Central administration of neurotensin (NT) results in a variety of neurobehavioral effects which, depending upon the administration site, resemble the effects of antipsychotic drugs (APDs) and psychostimulants. All clinically effective APDs exhibit significant affinities for dopamine D(2) receptors, supporting the hypothesis that an increase in dopaminergic tone contributes to schizophrenic symptoms. Psychostimulants increase extracellular dopamine (DA) levels and chronics administration can produce psychotic symptoms over time. APDs and psychostimulants induce Fos and NT expression in distinct striatal subregions, suggesting that changes in gene expression underlie some of their effects. To gain insight into the functions of NT, we analyzed APD and psychostimulant induction of Fos in NT knockout mice and rats pretreated with the NT antagonist SR 48692. In both NT knockout mice and rats pretreated with SR 48692, haloperidol-induced Fos expression was markedly attenuated in the dorsolateral striatum; amphetamine-induced Fos expression was reduced in the medial striatum. These results indicate that NT is required for the activation of specific subpopulations of striatal neurons in distinct striatal subregions in response to both APDs and psychostimulants. This review integrates these new findings with previous evidence implicating NT in both APD and psychostimulant responses.