Abstract
The amplitude of the hippocampal evoked response to the second of two identical auditory stimuli is suppressed relative to the response to the first stimulus. This inhibitory gating of sensory response has been linked to α-bungarotoxin-sensitive nicotinic receptors, which are found primarily on γ-amino butyric acid neurons in rat hippocampus. A recent study showed a high level of colocalization of α-bungarotoxin binding with immunoreactivity for nitric oxide synthase, the catalytic enzyme which produces nitric oxide, in rat hippocampus. To determine if loss of enzyme activity would alter normal sensory inhibition, Nω-nitro-l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, was continuously perfused through the ventricular system of anesthetized rats as they were tested for response to paired auditory stimuli. L-NAME, but not Nω-nitro-d-arginine methyl ester (D-NAME), the inactive enantiomer, produced a loss of sensory inhibition. To determine if the effect of nitric oxide was presynaptic or postsynaptic to nicotinic receptors, rats with lesions of the fimbria/fornix, which removes the medial septal projection to the hippocampus, were tested with nicotine in the presence of L- or D-NAME. Fimbria/fornix lesions normally reduce sensory inhibition, which is restored with systemic nicotine injections. Lesioned rats treated with D-NAME showed normal sensory inhibition upon injection of nicotine; lesioned rats treated with L-NAME did not. These data support the hypothesis that stimulation of a nicotinic receptor releases nitric oxide, which in turn mediates sensory inhibition. The nicotine-induced release of nitric oxide may explain why some of the behavioral effects of nicotine have a longer time course than predicted from desensitization of nicotinic receptors.
Footnotes
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Send reprint requests to: Dr. Catherine E. Adams, Department of Psychiatry, Box C268–71, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262.
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This work was supported by United States Public Health Service Grants 5P50 MH44212, R29 MH51931 to K.E.S. and the Veterans Administration Medical Service; and has previously been presented at the 1997 annual meeting of the Society for Neuroscience (23:659).
- Abbreviations:
- GABA
- γ-aminobutyric acid
- L-NAME
- Nω-nitro-l-arginine methyl ester
- d-NAME
- Nω-nitro-d-arginine methyl ester
- GTS-21 or DMXB
- 4-OH-MeO-benzylidine anabaseine
- α-BTX
- α-bungarotoxin
- N40
- identified as the maximum negativity in the auditory evoked potential between 20 and 60 msec after the auditory stimulus
- P20
- identified as the positivity in the auditory evoked potential immediately preceding the N40 wave
- TC ratio
- test/conditioning ratio
- EBSS
- Earle’s balanced salt solution
- NO
- nitric oxide
- NADPH
- diaphorase-nicotinamide-adenine dinucleotide phosphate-diaphorase
- AChE
- acetylcholinesterase
- Received February 4, 1998.
- Accepted June 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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