The present results are from rats that were intended as sham-operated controls in a study of unilateral lesion of the cortical barrel fields. These animals received a trephine hole through the skull, centered over the barrel fields of one hemisphere. Unexpectedly, they showed time-dependent behavioral and neurochemical asymmetries: 1 + 4 days after unilateral skull trephination they scanned an open field mainly with the contralateral vibrissae. Thereafter (days 7 + 14), scanning recovered to symmetry; however, an ipsilateral asymmetry was induced now by challenge with the dopamine receptor agonist apomorphine. At the same time period after skull trephination, an asymmetry of thigmotactic swimming had developed, with more thigmotactic swimming ipsilateral to the side of skull trephination. Neurochemically, there were indications for changes in neostriatal dopamine metabolism because the tissue levels of dopamine and dihydroxyphenylacetic acid were lower on the ipsilateral side in animals killed 6-16 days after trephination. The time courses of behavioral and neurochemical asymmetries after unilateral skull trephination paralleled those seen following unilateral barrel cortex lesion or unilateral removal of the corresponding contralateral vibrissae; however, without exception, the asymmetries after trephination were in the opposite direction than after cortex lesion or vibrissae removal. The possible mechanisms by which skull trephination might have affected behavior and neurochemistry are discussed, especially with respect to the vibrissae-barrel cortex system and the basal ganglia. Because trephination of the skull is routinely employed, both as a control procedure and for CNS manipulation, these results may have important implications for the design of future experiments.