Nicotine Receptor Subtype-Specific Effects on Auditory Evoked Oscillations and Potentials

Background: Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity. Methodology/Principal Findings: We examined the effects of nicotine, the alpha 7 nicotine receptor antagonist methyllycaconitine (MLA) the alpha 4 beta 4/alpha 4 beta 2 nicotine receptor antagonist dihydro-beta-erythroidine (DH beta E), and the alpha 4 beta 2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHbE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the alpha 4 beta 2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHbE blocks the effects of nicotine through a non-alpha 4 beta 2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHbE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHbE but not MLA blocked the effect of nicotine on event-related gamma. Conclusions/Significance: These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHbE sensitive mechanism, but suggests that this does not occur through activation of alpha 4 beta 2 receptors. Event-related gamma is strongly influenced by activation of alpha 4 beta 2, but not a7, receptor subtypes, while disruption of N40 amplitude requires the activation of multiple receptor subtypes.