The effects of two antipsychotic (dopamine antagonist) drugs, haloperidol and clozapine, and of two psychotomimetic (dopamine-releasing) drugs, methamphetamine and cocaine, on neurotensin (NT) concentrations in discrete regions of the caudate nucleus, nucleus accumbens and globus pallidus were examined. Multiple administrations of haloperidol (HA, 1 mg/kg), clozapine (20 mg/kg), methamphetamine (METH, 10 mg/kg) or cocaine (30 mg/kg) increased NT-like immunoreactivity (NTLI) in the whole striatum (caudate nucleus plus globus pallidus). The effects of combined HA and METH treatment on striatal NTLI were additive. In contrast, the effects of clozapine plus METH were not different from those caused by either drug alone. The caudate nucleus, nucleus accumbens and globus pallidus were dissected into nine areas based on anterior-posterior and medial-lateral position. Across the caudate areas, some differences in NTLI concentrations occurred when cocaine- and METH-treated groups were compared, even though whole striata in these groups did not differ significantly. The effects of the antipsychotic drugs in discrete caudate regions, alone or in combination with METH, confirmed the observations in the whole striata, although significant regional differences existed. There were also differential regional effects in the nucleus accumbens. Drug-induced changes in the NTLI content of the anterior nucleus accumbens were similar to those observed in the whole striatum, whereas NTLI changes in the posterior region of this structure often were opposite. Finally, NTLI concentrations in the globus pallidus were increased by Ha or METH treatment, but were not affected by clozapine or cocaine treatment. These findings suggest that NT systems throughout the entire striatum and nucleus accumbens do not respond in a homogeneous manner to these drugs which stimulate or block dopamine activity. The regional differences in NT responses may reflect different dopamine neurons which are affected differentially by dopamine-altering drugs.