A rodent's survival depends upon its ability to perceive odor cues necessary to guide mate selection, sexual behavior, foraging, territorial formation, and predator avoidance. Arguably, the need to discriminate odor cues in a complex olfactory environment requires a highly adaptable olfactory system. Indeed, it has been proposed that context-dependent modulation of the initial sensory relay could alter olfactory perception. Interestingly, 40% of the adrenergic innervation from the locus coeruleus, fibers that are activated by contextual cues, innervates the first relay station in the olfactory system (the main olfactory bulb). Here we utilize restricted pharmacological inhibition of olfactory bulb noradrenergic receptors in awake-behaving animals. We show that combined blockade of ␣ and ␤ adrenergic receptors does not impair two-odor discrimination behavior per se but does impair the ability to discriminate perceptually similar odors. Thus, contextual cues conveyed by noradrenergic fibers alter processing before the second synapse in the olfactory cortex, resulting in tuning of the ability to discriminate between similar odors.Particularly intriguing, but poorly understood, is the potential role of adrenergic modulation of the main olfactory bulb (MOB) in adults. The MOB receives strong innervation from the locus coeruleus (LC)-noradrenaline (NA) system, and in rodents ∼40% of LC fibers target the MOB. The fibers are known to be densest in the internal plexiform and granule cell layers, less dense in the external plexiform layer, and sparse in the glomerular layer (McLean et al. 1989) (Fig. 1). Both ␣ and ␤ adrenergic receptors are expressed by cells in the MOB (Pieribone et al. 1994;Woo and Leon 1995;Day et al. 1997). Current evidence suggests that the LC-NA system has a behaviorally meaningful role within the MOB of adult animals engaged in olfactory learning tasks. There is a modest but reproducible release of NA in the MOB during operant conditioning in adult mice (Brennan et al. 1998). In addition, detection of the rewarded odor, presumably relayed from the prefrontal cortex to LC, triggers a brief phasic increase in firing of LC neurons (Bouret and Sara 2004). Gray and coworkers also find that the topical application of propranolol, a ␤ adrenergic antagonist, to the MOB abolished changes in ␥ frequency (40-100 Hz) oscillations in the local field potential elicited by the rewarded odor in an odor discrimination task (Gray et al. 1986). The modulation of odor-induced local field potential oscillations has been postulated to play a role in olfactory learning (Martin et al. 2006). Surprisingly, although the adrenergic effect on odor-induced changes in local field potential oscillations found by Gray and coworkers was robust, propranolol did not change the ability of rabbits to discriminate between odors. Data presented in this paper provide an explanation for the paradoxical observation of Gray and coworkers, as we show that blockade of both ␣ and ␤ adrenergic receptors in the MOB is necessary to attain a chan...