Plasticity of neuronal covariances (functional plasticity) is controlled by behavior (Ahissar et al (1992) Science 257, 1412-1415). Whether this behavioral control involves neuromodulatory systems was tested by examining the effect of acetylcholine (ACh) and noradrenaline (NE) on functional plasticity in anesthetized animals and by comparing the effects of these neuromodulators in an anesthetized preparation to that of behavior in awake animals. Local ionotophoretic applications of these drugs during manipulations of activity covariance in guinea pig auditory cortex did not mimic the behavioral control of functional plasticity that was previously observed in awake monkeys. Thus, the hypotheses according to which these neuromodulators control functional plasticity independent of their concentration and time of release were not supported by our data. The significant plasticity induced nevertheless, by some of the conditionings in the presence of ACh and NE, suggests that factors, other than those that were experimentally controlled, could regulate this plasticity. These factors could be among others the timing of drug(s) applications relative to the conditioning time, the local concentrations of the drug(s) and/or the site of application with respect to the relevant synapses.