Neurotensin regulates intracellular calcium in ventral tegmental area astrocytes: Evidence for the involvement of multiple receptors

Recent evidence suggests that some types of neurotensin receptors may be ex pressed by astrocytes. In order to explore the function of neurotensin rece ptors in astrocytes, the effect of a neurotensin receptor agonist, neuroten sin(8-13), on intracellular Ca2+ dynamics in mixed neuronal/glial cultures prepared from rat ventral tegmental area was examined. It was found that ne urotensin(8-13) induces a long-lasting rise in intracellular Ca2+ concentra tion in a subset of glial fibrilary acidic protein-positive glial cells. Th is response displays extensive desensitization and appears to implicate bot h intracellular and extracellular Ca2+ sources. In the absence of extracell ular Ca2+, neurotensin(8-13) evokes only a short-lasting rise in intracellu lar Ca2+. The neurotensin-evoked intracellular Ca2+ accumulation is blocked by the phospholipase C inhibitor U73122 and by thapsigargin, suggesting th at it is initiated by release of Ca2+ from an inositol triphosphate-depende nt store. The Ca2+-mobilizing action of neurotensin(8-13) in astrocytes is dependent on at least two receptors, because the response is blocked in par t only by SR48692, a type 1 neurotensin receptor antagonist, and is blocked completely by SR142948A, a novel neurotensin receptor antagonist. The find ing that the type 2 neurotensin receptor agonist levocabastine fails to mim ic or alter the effects of neurotensin(8-13) on intracellular Ca2+ makes it unlikely that the type 2 neurotensin receptor is involved. In summary, these results show that functional neurotensin receptors are pr esent in cultured ventral tegmental area astrocytes and that their activati on induces a highly desensitizing rise in intracellular Ca2+. The pharmacol ogical profile of this response suggests that a type 1 neurotensin receptor is involved but that another, possibly novel, non-type 2 neurotensin recep tor is also implicated. If present in vivo, such signalling could be involv ed in some of the physiological actions of neurotensin. (C) 2000 IBRO. Publ ished by Elsevier Science Ltd.