Involvement of nitric oxide, cyclic GMP and phosphodiesterase 5 in excitatory amino acid and GABA release in the nucleus accumbens evoked by activation of the hippocampal fimbria.
It is known that the nucleus accumbens contains all elements of the nitric oxide (NO)-cyclic GMP (cGMP) system but the role of NO in this nucleus is not well understood. We investigated the contribution of the NO-cGMP system in the neurotransmission elicited by hippocampal nerve signals which are propagated to the nucleus accumbens via the fornix/fimbria. This glutamatergic hippocampus-accumbens projection was electrically stimulated for short periods in the urethane-anaesthetized rat. The nucleus accumbens was simultaneously superfused by the push-pull technique with compounds that influence the NO system and the released glutamate, aspartate and GABA were determined in the superfusate. Superfusion of the nucleus accumbens with the NO donor, PAPA/NO, enhanced basal release of the investigated amino acids with a complex concentration dependency. The release of glutamate and aspartate was also increased by the inhibitor of phosphodiesterase 5, UK-114,542. The PAPA/NO-elicited release of glutamate and aspartate was diminished by superfusion with the inhibitor of guanylyl cyclase, NS 2028. Basal release of amino acid transmitters was not influenced by NS 2028 and the NO synthase inhibitor, 7-NINA.Electrical stimulation of the fornix/fimbria increased the outflow of aspartate, glutamate and GABA in the nucleus accumbens. The stimulation-evoked release was abolished by superfusion of the nucleus with tetrodotoxin and strongly diminished by NS 2028, 7-NINA and N(G)-nitro-L-arginine methyl ester (L-name), while PAPA/NO facilitated stimulation-evoked release of these neurotransmitters. UK-114,542 also enhanced the evoked release of glutamate and aspartate while evoked GABA release was not influenced by the phosphodiesterase inhibitor. These findings indicate that NO plays the role of an excitatory transmitter in the nucleus accumbens and that nerve signals from the hippocampus propagated via fornix/fimbria induce NO synthesis in the nucleus accumbens. NO does not exert a tonic influence on basal release but facilitates release of aspartate, glutamate and GABA through increased cGMP synthesis. Phosphodiesterase 5 seems to be involved in the termination of the NO effect in glutamatergic but not in GABAergic neurons.
Kraus
M M
MM
Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Peter-Mayr-Strae 1, A-6020 Innsbruck, Austria.
Prast
H
H
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002404:Catheterization; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000378:metabolism*; D020712:Fornix, Brain / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018846:Excitatory Amino Acids; D020030:Nitric Oxide Donors; D001224:Aspartic Acid; D009569:Nitric Oxide; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP