Numerous lines of evidence indicate that neural information is exchanged between the cerebral hemispheres via the corpus callosum. Unilateral ablation lesions of barrel field cortex (BFC) in adult rats induce strong suppression of background and evoked activity in the contralateral barrel cortex and significantly delay the onset of experience-dependent plasticity. The present experiments were designed to clarify the basis for these interhemispheric effects. One possibility is that degenerative events, triggered by the lesion, degrade contralateral cortical function. Another hypothesis, alone or in combination with degeneration, is that the absence of interhemispheric activity after the lesion suppresses contralateral responsiveness. The latter hypothesis was tested by placing an Alzet minipump subcutaneously and connecting it via a delivery tube to a cannula implanted over BFC. The minipump released muscimol, a GABA(A) receptor agonist at a rate of 1 mul/h, onto one barrel field cortex for 7 days. Then with the pump still in place, single cells were recorded in the contralateral BFC under urethan anesthesia. The data show a approximately 50% reduction in principal whisker responses (D2) compared with controls, with similar reductions in responses to the D1 and D3 surround whiskers. Despite these reductions, spontaneous firing is unaffected. Fast spiking units are more sensitive to muscimol application than regular spiking units in both the response magnitude and the center/surround ratio. Effects of muscimol are also layer specific. Layer II/III and layer IV neurons decrease their responses significantly, unlike layer V neurons that fail to show significant deficits. The results indicate that reduced activity in one hemisphere alters cortical excitability in the other hemisphere in a complex manner. Surprisingly, a prominent response decrement occurs in the short-latency (3-10 ms) component of principal whisker responses, suggesting that suppression may spread to neurons dominated by thalamocortical inputs after interhemispheric connections are inactivated. Bilateral neurological impairments have been described after unilateral stroke lesions in the clinical literature.