Consistent with previous reports 
, nicotine significantly increased amplitude of the P20 response to the first click of a paired-click stimulus (S1), but failed to alter response to the second (S2) click. Administration of the α4β4/α4β2 antagonist DHβE by itself did not affect P20 amplitude, but blocked nicotine-induced increases in P20 amplitude. In contrast, administration of the highly selective α7 antagonist MLA did not affect the P20 response when presented alone and failed to block nicotine induced enhancements of P20 amplitude. Taken as a whole, this pattern of data suggests that the ability for nicotine to enhance P20 amplitude occurs primarily through activation of a DHβE sensitive, and not α7 receptor subtype sensitive mechanism. In contrast to the effects of receptor specific antagonists, administration of the α4β2 agonist AZD3480 had no effect on P20 amplitude, consistent with previous findings in which the effect of nicotine on P20 amplitude was not disrupted in β2 knockout mice. DHβE has approximately 10 fold higher affinity at α4β4 receptors than at α4β2 
, suggesting that the enhancing effects of nicotine on the mouse P20 are mediated by α4β4 receptors. The β4 receptor subunit plays a key role in mediating the rewarding and addicting effects of nicotine 
and is expressed in brain regions that are likely important for the P50 response, such as the medial habenula. It should be noted that the effect of DHβE was not simply to block the effect of nicotine on P20 but rather produced a significant decrease in amplitude relative to saline vehicle or to DHβE treatment alone. This suggests that DHβE actually reversed the direction of the effect of nicotine on P20 amplitude and that this likely occurred through a mechanism other than that activated by DHβE treatment alone. While previous reports have suggested a role for α7 in regulating both P20 amplitude and gating in rodents 
, the current study failed to provide evidence consistent with this notion. It is likely that there are multiple nicotinic receptor subtypes that mediate the effect of nicotine on P20 amplitude, including the α7 and β4 subtypes, and that inactivation of α7 activity alone is not sufficient to fully block the response to nicotine. Interestingly, a non-significant (p
0.08) trend towards reduced P20 amplitude was observed following MLA treatment alone, suggesting that blockade of the α7 receptor in the absence of nicotine produced an effect opposite to that seen following agonist treatment, which would be consistent with the notion of a limited regulatory role of α7 in P20 amplitude. Also consistent with the findings on P20 amplitude, MLA did not disrupt any aspect of P20 gating, either when administered alone or prior to nicotine treatment. In contrast, DHβE + nicotine produced a significant disruption of P20 gating, primarily due to a reduction in S1 response. This suggests that the effect of nicotine on P20/P50 gating may occur through a DHβE sensitive mechanism.
Similar to previous reports, nicotine significantly decreased N40 amplitude 
. Administration of the α4β2 agonist AZD3480 significantly reduced N40 amplitude in a manner consistent with that seen following nicotine treatment. Likewise pretreatment with DHβE blocked the ability for nicotine to attenuate N40 amplitude. This pattern of results is consistent with evidence that nicotine alters N40 response through activation of the β2 subunit 
. A significant reduction in N40 was observed following MLA treatment alone, suggesting a possible role for α7 in mediating the N40 response. While this result is also consistent with the notion that blockade of the α7 receptor may have subsequently led to increased activation of the α4β2 receptor, MLA pretreatment was also sufficient to block the effect of nicotine on N40 response. Thus, stimulation of α7 receptor may play some role in regulating N40 amplitude. The N40, like the P20, displayed gating such that responses to S1 were significantly larger than responses to S2. However, unlike the P20, there was no interaction between stimulus and drug treatment, suggesting that N40 gating was not significantly affected by treatment with any of the antagonists used here. In contrast, AZD3480 significantly reduced gating, largely by reducing amplitude of the S1 component. These results suggest that the mechanisms that govern N40 gating are largely consistent with those that govern N40 amplitude and primarily involve stimulation of the β2 receptor.
Gamma activity has been associated with perceptual and cognitive processes as well as positive and negative symptoms in schizophrenia 
. In the present study, nicotine increased event-related gamma oscillations, replicating a previous study in our laboratory and a previous report regarding the effects of smoking on gamma 
. The nicotine-induced increases in evoked gamma were blocked by DHβE but not by MLA, suggesting a role for the α4β2 or α4β4 receptor in mediating these effects. Consistent with this interpretation, treatment with AZD3480 significantly increased both baseline FFT and event-related power within the gamma range, further suggesting that α4β2 receptors are critical to this effect. While there is much evidence to suggest therapeutic effects of nicotine on schizophrenia symptomology and cognitive function, few studies have assessed the effect of nicotine on gamma oscillations. The findings reported here raise the possibility that nicotine could produce some of its therapeutic effects through enhancement of gamma activity, and that this likely occurs primarily through stimulation of the β2 receptor subunit.