Interactions between striatal dopamine (DA) and neurotensin (NT) have been suggested by anatomical, behavioral, and biochemical studies. Nigrostriatal DA neurons, in contrast to mesocotticolimbic DA neurons, do not appear to contain NT. Thus, distinct neuronal elements subserve interactions between DA and NT within the striatum. We have previously demonstrated that reserpine-induced depletion of striatal DA is accompanied by a dose-and time-dependent increase in striatal NT concentrations. In order to further characterize the effects of reserpine and to define the mechanism by which reserpine acts to increase striatal NT concentrations, we have used immunohistochemical and biochemical approaches. lmmunohistochemical examination of rats pretreated with reserpine revealed marked increases in the density of NT-like immunoreactive (NT-Ii) perikarya and fibers, and the development of NT-Ii patches. Pretreatment with reserpine had no apparent effect on NT synthesis, as assessed by examination of cycloheximide-induced inhibition of protein synthesis. However, reserpine administration resulted in a significant decrease in the release of both DA and NT into the striatal extracellular fluid, as measured by in viva microdialysis. These data suggest that the increase in striatal NT concentrations observed after reserpine treatment results from decreased release, rather than increased synthesis of the peptide.Neurotensin (NT) is a tridecapeptide originally isolated from bovine hypothalamus Leeman, 1973,1976) which is heterogeneously distributed through the CNS (Carraway and Leeman, 1976;Uhl et al., 1977;Jennes et al., 1982;Uhl, 1982). The demonstration that NT perikarya, fibers, and receptors exist within the striatum (Young and Kuhar, 198 1;Jennes et al., 1982;Uhl et al., 1982), a brain region known to contain high concentrations of dopamine (DA), has led to studies aimed at elucidating the possible interactions between these transmitters/ modulators in this brain region. Nigrostriatal DA system function is influenced by NT. For example, NT enhances both basal Received Feb. 10, 1989; revised Apr. 27, 1989; accepted June 1, 1989. This and stimulated DA release from striatal slices; these effects may be mediated by NT receptors localized to the terminals of dopaminergic axons (De Quidt and Emson, 1983;Quirion et al., 1985;Hetier et al., 1988). Striatal NT levels have been shown to be influenced by DA; dopamine receptor antagonists have been reported to alter striatal NT levels and distribution (Govoni et al., 1980;Goedert et al., 1985;Frey et al., 1986;Nemeroff, 1986;Letter et al., 1987; Eggerman and Zahm, 1988). We have recently demonstrated that reserpine, which depletes monoamines by disrupting their vesicular storage, produces a dose-and time-related increase in striatal NT concentrations (Bean et al., 1989). The influence of reserpine on striatal NT levels might be anticipated on the basis of a postulated tonic inhibitory influence of DA on striatal NT levels (Merchant et al., 1988a). The increase in striatal NT tiss...

The mechanisms of action which account for the effectiveness of clozapine as a pharmacotherapy for the treatment of neuroleptic non-responders and neuroleptic intolerant schizophrenic subjects remain elusive. We review recent data concerning the actions of clozapine in laboratory animals, and discuss the likely sites of action of clozapine and the receptors through which clozapine acts. We suggest that actions at dopamine D(2) receptors in the caudate nucleus and putamen underlie the extrapyramidal side effects of conventional neuroleptics. In contrast, we propose that clozapine acts in the prefrontal cortex, specifically targeting an as yet unidentified DA receptor of the D(2) family, to exert therapeutic actions in neuroleptic non-responders. We suggest that the ability of clozapine to augment extracellular dopamine levels in the prefrontal cortex may represent a key mechanism contributing to the therapeutic effects of this drug, and suggest some alternative approaches which might be expected to result in effects similar to those of clozapine.