Vol. 299, Issue 1, 332-342, October 2001

Behavioral Evidence for the Interaction of Oleamide with Multiple Neurotransmitter Systems

Irina Fedorova, Akihiro Hashimoto, Robert A. Fecik, Michael P. Hedrick, Lumír O. Hanu, Dale L. Boger, Kenner C. Rice and Anthony S. Basile

Laboratory of Bioorganic Chemistry (I.F., L.O.H., A.S.B.) and Laboratory of Medicinal Chemistry (A.H., K.C.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Chemistry and the Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (R.A.F., M.P.H., D.L.B.)

While the endogenous fatty acid amide oleamide has hypnotic properties, neither the breadth of its behavioral actions nor the mechanism(s) by which these behaviors may be mediated has been elucidated. Therefore, the effects of oleamide on the performance of rats in tests of motor function, analgesia, and anxiety were investigated. Oleamide reduced the distance traveled in the open field (ED₅₀ = 14, 10-19 mg/kg, mean, 95% confidence interval), induced analgesia and hypothermia, but did not cause catalepsy. Moreover, a dose of oleamide without effect on motor function was anxiolytic in the social interaction test and elevated plus-maze. These actions of a single dose of oleamide lasted for 30 to 60 min. While rats became tolerant to oleamide following 8 days of repeated administration, oleamide is a poor inducer of physical dependence. Pretreatment with antagonists of the serotonin (5HT)_1A, 5HT_2C, and vanilloid receptors did not modify oleamide's effects. However, the cannabinoid receptor antagonist SR 141716A inhibited oleamide-induced analgesia in the tail-flick assay, the -aminobutyric acid (GABA)_A receptor antagonist bicuculline reversed the analgesia and hypothermia, and the dopamine D₂ receptor antagonist L 741626 blocked oleamide's locomotor and analgesic actions. Interestingly, oleamide analogs resistant to hydrolysis by fatty acid amide hydrolase (FAAH) maintained but did not show increased behavioral potency or duration of action, whereas two FAAH inhibitors produced analogous behavioral effects. Thus, oleamide induces behaviors reminiscent of the actions of endogenous cannabinoids, but the involvement of GABAergic and dopaminergic systems, either directly or indirectly, in the actions of oleamide cannot be ruled out.