the basis of the essential amino acid L-valine and nicotinic/ isonicotinic acid. Previous data have shown that some of them (positional isomers with codes M6 and P6) can significantly improve cognitive functions in rodents (mice and rats) while changing serotonin content in mouse brain and monoamine levels in rat hippocampus [1,2]. Purpose of the study was to evaluate the influence of the tested compounds − M6 and P6 on altered cognitive function of experimental mice and rats with syndrome of social isolation (SI), accompanied by some biochemical changes in neurotransmission in rat hippocampus. Methods: An experimental model of social isolation (over 6 weeks) in mature male Wistar rats and in male Albino ICR mice was used. The animals were treated with effective doses of compounds (100 mg/kg bw, i.p., for 3 days). Changes in their cognitive functions after SI and modulating effect of peptidomimetics were studied: learning and memory (Step-through test) and exploratory activity (Hole-board test). The changes in cholinergic and serotonergic neurotransmission in hippocampus of rats (grouped and SI) were studied, namely synaptosomal tritiated serotonin uptake, [3 H]serotonin and [3 H]acetylcholine release in hippocampal slices, using liquid scintillation methods. The levels were compared to controls − SI animals and collectively reared rats. T-test of Student Fisher and ANOVA were used to assess behavioral and radiometric data. The values of p < 0.05 were considered as statistically significant. Results: Cognitive dysfunctions (known as SI syndrome) were confirmed both in mice and rats. Established cognitive changes were accompanied by alteration in the release of some neuromediators in hippocampus − i.e. the levels of serotonin and acetylcholine. After 3-day administration of the compounds M6
S243
and P6, significant modulating effects upon central nervous system of the SI rats were observed. It was found out that the two isomeric peptidomimetics modulated significantly some basic memory functions (long-term memory and exploratory behavior). Spatial memory and fear conditioned memory decreased as demonstrated by data in the Hole-board test and Step-through test. In the same time the two compounds altered significantly serotonin release and especially serotonin uptake in the hippocampal tissue of SI treated animals in comparison to both control groups − collectively reared and SI rats. M6 and P6 exerted also significant effects upon acetylcholine release in hippocampus in SI rats with one of the isomers significantly decreasing acetylcholine release. The influence of the new compounds on serotonin and acetylcholine levels in the hippocampus of SI animals deserves further studies especially with regard to the ratio between ACh and 5-HT release in brain cortex. The observed variation in effects of M6 and P6 could be explained with their positional isomery and physicochemical differences. Conclusion: The newly synthesized peptidomimetics may be effective modulators of changed animal behavior and cognition due to their possible affinity not just towards the mitochondrial enzyme MAO, but also to some serotonin receptors in hippocampus. The tested functional peptidomimetics promise future development as potential pharmacological agents. References [1] Encheva, E., Stancheva, S., Alova, L., Tancheva, L., Petkov, V.V., & Tsekova, D., 2010. Modulating effect of new L-valine derivatives on brain serotonin uptake in aggressive socially isolated mice. European Neuropsychopharmacology, 20, S262-S263. [2] Stancheva, S., Alova, L., Tancheva, L., Petkov, V.V., Encheva, E., Tsekova, D., & Novoselski, M., 2010. Learning, Memory and Biogenic Amine Levels in Rat Hippocampus after Treatment with New L-Valine Derivatives. Journal of Medical Chemical, Biological & Radiological Defense, 8, 281.
P.1.g.069 D-serine prevents cognitive deficits caused by acute stress G.D. Guercio1 ° , C. Madeira1 , L.E. Bevictori1 , C. Vargas-Lopes1 , R. Panizzutti1 1 Biomedical Sciences Institute, Rio de Janeiro, Brazil Stressful events are inevitable in modern life. Although it is generally accepted that chronic stress promotes cognitive deficits, the effects of acute stress on cognition are more complex. Increasing evidence indicates that acute stress can disrupt cognitive functions mediated by the N-methyl-D-aspartate receptor (NMDAR), although the mechanisms are not fully understood yet. D-serine is the major endogenous co-agonist of the NMDAR, and is produced in the brain exclusively by the serine racemase. Importantly, serine racemase can be inhibited by phosphorylation on serine residues, resulting in lower D-serine levels. D-serine is crucial to long term potentiation induction and it also contributes to learning and memory. Also, D-serine is involved in sensorimotor gating, a filtering mechanism that is thought to prevent sensory overload. However, regulation of D-serine by acute stress remains to be investigated. Here we examined whether the D-serine pathway is regulated by acute stress. We studied the biochemical and behavioral effects of acute restraint stress in C57BL/6 male mice. After 90 minutes of acute restraint stress, the animals had a large increase in plasma levels of corticosterone measured by radioimmunoassay (unpaired
P.1.g. Basic and clinical neuroscience − Neuropharmacology
P.1.g.066 Altered presynaptic and postsynaptic transmission in dorsal raphe neurons of GIRK2 knockout mice Llamosas1 ° ,
Ugedo1 ,
Torrecilla1
1 University
N. L. M. of the Basque Country, pharmacology, Leioa − Bizkaia, Spain It is well known that G protein-coupled inwardly rectifying K+ (GIRK) channels containing GIRK2 subunit play an important role controlling excitability of several brain areas. On the postsynaptic side, these K+ channels can be activated by different G protein-coupled receptors and mediate the slow inhibitory effects of many neurotransmitters. However, on the presynaptic side, controversial results have been obtained from studies assessing the contribution of GIRK channels in the presynaptic inhibition of neurotransmitter release in different brain areas. In this context, we studied the involvement of GIRK channels in 5-HT, GABAergic and glutamatergic synaptic activity in Dorsal Raphe (DR) neurons in mice lacking Girk2 gene. For this purpose, whole-cell patchclamp experiments were performed in slices containing DR. Outward currents evoked by agonists for 5-HT1A receptors (5-CT) and GABAB receptors (baclofen) were examined, as well as the spontaneous and evoked excitatory and inhibitory postsynaptic currents (sEPSC/eEPSC and sIPSC/eIPSC, respectively). In wild-type mice, application of 5-CT (100 nM) and baclofen (30mM) onto DR slices elicited outward currents that were largely diminished in GIRK2 knockout mice (p < 0.001). This great reduction in the amplitude of the currents suggests the involvement of GIRK2 subunit in the postsynaptic currents induced by 5-HT1A and GABAB receptors. Moreover, significant changes were observed in the GABAergic presynaptic activity in GIRK2 knockout mice. Thus, frequency and amplitude of sIPSC were significantly decreased in GIRK2 knockout mice compared to wild-type mice (p < 0.01 and p < 0.001, respectively). Furthermore, the study of the GABAergic synaptic plasticity revealed that compared to wildtype mice, GIRK2 knockout mice had a significant increase in the number of neurons which showed paired-pulse facilitation. Altogether, this results suggest a reduced presynaptic GABA release compared to wild-type mice. Next, we investigated whether this difference in GABA release could be due to an alteration of 5-HT transmission in GIRK2 knockout mice. The application of the 5-HT1A receptor antagonist, WAY100635 (1 mM) produced an increase in the frequency of sIPSC in wild-type mice, but this effect was significantly smaller in GIRK2 knockout group (p < 0.05). Presynaptic release of glutamate remained unaltered, as no significant changes were found in the frequency and amplitude of sEPSC or in the AMPA/NMDA ratio of eEPSC in DR neurones of GIRK2 knockout group compared to wild-type mice. Overall, this study demonstrates that in DR, GIRK2 subunit containing GIRK channels are the main inhibitory effectors of the postsynaptic actions of 5-HT1A and GABAB receptors, shown by almost absent agonist-induced outward currents in GIRK2 knockout mice. Regarding presynaptic transmission, these results indicate that Girk2 gene deletion reduces GABA release at least in part by affecting 5-HT transmission in DR neurons. Disclosure statement: Supported by Saiotek S-PE11UN055, FIS PI12/00613, Basque Government IT747−13 and University of the Basque Country UFI 11/12. N Llamosas has a grant from UPV/EHU.
P.1.g.067 The GalR1–GalR2 heteroreceptor complex can be the receptor for galanin fragment 1−15 D.O. Borroto Escuela1 ° , F. Calvo1 , M. Narvaez2 , W. RomeroFernandez1 , C. Millon2 , M. Di Palma1 , M. P´erez-Alea3 , M. Tena4 , L.F. Agnati1 , A.O. Tarakanov5 , P. Garriga4 , Z. D´ıazCabiale2 , K. Fuxe1 1 Karolinska Institutet, Division of Cellular and Molecular Neurochemistry. Department of Neuroscience, Stockholm, Sweden; 2 Universidad de M´alaga, Facultad de Medicina Departamento de Fisiolog´ıa, M´alaga, Spain; 3 Institut de Recerca Vall d’Hebron, Lab Animal Models and Cancer, Barcelona, Spain; 4 Universitat Polit`ecnica de Catalunya, Departament d’Engieneria Qu´ımica, Barcelona, Spain; 5 Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, Saint Petersburg, Russia In the last decade the importance of the role of neuropeptides, including Galanin, and its receptors in the treatment of stressrelated mood disorder is becoming increasingly apparent. Galanin receptor (GalR) subtypes linked to central galanin neurons may form heteromers with each other and other types of GPCRs in the CNS [1]. Previous work has established homodimerization and internalization of GalR1 in living CHO cells using FRET and time lapse confocal imaging [2]. Thus, GalR1 can exist as a dimer in the plasma membrane which may undergo desensitization and internalization upon agonist activation with Gal1−29. Furthermore, we have examined the possible existence of GalR-5-HT1A heteromers in HEK-293 cells using a proximitybased FRET assay [3]. Using CRE-luciferase and SRE-luciferase reporter assays it was found that signaling either the mitogenactivated protein kinase (MAPK) or of adenylyl cyclase (AC) pathways by these heteromers results in a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of Gi/o linked to each of the receptors followed by an exaggerated inhibition of AC or stimulation of MAPK activity [3]. These receptor heteromers may exist in the ascending raphe 5-HT pathways in view of the demonstration of antagonistic GalR-5-HT1A receptor interactions in the limbic regions and in the raphe reducing the affinity of the 5-HT1A receptors. GalR1 and GalR2 in particular are found in many regions of the CNS as demonstrated with in situ hybridization, radioligand binding and immunohistochemical studies and have all a high affinity for galanin. By means of Bioluminescence Resonance energy transfer (BRET2) evidence has for the first time been obtained for the existence of GalR1– GalR2 heteromers in living HEK293T cells. Through confocal laser microscopy the GalR1YFP and GalR2GFP2 were also shown to be colocated in the plasma membrane of these cells. Furthermore, in situ Proximity Ligation Assay indicated the existence of the GalR1–GalR2 heteroreceptor complexes in discrete areas of the brain. Signaling by either the MAPK, AC or PLC/PKC pathways initiated from these heteromers indicated preferential binding of the N-terminal galanin fragment 1−15 versus galanin 1−29 to the GalR1–GalR2 heteromer. A bioinformatic analysis suggested the existence of a basic set of three homology amino acid protriplets in the two participating receptors which may contribute to the formation of the GalR1–GalR2 heteromer by participating in guide-clasp interactions in the receptor interface. These current observation can explain the differential effects previously observed of N-terminal galanin fragment 1−15 versus galanin 1−29 in the central cardiovascular function. Thus, galanin fragment binding sites were in the 1990ies inter alia discovered in the
P.1.g. Basic and clinical neuroscience − Neuropharmacology hippocampus, striatum and cerebral cortex by radioligand biding and may thus reflect the presence of GalR1–GalR2 heteroreceptor complexes. The presence of these complexes in discrete brain regions that preferentially bind the N-terminal galanin fragment, introduces novel therapeutic strategies for treatment of depression by targeting the GalR1–GalR2 heteroreceptor complexes which can be linked to limbic 5-HT1A receptors. References [1] Fuxe K, Borroto-Escuela DO, Romero-Fernandez W et al., 2012 On the existence and function of galanin receptor heteromers in the central nervous system. Frontiers in endocrinology 3, 127. [2] Wirz SA, Davis CN, Lu X, Zal T, Bartfai T. 2005 Homodimerization and internalization of galanin type 1 receptor in living CHO cells. Neuropeptides 39, 535–546. [3] Borroto-Escuela DO, Narvaez M, Marcellino D et al., 2010 Galanin receptor-1 modulates 5-hydroxtryptamine-1A signaling via heterodimerization. Biochem Biophys Res Commun 393, 767–772.
P.1.g.068 Effect of L-valine peptidomimetics on cognition and neurotransmission in the hippocampus of socially isolated rats E.N. Encheva1 ° , L.P. Tancheva2 , L. Alova2 , L. Shikova2 , M. Kaneva2 , R. Klisurov3 , D. Tsekova4 1 Medical University of Sofia, Dept. of Physiology, Sofia, Bulgaria; 2 Bulgarian Academy of Sciences, Institute of Neurobiology, Sofia, Bulgaria; 3 Medical University of Sofia, Dept. of Pharmacology, Sofia, Bulgaria; 4 University of Chemical Technology and Metallurgy, Dept. of Organic Chemistry, Sofia, Bulgaria Introduction: New functional peptidomimetics were synthesized on the basis of the essential amino acid L-valine and nicotinic/ isonicotinic acid. Previous data have shown that some of them (positional isomers with codes M6 and P6) can significantly improve cognitive functions in rodents (mice and rats) while changing serotonin content in mouse brain and monoamine levels in rat hippocampus [1,2]. Purpose of the study was to evaluate the influence of the tested compounds − M6 and P6 on altered cognitive function of experimental mice and rats with syndrome of social isolation (SI), accompanied by some biochemical changes in neurotransmission in rat hippocampus. Methods: An experimental model of social isolation (over 6 weeks) in mature male Wistar rats and in male Albino ICR mice was used. The animals were treated with effective doses of compounds (100 mg/kg bw, i.p., for 3 days). Changes in their cognitive functions after SI and modulating effect of peptidomimetics were studied: learning and memory (Step-through test) and exploratory activity (Hole-board test). The changes in cholinergic and serotonergic neurotransmission in hippocampus of rats (grouped and SI) were studied, namely synaptosomal tritiated serotonin uptake, [3 H]serotonin and [3 H]acetylcholine release in hippocampal slices, using liquid scintillation methods. The levels were compared to controls − SI animals and collectively reared rats. T-test of Student Fisher and ANOVA were used to assess behavioral and radiometric data. The values of p < 0.05 were considered as statistically significant. Results: Cognitive dysfunctions (known as SI syndrome) were confirmed both in mice and rats. Established cognitive changes were accompanied by alteration in the release of some neuromediators in hippocampus − i.e. the levels of serotonin and acetylcholine. After 3-day administration of the compounds M6
S243
and P6, significant modulating effects upon central nervous system of the SI rats were observed. It was found out that the two isomeric peptidomimetics modulated significantly some basic memory functions (long-term memory and exploratory behavior). Spatial memory and fear conditioned memory decreased as demonstrated by data in the Hole-board test and Step-through test. In the same time the two compounds altered significantly serotonin release and especially serotonin uptake in the hippocampal tissue of SI treated animals in comparison to both control groups − collectively reared and SI rats. M6 and P6 exerted also significant effects upon acetylcholine release in hippocampus in SI rats with one of the isomers significantly decreasing acetylcholine release. The influence of the new compounds on serotonin and acetylcholine levels in the hippocampus of SI animals deserves further studies especially with regard to the ratio between ACh and 5-HT release in brain cortex. The observed variation in effects of M6 and P6 could be explained with their positional isomery and physicochemical differences. Conclusion: The newly synthesized peptidomimetics may be effective modulators of changed animal behavior and cognition due to their possible affinity not just towards the mitochondrial enzyme MAO, but also to some serotonin receptors in hippocampus. The tested functional peptidomimetics promise future development as potential pharmacological agents. References [1] Encheva, E., Stancheva, S., Alova, L., Tancheva, L., Petkov, V.V., & Tsekova, D., 2010. Modulating effect of new L-valine derivatives on brain serotonin uptake in aggressive socially isolated mice. European Neuropsychopharmacology, 20, S262-S263. [2] Stancheva, S., Alova, L., Tancheva, L., Petkov, V.V., Encheva, E., Tsekova, D., & Novoselski, M., 2010. Learning, Memory and Biogenic Amine Levels in Rat Hippocampus after Treatment with New L-Valine Derivatives. Journal of Medical Chemical, Biological & Radiological Defense, 8, 281.
P.1.g.069 D-serine prevents cognitive deficits caused by acute stress G.D. Guercio1 ° , C. Madeira1 , L.E. Bevictori1 , C. Vargas-Lopes1 , R. Panizzutti1 1 Biomedical Sciences Institute, Rio de Janeiro, Brazil Stressful events are inevitable in modern life. Although it is generally accepted that chronic stress promotes cognitive deficits, the effects of acute stress on cognition are more complex. Increasing evidence indicates that acute stress can disrupt cognitive functions mediated by the N-methyl-D-aspartate receptor (NMDAR), although the mechanisms are not fully understood yet. D-serine is the major endogenous co-agonist of the NMDAR, and is produced in the brain exclusively by the serine racemase. Importantly, serine racemase can be inhibited by phosphorylation on serine residues, resulting in lower D-serine levels. D-serine is crucial to long term potentiation induction and it also contributes to learning and memory. Also, D-serine is involved in sensorimotor gating, a filtering mechanism that is thought to prevent sensory overload. However, regulation of D-serine by acute stress remains to be investigated. Here we examined whether the D-serine pathway is regulated by acute stress. We studied the biochemical and behavioral effects of acute restraint stress in C57BL/6 male mice. After 90 minutes of acute restraint stress, the animals had a large increase in plasma levels of corticosterone measured by radioimmunoassay (unpaired