Abstract
Some cognition enhancers were previously shown to potently prevent antagonism of the N-methyl-d-aspartate (NMDA)-evoked release of norepinephrine (NE) brought about in slices of rat hippocampus by kynurenic acid, an endogenous NMDA receptor blocker. We have examined the impact of putative nootropic agents in the kynurenate test performed with slices of human cerebral cortex from patients undergoing neurosurgery. In slices of human neocortex, local application of NMDA evoked release of [3H]NE; the effect of NMDA was antagonized by several NMDA receptor antagonists, including kynurenic acid. The antagonism of the NMDA-evoked [3H]NE release produced by 300 μM kynurenate was potently (EC50<10 μM) prevented by most of the nootropics tested, including aniracetam, oxiracetam, d-cycloserine, and the glutamate analog CR 2249 (but not its enantiomer CR 2361). Nicotine or tacrine (up to 10 μM) did not show any effect in the kynurenate test. Nicotine (30–100 μM) itself increased the release of [3H]NE; interestingly, the nicotine-evoked overflow was blocked not only by the nicotin receptor antagonist mecamylamine but also by NMDA receptor antagonists, suggesting an indirect mechanism mediated by glutamate/aspartate release. To conclude, the similarities between the data obtained here with human neocortex slices and those previously obtained in the rat indicate that the kynurenate test performed with rat brain slices may represent a useful biochemical assay to study cognition-enhancing drugs.
Footnotes
-
Send reprint requests to: Maurizio Raiteri, Department of Experimental Medicine, Pharmacology and Toxicology Section, Viale Cembrano 4, 16148 Genoa, Italy. E-mail: M.Raiteri{at}pharmatox.unige.it
-
↵1 This work was supported by grants from National Research Council Target Project on Biotechnology and from the Italian Ministry of Health “Progetto AIDS” 1997 (contract 30A.0.58).
- Abbreviations:
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- CGS 19755
- 4-phosphonomethyl-2-piperidinecarboxylic acid
- CR 2249
- (S)-4-amino[(4,4-dimethylcyclohexyl)amino]oxopentanoic acid
- d-AP5
- d-2-amino-5-phosphopentanoate
- GBR12909
- 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride
- NE
- norepinephrine
- NMDA
- N-methyl-d-aspartate
- Received December 21, 1998.
- Accepted March 16, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|