The pattern of activity and excitability of cortical neurons and neuronal circuits is dependent upon the interaction between glutamatergic and GABAergic fast-activating transmitter systems as well as the state of the more slowly acting transmitters such as ACh, norepinephrine, 5-HT, and histamine. Through the activation of GABAA receptors, GABAergic neurons regulate the amplitude and duration of EPSPs and, in so doing, control the level of functional activation of NMDA receptors. In contrast, activation of muscarinic, adrenergic, serotoninergic, histaminergic, and glutamate metabotropic receptors controls the excitability and pattern of action potential generation in identified pyramidal cells through increases or decreases in various K+ conductances. Activation of muscarinic, alpha 1-adrenergic, or glutamate metabotropic receptors on layer V burst-generating corticotectal or corticopontine neurons results in depolarization through a reduction in a K+ conductance and a switch in the firing mode from repetitive burst firing to single-spike activity. In contrast, activation of muscarinic, beta-adrenergic, H2-histaminergic, and serotoninergic receptors on regular-spiking layer II/III, V, and/or VI corticogeniculate pyramidal cells results in a decrease in spike frequency adaptation and increased responsiveness to depolarizing inputs through a reduction in a slow Ca(2+)-activated K+ current IAHP, and/or a voltage-dependent K+ current, IM. Through these, and other, mechanisms the spatial and temporal pattern of activity generated in cortical circuits is regulated by both intracortical and extracortical neurotransmitter systems.