It was previously reported that following striatal dopamine depletion or pharmacological blockade of dopamine neurotransmission, neurotensin immunoreactivity is elicited in at least two distinct subpopulations of striatal neurons (Neuroscience Vol. 46, pp. 335-350, 1992). Recently it was shown that Fos immunoreactivity, interpreted as an indicator of enhanced neuronal activity, is appreciably co-localized in only one of the subpopulations of neurotensin-immunoreactive neurons observed following blockade of the dopamine D2 receptor (Neuroscience Vol. 57, pp. 649-660, 1993). In the present study, similar methods were used to determine the degree of co-localization of Fos and neurotensin immunoreactivity in striatal neurons in response to the dopamine-depleting effects of 6-hydroxydopamine lesions and reserpine administration. It was observed that following these treatments, a subpopulation of neurons at the small end of the medium size range exhibited light neurotensin immunoreactivity and frequent co-localization with Fos immunoreactivity. This population was predominant after reserpine administration in the dorsolateral quadrant of the striatum. Another subpopulation comprised larger neurons that exhibited intense neurotensin immunoreactivity in perikarya and proximal processes that was rarely co-localized with Fos immunoreactivity. This type of neuron was observed following all the drug treatments but was present almost to the exclusion of the smaller type of cells three days following ventral midbrain 6-hydroxydopamine lesions, being mainly located in the dorsomedial and ventrolateral portions of the striatum. The present data support the results of the preceding studies in being consistent with the existence of two subpopulations of striatal neurons that accumulate neurotensin following dopamine depletion. The possibility is considered that one subpopulation accumulates neurotensin in response to co-ordinate increases in neuronal activity and neurotensin synthesis, and the other as a result of decreased release.