Abstract
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 γ-aminobutyric acid (GABA)Areceptor 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.
Footnotes
-
This study was supported by the Skaggs Institute for Chemical Biology, the National Institutes of Health (CA42056, to D.L.B.), and the American Cancer Society (Fellowship 576211, to R.A.F.).
- Abbreviations:
- AEA
- arachidonyl ethanolamide
- CB
- cannabinoid
- FAAH
- fatty acid amide hydrolase
- 5HT
- serotonin
- GABA
- γ-aminobutyric acid
- DMSO
- dimethyl sulfoxide
- MPE
- maximum possible effect
- CI
- confidence interval
- ANOVA
- analysis of variance
- Received April 11, 2001.
- Accepted June 15, 2001.
- U.S. Government
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|