The transition from sleep to waking is associated with the abolition of spindle waves and the appearance of tonic activity in thalamocortical neurons and thalamic reticular/perigeniculate GABAergic cells. We tested the possibility that changes such as these may arise through modulation of the leak potassium current, IKL, by examining the effects of neurotransmitters known to modulate this current on spindle wave generation in the ferret geniculate slice maintained in vitro. Local application of agents that reduce IKL in thalamocortical neurons, including acetylcholine, DL-muscarine chloride and the glutamate metabotropic receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), to spontaneously spindling thalamocortical neurons resulted in a 5-10 mV membrane depolarization and the abolition of spindle waves. Local application of 1S,3R-ACPD and cholecystokinin-8-sulfate, both of which reduce IKL, to GABAergic neurons of the perigeniculate nucleus resulted in a 10-20 mV membrane depolarization, appearance of tonic discharge and the abolition of spindle wave generation. Local application of 1S,3R-ACPD and cholecystokinin to the perigeniculate nucleus while recording from thalamocortical neurons resulted in the abolition of spindle wave-associated inhibitory postsynaptic potentials and the occurrence of a continuous barrage of smaller amplitude inhibitory postsynaptic potentials, presumably in response to depolarization and tonic discharge of perigeniculate neurons. These results indicate that modulation of IKL in thalamocortical neurons and perigeniculate neurons is capable of abolishing the generation of spindle waves in thalamic networks. Through the modulation of IKL, ascending and descending activating systems may control the state of the thalamus such that the transition from slow wave sleep to waking is associated with the abolition of slow, synchronized rhythms and the facilitation of a state that is conducive to sensory receptor field analysis, arousal and perception.