Norepinephrine (NE) and serotonin (5-HT) are important modulators of early odor preference learning. NE can act as an unconditioned stimulus (UCS), whereas 5-HT facilitates noradrenergic actions. In this study, we examined the phosphorylation of an important transcription factor, cAMP response element binding protein (CREB), which has been implicated in long-term-memory formation (McLean et al. 1999) during NE-induced odor preference learning in normal and olfactory bulb 5-HT-depleted rat pups. We also examined NE modulation of olfactory nerve-evoked field potentials (ON-EFPs) in anesthetized normal and bulbar 5-HT depleted pups. Systemic injection of 2 mg/kg isoproterenol (beta-adrenoceptor agonist) induced odor preference learning, enhanced pCREB expression in the olfactory bulbs at 10 min after odor pairing, and increased ON-EFPs in normal rat pups but not in bulbar 5-HT-depleted rat pups. A dose of 6 mg/kg isoproterenol, which was ineffective in modulating these measures in normal rat pups, induced odor preference learning, enhanced phosphorylated CREB (pCREB) expression, and increased ON-EFPs in bulbar 5-HT-depleted pups. These outcomes suggest that NE and 5-HT promote specific biochemical and electrophysiological changes that may critically underlie odor preference learning.