Stimulation of the alpha4beta2 nicotinic receptor by 5-I A-85380 improves auditory gating in DBA/2 mice

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.