Segieth, Joanna Urszula; (1998) Regulatory effects of nitric oxide on amino acid and monoamine transmitter release in the brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The effects of nitric oxide (NO) on neurotransmitter release in the hippocampus were investigated using in vivo microdialysis in conscious rats in an attempt to clarify the regulatory role of this messenger over basal and NMDA-evoked monoamine and amino acid release in this brain structure. 1. Infusion of N-methyl-D-aspartate (NMDA) caused a concentration-dependent increase in amino acid release and a decrease in monoamine release. 2. Infusion of S-nitroso-acetylpenicillamine (SNAP) at 5mM enhanced glutamate (L-GLU), aspartate (L-ASP) and γ-aminobutyric acid (GABA) release whilst at 500μM the donor decreased the release of these amino acids. In contrast, the release of dopamine (DA) and 5-hydroxytryptamine (5-HT) was reduced at 5mM but increased at 500μM SNAP. 3. The nitric oxide synthase (NOS) inhibitors 7-nitroindazole-monosodium salt (7-NINA), a selective neuronal NOS inhibitor, and NG -nitro-L-arginine-methyl-esther (L-NAME), a non-selective inhibitor, were used to investigate whether the source of NO production (endothelial or neuronal) is important in determination of the final response. L-NAME at 1mM increased whilst 7-NINA, with exception of DA, decreased the levels of neurotransmitters. Co-infusion of the NOS inhibitors with NMDA blocked the NMDA-induced increase in L-GLU and L-ASP release. Both inhibitors reversed the NMDA-evoked inhibition of monoamine release. 4.Infusion of both inhibitors led to a decrease in the extracellular levels of citrulline (L-CIT). In contrast, arginine (L-ARG) levels were decreased by 7-NINA and increased by L-NAME. 5. The possible involvement of NO in the modulation of L-ARG and L-CIT release from glial cells in vitro was also investigated. In cultured cerebellar glia, SNAP caused a concentration-and Ca2+-dependent release of L-ARG whilst the release of L-CIT was found to be neither concentration-nor Ca2+-dependent. Administration of 8-bromo- cyclic-guanosine-monophosphate enhanced L-ARG and decreased L-CIT release whilst L-NAME caused a decline in the release of both amino acids from these cells. 6. It is concluded that NO modulates neurotransmitter release in the ventral hippocampus in vivo. The prevailing extracellular concentration of NO and also its source are important in determining the final response. In addition, this study has provided evidence that glial cells release L-ARG and that this might be involved in the supply of substrate to neurones during periods of sustained NOS activity.

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