At present the mechanism by which nicotine enhances P20 amplitude is not entirely clear, although both a7 and a4b2 nicotinic receptors have been implicated. Transgenic mice lacking the b2 subunit show a typical nicotineinduced enhancement in P20 response to the first stimulus of a paired stimulus presentation but fail to show the normal nicotineinduced decrement in N40 S1 response, suggesting that the role of the a4b2 EX 527 receptor in sensory gating primarily involves the b2 subunit and is limited to regulation of the N40, but not P20, ERP component. While the a7 receptor has been shown to influence P20 response, this appears to occur primarily through decreased amplitude of response to the second stimulus of a stimulus pair, with S1 being relatively unchanged. Much less is presently known about how nicotine influences gamma EEG. To resolve these questions, the present study examined the effects of nicotine, the a7 nicotinic acetylcholine receptor antagonist methyllycaconitine, the a4b4/a4b2 nicotinic acetylcholine receptor antagonist dihydro-beta-erythroidine and the a4b2 receptor agonist AZD3480 on amplitude and gating of the P20 and N40 ERP components as well as baseline and evoked gamma oscillations in mice. In contrast, administration of the highly selective a7 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 DHbE sensitive, and not a7 receptor subtype sensitive mechanism. In contrast to the effects of receptor specific antagonists, administration of the a4b2 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 b2 knockout mice. DHbE has approximately 10 fold higher affinity at a4b4 receptors than at a4b2, suggesting that the enhancing effects of nicotine on the mouse P20 are mediated by a4b4 receptors. The b4 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 DHbE 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 DHbE treatment alone. This suggests that DHbE 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 DHbE treatment alone. While previous reports have suggested a role for a7 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 a7 and b4 subtypes, and that inactivation of a7 activity alone is not sufficient to fully block the response to nicotine.