Several points are particularly relevant to an understanding of the effects of clonidine in the brain: Clonidine appears to act preferentially at alpha-2 adrenergic receptors and, in systemic doses of less than 50-100 microgram/kg, to exert its effects at autoreceptors, which initially decrease noradrenergic neuronal firing rates, NE release, and NE turnover. This action results in functional decreases of the usual effects of these neurons at their post synaptic alpha-1 and beta-adrenergic receptor-mediated projections, which are widely distributed throughout the limbic system, cerebrum, cerebellum, and spinal cord. Higher doses of clonidine appear to produce agonist effects at alpha-1 adrenergic receptors, counteracting the effects of decreases in firing rates and turnover. However, decreased function at beta receptors would continue after these higher doses owing to continued inhibition of neuronal activity and the lack of direct effects of clonidine on beta receptors. Receptors for GABA, endorphins, substance P, and ACh on LC neurons provide an anatomical and physiological basis for interactions among systems utilizing these substances as neurotransmitters in that they act on a common final noradrenergic pathway. These noradrenergic pathways, in turn, also project to and mediate functional changes in areas utilizing other neurotransmitters. Although these changes affect numerous types of behavior and responses that are measurable by psychopharmacologists, it is the neurons of the locus coeruleus and other noradrenergic neurons with similar receptor combination that provide the entry point to this NE system. Studies of the LC, therefore, may help to determine the nature of these specific effects and to characterize the effects of clonidine and other alpha-2 agonists on the brain.