The effect of clonidine (5-20 micrograms/kg i.v.) on the activity of single, identified dopamine neurons in the ventral tegmental area of the mesencephalon was studied in chloral hydrate-anesthetized male rats. Clonidine regularized cell firing without affecting the firing rate of the neurons. This effect was blocked by idazoxan (0.5 mg/kg i.v.) or yohimbine (1.0 mg/kg i.v.), but not by phentolamine (1.0 mg/kg i.v.), indicating that clonidine acts at central alpha 2-adrenoceptors. Idazoxan or yohimbine alone produced deregularization and excitation of cell firing. Pretreatment with reserpine (5 mg/kg s.c.) 4 h before the experiment abolished the neuromodulatory effect of clonidine. Thus, the regularization of ventral tegmental area dopamine cell firing by clonidine is indirect and dependent on endogenous monoamines in brain, and, in principle, a tonic adrenergic control of DA cell firing pattern is indicated. The regularization of DA cell activity produced by clonidine may underlie certain therapeutic neuropsychiatric actions of the drug.