Effects of intracerebroventricular D-myo-inositol-1,2,6-trisphosphate (PP56), a proposed neuropeptide Y (NPY) antagonist, on locomotor activity, food intake, central effects of NPY and NPY-receptor binding.
D-myo-Inositol-1,2,6-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.
Heilig
M
M
Department of Neuropharmacology, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
Edvinsson
L
L
Wahlestedt
C
C
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D004435:Eating / Q000187:drug effects*; D006801:Humans; D006963:Hyperphagia / Q000139:chemically induced / Q000188:drug therapy; D007103:Immobilization / Q000502:physiology; D007276:Injections, Intraventricular; D007295:Inositol Phosphates / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008566:Membranes / Q000378:metabolism / Q000648:ultrastructure; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017476:Receptors, Neuropeptide Y; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007295:Inositol Phosphates; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D017981:Receptors, Neurotransmitter; C059368:atrinositol