Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems

J Pharmacol Exp Ther. 2001 Oct;299(1):332-42.


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, 5HT2C, 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 gamma-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amidohydrolases / metabolism
  • Animals
  • Anxiety / psychology
  • Behavior, Animal / drug effects*
  • Body Temperature / drug effects
  • Catalepsy / chemically induced
  • Drug Tolerance
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Male
  • Motor Activity / drug effects
  • Neurotransmitter Agents / physiology*
  • Oleic Acids / adverse effects
  • Oleic Acids / chemical synthesis
  • Oleic Acids / pharmacology*
  • Pain Measurement / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Social Behavior
  • Substance Withdrawal Syndrome / psychology


  • Enzyme Inhibitors
  • Neurotransmitter Agents
  • Oleic Acids
  • oleylamide
  • Amidohydrolases
  • fatty-acid amide hydrolase