Inhibition of nitric oxide synthase prevents alpha 7 nicotinic receptor-mediated restoration of inhibitory auditory gating in rat hippocampus

The hippocampus rapidly inhibits its response to repetitive auditory stimul ation, an example of an auditory sensory gating mechanism involved in human psychopathology. The neuronal basis of this inhibitory gating mechanism ha s been investigated in rats. Activation of the alpha 7 nicotinic receptor i s required. alpha 7 nicotinic receptor activation also releases nitric oxid e in the hippocampus and blockade of nitric oxide synthase reduces inhibito ry gating of auditory response. There has not been a direct demonstration t hat blockade of nitric oxide synthase specifically prevents alpha 7 nicotin ic receptor activation of the inhibition of auditory response. Therefore, t he goal of the present study was to determine whether this functional effec t of alpha 7 receptor activation requires release of nitric oxide. Lesions of the fimbria-fornix disrupt auditory gating by preventing cholinergic sti mulation of the hippocampus. Following recovery from this surgery, rats wer e administered 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A; 10 mg/kg, s c), an agonist at the alpha 7 receptor. DMXB-A restored auditory gating in the fimbria-fornix-lesioned rats, indicating that activation of the alpha 7 nicotinic receptor alone is sufficient to restore auditory gating followin g lesions of the fimbria-fornix. However, intracerebroventricular infusion of N-omega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synt hase, blocked the DMXB-A-mediated restoration of auditory gating; infusion of the inactive D-enantiomer did not. Restoration of auditory gating by DMX B-A in the fimbria-fornix-lesioned rats was blocked by intracerebroventricu lar infusion of alpha-bungarotoxin, but not by mecamylamine or dihydro-beta -erythroidine. Together, these data support the hypothesis that nitric oxid e mediates alpha 7 nicotinic receptor activation of gating of auditory resp onse in rat hippocampus. (C) 2000 Elsevier Science B.V. All rights reserved .