Noradrenergic modulation of the glutamatergic-GABAergic synapses between mitral/tufted (M/T) and granule cells has been implicated in some forms of olfactory learning (Brennan et al., 1990). Norepinephrine (NE) has been shown to disinhibit mitral cells (Jahr and Nicoll, 1982), but its site of action is not well defined. The effects of NE on synaptic transmission between monosynaptically coupled pairs of mitral and granule cells have been examined using primary culture and whole- cell recording techniques. Intracellular stimulation of M/T cells evoked dual-component EPSPs in granule cells consisting of both NMDA and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) receptor-mediated mechanisms. The EPSPs were reversibly inhibited by approximately 50% during application of 30 microM NE. NE had no effect, however, on the membrane current evoked by exogenous application of glutamate, indicating a presynaptic site of action. The effect of NE on EPSPs was mimicked by the alpha-adrenergic agonist clonidine but not by the beta-adrenergic agonist isoproterenol. NE had no significant effect on either accommodation or macroscopic currents in either M/T or granule cells. NE also inhibited spontaneous GABAergic IPSPs recorded in M/T cells, by a presynaptic alpha-adrenergic-mediated mechanism. These results support previous results suggesting a disinhibitory role for NE in the olfactory bulb. This action, however, is at least in part mediated by a reduction in mitral cell-mediated granule cell excitation.