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Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion throughout cortex. N-methyl-D-aspartate (NMDA) receptors play a crucial role in the initiation of long-term memory. Neurochemical mechanisms underlying the transient memory storage required for working memory, however, remain obscure. Auditory sensory memory, which refers to the ability of the brain to retain transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, represents one of the simplest components of the brain working memory system. Functioning of the auditory sensory memory system is indexed by the generation of a well-defined event-related potential, termed mismatch negativity (MMN). MMN can thus be used as an objective index of auditory sensory memory functioning and a probe for investigating underlying neurochemical mechanisms. Monkeys generate cortical activity in response to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological micromanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in primary auditory cortex. These findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Furthermore, they suggest a crucial role of cortical NMDA receptors in the assessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance.Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As compared with long-term memory, which is critically dependent upon hippocampal long-term potentiation, critical substrates for working memory are distributed in a modality specific fashion throughout cortex (1, 2). On a neurophysiological level, working memory has been linked to transient, task-related alterations in the firing rates of neurons in modality-specific brain regions, permitting the use of intracortical recordings to investigate neurochemical mechanisms underlying functioning of the brain working memory system (3-5).Cortical information processing is critically dependent upon the interplay between glutamatergic and y-aminobutyric acid (GABA)ergic neurotransmission. Glutamate is the primary excitatory amino transmitter in mammalian cortex, being present in approximately 60% of cortical neurons and 100% of cortical pyramidal neurons. Glutamatergic fibers mediate all thalamocortical and corticortical projections within cortex, as well as corticofugal projections from cortex to subcortical structures. Within cortex, the interplay...