Altered levels of catecholamines (dopamine or norepinephrine) or perturbations in their relationship to other neurotransmitter systems (particularly the cholinergic system) have been suggested as causal factors in several human mental disorders. Herpes simplex virus infection of the central nervous system alters catecholamine metabolism and has been suggested to be a causative factor in certain forms of mental illness. As a means of studying chronic HSV infection, we have developed a dual inoculation procedure employing footpad inoculation followed at a 2-week interval by intracerebral challenge with an identical HSV inoculation. In addition, we have employed daily, peripheral injections of d-l-amphetamine to further aid in the study of HSV effects on behavior. Central HSV infection, in the immunized animal, led to a significant decrease in locomotor activity and to an alteration in the response of the infected animal to amphetamine (a shifting of the dose response curve to the right). These results suggest that chronic HSV infection of the CNS leads to a decrease in activity of the catecholaminergic system that may involve either alterations in the release of dopamine and norepinephrine or their effect on postsynaptic receptors.