Neurotensin is an endogenous neuropeptide that produces many CNS effects that are similar to the behavioral and physiological alterations seen after administration of antipsychotic drugs to laboratory animals. As previously reported, sub-chronic (3 week) and acute (single injection) treatment with haloperidol (1 mg/kg), a clinically effective antipsychotic drug increases neurotensin concentrations in the nucleus accumbens and the caudate nucleus. In contrast, a tricyclic antidepressant (desipramine, 10 mg/kg), an anxiolytic (chlordiazepoxide, 25 mg/kg) and a histamine H1 receptor antagonist (diphenhydramine, 20 mg/kg) did not alter neurotensin concentrations in these brain regions after sub-chronic or acute treatment. These data demonstrate pharmacologic specificity to the antipsychotic drug-induced increases in regional brain neurotensin concentrations, and support the hypothesis that these changes may contribute to the clinical efficacy of these drugs.