Different nitric oxide synthase inhibitors cause rapid and differential alterations in the ligand-binding capacity of transmitter receptors in the rat cerebral cortex
ABSTRACT Inhibitors of nitric oxide (NO) synthesis reduce postlesional neuronal death during reperfusion injury by reducing the NO-mediated increase in excitatory neurotransmitter-release. The protective effects of various NO-synthase (NOS) inhibitors differ due to their isoform selectivity. The effects of NO-mediated excessive neurotransmitter supply are transmitted via specific neurotransmitter receptors expressed by the target cells. We report changes in the ligand-binding of different excitatory and inhibitory neurotransmitter-receptors studied by in vitro receptor autoradiography after in vivo-application of NOS-inhibitors. Since the constitutively expressed neuronal NOS-I is area-specifically distributed within the rat cortex, numerous cortical areas were studied in non-lesioned rats, in order to analyze the area-specific effects of NOS-inhibitors. The results showed that the NOS-I-specific inhibitor 7-nitroindazole increased binding of 3H-muscimol, 3H-pirenzepine and 3H-kainate, whereas the less isoform-specific, general NOS-inhibitor L-nitroarginine increased binding of 3H-muscimol and 3H-AMPA in most cortical areas, leaving 3H-kainate binding almost unchanged. The water soluble L-nitroarginine-methylester caused similar effects to those of L-nitroarginine which changed over a period of chronic treatment. The inhibitory GABAA-receptors were increased after NOS-inhibition in most cortical areas, whereas binding of 3H-Oxotremorine-M (acetylcholine receptors), 3H-MK-801 (NMDA-receptors) and 3H-AMPA (AMPA receptors) was affected differently among the cortical areas. Strongest alterations of ligand-binding capacity after administration of NOS-inhibitors were seen in cortical areas known to contain the highest packing densities of NOS-I-positive interneurons such as the piriform and entorhinal cortices, indicating that, in normal animals, neurotransmission and probably cognitive information processing would be affected by the pharmacological modulation of nitric oxide production.
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ABSTRACT: Cholinergic and dopaminergic systems are involved in spatial memory and are modulated by nitric oxide (NO); NO has well documented effects on place learning in rodents. The aim of the present study was to investigate the effect of NOS inhibition on place learning in the water maze and to evaluate the relationships between NOS inhibition, learning performance, dopamine (DA) D2 and muscarinic acetylcholine (mACh) receptors. Male Sprague-Dawley rats received the NOS inhibitor Nomega-Nitro-l-Arginine (l-NA), or saline and were trained in the water maze. Rats that were not trained, but received the same treatments were also included. Following treatments with or without water maze training, [3H]-QNB and [3H]-spiperone binding in cortex, striatum and hippocampus were determined to assess the effects of NOS inhibition and/or learning on DA D2 and mACh receptor regulation. The overall results of the present study showed that: (1) NOS inhibition impairs performance in the MWM; (2) NOS inhibition does not affect specific binding to DA D2 (striatum and hippocampus) and mACh (cortex and hippocampus) receptors; (3) MWM training lowers D2 and mACh receptor binding in cortical regions.Pharmacology Biochemistry and Behavior 06/2005; 81(1):32-40. DOI:10.1016/j.pbb.2005.02.008 · 2.82 Impact Factor
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ABSTRACT: The present experiment was carried out to determine the effectiveness of nitric oxide synthase inhibitors: 7-nitroindazole and aminoguanidine in modulating the toxicity of aluminium chloride on acetylcholine esterase activity, as well as behavioural and morphological changes of Wistar rats. For biochemical analysis the animals were killed 10 min, 3 h, 3 days and 30 days after the treatment and forebrain cortex, striatum, basal forebrain and hippocampus were removed. The biochemical changes observed in neuronal tissues show that nitric oxide synthase inhibitors exert as protective action in aluminium chloride-treated animals. In the present study, active avoidance learning was significantly impaired after aluminium chloride injection, while pretreatment with nitric oxide synthase inhibitors prevented the behavioural deficits caused between 26th and 30th day after intrahippocampal application of neurotoxin. Our data suggest that aluminium may cause learning and memory deficits, while the treatment with specific nitric oxide synthase inhibitors may prevent learning and memory deficits caused by aluminium chloride. We have also applied immunohistochemical techniques to identify neuronal- and inducible-nitric oxide synthase expression 30 days after aluminium chloride and nitric oxide synthase inhibitors injections. Our data suggest that 7-nitroindazole and aminoguanidine can be effective in the protection of toxicity induced by aluminium chloride.Brain research bulletin 04/2010; 81(6):641-6. DOI:10.1016/j.brainresbull.2010.01.004 · 2.97 Impact Factor
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ABSTRACT: Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. The involvement of ionotropic glutamate NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainite (KA) receptors in the induction of NO production in the rat brain was examined after injection of kainate, non-NMDA receptor agonist, KA+6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), selective AMPA/KA receptor antagonist, or KA+2-amino-5-phosphonopentanoic acid (APV), selective NMDA receptor antagonist. Competitive glutamate receptor antagonists were injected with KA 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 the ipsi- and contralateral hippocampus, forebrain cortex, striatum and cerebellum homogenates. The detected increase of NO production in distinct brain regions, which are functionally connected via afferents and efferents, suggests that these regions are affected by the injury. The effect of KA on nitrite production was blocked by the glutamate antagonists. Intrahippocampal KA+CNQX injection resulted in decrease of nitrite production, around control levels, in all tested brain structures. Significant decrease in nitrite levels was found only in comparison to KA-treated animals, i.e. the overall effect of selective AMPA/KA receptor antagonist was a decrease of KA-induced excitotoxicity. The accent effect of intrahippocampal KA+APV injection resulted, also, in decrease of nitrite production. However, this effect was detected after 5 min from the injection indicating the existence of an NMDA receptor-mediated component of basal nitrite production in physiological conditions and difference in mechanisms and time dynamics between CNQX and APV. The used antagonists showed same pattern in all tested brain structures. APV and CNQX both expressed sufficient neuroprotection in sense of reducing nitrite concentrations, but with differential effect in mechanisms and time dynamics. Our findings suggest that NMDA and AMPA/KA receptors are differentially involved in NO production.Brain Research Bulletin 10/2005; 67(1-2):133-41. DOI:10.1016/j.brainresbull.2005.06.019 · 2.97 Impact Factor