European Journal of Pharmacology, 209 (1991) 27-32 27 © 1991 Elsevier Science Publishers B.V. All rights reserved 0014-2999/91/$03.5(I EJP 52180 Effects of intracerebroventricular D-myo-inositol-l,2,6-trisphosphate (PP56), a proposed neuropeptide Y (NPY) antagonist, on locomotor activity, food intake, central effects of NPY and NPY-receptor binding Markus Heilig 1, Lars Edvinsson z and Claes Wahlestedt 3 I Department of Neuropharmacology, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037, U.S.A., 2 Department ()[ Internal Medicine, Utm'ersity of Lund, Lund, Sweden and ~Dicision of Neurobiology, Department of Neurology and Neuroscience, Cornell Unicersity Medical College, New York, ArE, U.S.A. Received 28 May 1991, revised MS received l0 September 1991, accepted 17 September 1991 D-myo-Inositol-l,2,6-trisphosphate (PP56) is a novel experimental drug which is structurally related to the intracellular second messenger IP3. Among other pharmacological effects, PP56 has been shown to antagonize neuropeptide Y (NPY) induced vasoconstriction with a high degree of specificity. We examined the effects of i.c.v. PP56 on locomotor activity and food intake in rats, and on the hypoactivity and hyperphagia induced by NPY. In the open field, PP56 given alone increased locomotor activity by up to 85%. It did not prevent NPY induced hypoactivity to any extent. PP56 given alone did not affect food intake except for a small increase after the highest dose tested (200 nmol). When NPY was given after pretreatment with PP56, NPY induced hyperphagia was significantly reduced. A similar effect, however, was seen with regard to the hyperphagia produced by another orexigenic peptide, galanin. PP56 did not affect the binding of 125I-NPY to brain membranes in vitro, or to cells of two different neuroblastoma cell lines which selectively express NPY Y1 or Y2 receptors. In summary, PP56 acted as a locomotor stimulant per se. Only one of the two tested central effects of NPY could be antagonized by PP56, and then only partially and in a non-specific manner. The central effects of PP56 do not seem to be produced at the level of NPY receptors. Neuropeptide Y (NPY); IP3; Locomotion; (Feeding); (Receptors) 1. Introduction D-myo-Inositol-l,2,6-trisphosphate (PP56; U.S. Pat. No. 4735963) is a stereoisomer of the intracellular second messenger, 1,4,5-IP3 (Berridge and Irvine, 1989). In contrast to this compound, however, PP56 does not lead to the release of intracellular Ca 2+ (Authi et al., 1989). Whether PP56 interacts with the IP 3 systems in other ways is currently not known. Some interesting pharmacological effects of PP56 have, however, been reported after its peripheral administration to experi- mental animals and humans. These effects include inhibition of inflammatory reactions (Claxson et al., 1990), inhibition of oedema formation in skin burn injury (Cassuto et al., 1990) and prevention of diabetic complications (Ruf et al., 1990). In addition, the results of in vitro and in vivo experiments suggest that PP56 Correspondence to: M. Heilig, Department of Neuropharmacology, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037, U.S.A. can selectively block the action of neuropeptide Y (NPY) (Edvinson et al., 1990; Sun et al., unpublished). The cellular and molecular mechanisms of this antago- nism are not known. No data are available on possible central effects of PP56. NPY, a 36 amino acid (a.a.) neuromessenger origi- nally isolated from the porcine brain (Tatemoto et al., 1982) is present in high amounts in both the peripheral (PNS) and the central nervous system (CNS) of mam- mals (Lundberg et al., 1982; Adrian et al., 1983). Bind- ing sites for NPY have been demonstrated (Und6n et al., 1984), and a heterogeneity of both central and peripheral NPY receptors seems to exist (Wahlestedt et al., 1986; Heilig et al., 1988; Wahlestedt et al., 1990). Numerous effects of centrally administered NPY have been reported, and these have recently been reviewed (Heilig and Widerl6v, 1990). Two of the most promi- nent central effects of NPY are sedation, as expressed by decreased locomotor activity in the open field and stress protective action (Heilig and Murison, 1987a,b; Heilig et al., 1989), and hyperphagia (e.g. Levine and Morley, 1984; Kaye et al., 1990).