Brain lipids that induce sleep are novel modulators of 5-hydroxytrypamine receptors.
Amide derivatives of fatty acids were recently isolated from cerebrospinal fluid of sleep-deprived animals and found to induce sleep in rats. To determine which brain receptors might be sensitive to these novel neuromodulators, we tested them on a range of receptors expressed in Xenopus oocytes. cis-9,10-Octadecenamide (ODA) markedly potentiated the action of 5-hydroxytryptamine (5-HT) on 5-HT2A and 5-HT2C receptors, but this action was not shared by related compounds such as oleic acid and trans-9,10-octacenamide. ODA was active at concentrations as low as 1 nM. The saturated analog, octadecanamide, inhibited rather than potentiated 5-HT2C responses. ODA had either no effect or only weak effects on other receptors, including muscarinic cholinergic, metabotropic glutamate, GABA(A), N-methyl-D-asparate, or alpha-amino-3-hydroxy-5-methyl-4-isoxozolepropionic acid receptors. Modulation of 5-HT2 receptors by ODA and related lipids may represent a novel mechanism for regulation of receptors that activate G proteins and thereby play a role in alertness, sleep, and mood as well as disturbances of these states.
Huidobro-Toro
J P
JP
Unidad Regulacion Neurohumoral, Departamento de Fisiologia, Facultad Ciencias Biologias, Pontificia, Universidad Catolica de Chile, Santiago.
Harris
R A
RA
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000502:physiology*; D002531:Cerebellum / Q000502:physiology; D002554:Cerebrosides / Q000302:isolation & purification / Q000494:pharmacology* / Q000502:physiology; D005260:Female; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009829:Oleic Acids / Q000302:isolation & purification / Q000494:pharmacology* / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000577:Amides; D002554:Cerebrosides; D009829:Oleic Acids; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D012701:Serotonin; C029407:oleylamide; D007608:Kainic Acid