Effects of dopamine depletion on striatal neurotensin: biochemical and immunohistochemical studies

Abstract

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...

Neurotensin-deficient mice show altered responses to antipsychotic drugs

“…This suggestion is consistent with several studies that have reported that D 2 antagonists and other treatments that disrupt dopaminergic function result in the appearance of at least two distinct populations of NT neurons (38)(39)(40)(41)(42). One of these groups of NT cells is concentrated in the matrix compartment of the dorsomedial and ventrolateral striata; these cells rarely express Fos (38,42).…”

“…Whereas the observation that D 2 antagonist administration results in the appearance of NT cells that were previously below detection threshold suggests that basal functional activity of these cells may be low, several in vivo microdialysis studies have found detectable levels of NT in the striatum (39,51,52), consistent with a tonic regulation of striatal function by NT.…”

Lateral preoptic and ventral pallidal roles in locomotion and other movements

“…With the hal-SCH combo used in this study, we sought to replicate complete dopamine depletion based on empirical data showing that an extraordinary effect on the distribution of striatal neurotensin immunoreactivity caused by reserpine (Bean et al, 1989) was reproduced only with a combo of hal and SCH at these doses (Zahm, 1992). Lesser doses of dopamine antagonist and dopamine-depleting 6-hydroxydopamine lesions failed to replicate the unique effect of reserpine, so the drug effect was attributed to the production of CNS extracellular concentrations of antagonist adequate to achieve full blockade of dopamine receptors.…”

Distinct and interactive effects of d-amphetamine and haloperidol on levels of neurotensin and its mRNA in subterritories in the dorsal and ventral striatum of the rat

“…Furthermore, Wagstaff et al (1996) recently reported in vivo microdialysis data showing that the D 2-like antagonist eticlopride produces decreased extracellular neurotensin in the nucleus accumbens and a medial part of the dorsal striatum, which in the same condition exhibit increases in NT/N mRNA synthesis (present results; see also . Conversely, Wagstaff et al (1996) reported no change in extracellular neurotensin in the lateral part of dorsal striatum (see also Bean et al, 1989), where synthesis under this pharmacologic condition has been shown to be very robust (Merchant et al, 1991;Augood et al, 1991;. Finally, Wagstaff et al (1996) observed that increased extracellular levels of neurotensin were generated in the nucleus accumbens in response to administration of quinpirole, a dopamine D 2-like agonist that has no reported stimulatory effect on accumbal NT/N mRNA or peptide synthesis (Merchant and Dorsa, 1993;Zahm, unpublished observations).…”

“…As in a number of previous studies from this laboratory (Eggerman and Zahm, 1988;Zahm and Johnson, 1989;Zahm, 1992;Senger et al, 1993;Zahm, 1995, 1996), the analysis of the material in the present study relied on the observation that neurotensin peptide and NT/N mRNA are present in largely undetectable or barely detectable amounts in neurons in much of the dorsal striatum of naive and vehicle-treated rats (see also Jennes et al, 1982;Bean et al, 1989). Thus, increases in the areal density of immunolabeled and hybridized neurons in response to drug treatments were interpreted as increases in the amount of neurotensin or its NT/N mRNA in neurons to levels exceeding a threshold for detection.…”