ABSTRACT
The 5-HT(3) receptor antagonist, ondansetron, has been shown to correct the auditory gating deficit in medicated schizophrenia patients. Inhibition of 5-HT(3) receptors releases acetylcholine, the endogenous ligand for nicotinic acetylcholine receptors. The schizophrenia-related auditory gating deficit is modulated, in part, by nicotinic acetylcholine receptors, as is the mouse (DBA/2) model of the deficit. The present study assessed the effects of both acute and chronically administered ondansetron on auditory gating in DBA/2 mice. Auditory gating is defined as a decrease in amplitude of response to the second of a paired identical auditory stimulus presented 0.5 s following an initial auditory stimulus. Acute ondansetron administration at the lowest dose (0.1 mg/kg, IP) tested had no effect, while other doses (0.33 and 1 mg/kg, IP) produced improvements in auditory gating. The improvements were produced through both an increase in response to the first auditory stimulus and a decrease in the response to the second auditory stimulus. Co-administration of an alpha7 nicotinic acetylcholine receptor antagonist, alpha-bungarotoxin, or the alpha4beta2 nicotinic acetylcholine receptor antagonist dihydro-beta-erythroidine, with the 0.33 mg/kg dose of ondansetron blocked the improvement in auditory gating produced by ondansetron alone. There was no difference in response between the chronically injected mice and naive mice. Both showed improved auditory gating, thus, demonstrating no "carry over" effect of daily injections. These data demonstrate that indirect stimulation of nicotinic acetylcholine receptors by ondansetron can improve auditory gating parameters in DBA/2 mice.
Subject(s)
CA3 Region, Hippocampal/drug effects , Ondansetron/pharmacology , Receptors, Nicotinic/physiology , Receptors, Serotonin, 5-HT3/physiology , Sensory Gating/drug effects , Acoustic Stimulation , Analysis of Variance , Animals , Bungarotoxins/pharmacology , CA3 Region, Hippocampal/physiology , Dihydro-beta-Erythroidine/pharmacology , Dose-Response Relationship, Drug , Electrophysiology , Evoked Potentials, Auditory/drug effects , Evoked Potentials, Auditory/physiology , Female , Male , Mice , Mice, Inbred DBA , Nicotinic Antagonists/pharmacology , Sensory Gating/physiology , Serotonin Antagonists/pharmacologyABSTRACT
Abnormal auditory gating is a symptom of schizophrenia which has been proposed to be mediated through the alpha7 nicotinic acetylcholine receptor (nAChR). It has been shown that the non-selective nicotinic agonist nicotine has an influence on auditory gating in part by acting on the alpha4beta2 nAChR. The goal of this study was to determine the effect of 5-I A-85380, an agonist for the alpha4beta2 nAChR, in an inbred mouse model with a deficiency for auditory gating. Anesthetized DBA/2 mice were administered 5-I A-85380 alone and in combination with the alpha4beta2 nAChR antagonist, dihydro-beta-erythroidine, or the alpha7 nAChR antagonist, alpha-bungarotoxin. A recording electrode in the CA3 region of the hippocampus recorded P20-N40 waveforms in response to two auditory stimuli. The amplitudes of the response to the first and second clicks were used to determine TC ratios, the measure of auditory gating. 5-I A-85380 significantly decreased the TC ratios by selectively increasing the response amplitudes to the first click with no significant influence on the response amplitudes to the second click. The effect was blocked by dihydro-beta-erythroidine whereas alpha-bungarotoxin had no effect on response amplitude to either click. Although the alpha7 nAChR may mediate the hippocampal response of DBA/2 mice to the second click, the alpha4beta2 nAChR appears to modulate the response to the first click. Thus, the present study implicates the involvement of more than one subtype of nAChR in the auditory gating of DBA/2 mice, specifically the alpha4beta2 nAChR, and its role in the response amplitude to the first stimulus.
