The sleep-inducing properties of cis-oleamide (cOA) may reflect quenching of the FAAH enzyme, which degrades the endocannabinoid anandamide (Mechoulam et al. 1997). cOA is itself an inhibitor of FAAH and we have previously reported that at a dose of 32 mM it fails to inhibit LTP. Here we investigate the effects of FAAH inhibition (1,1,1-trifluoro10(Z)-nonadecen-2-one (TFNO) ± cOA) and of uptake inhibition (AM404) on LTP induction by high-frequency stimulation (HFS) in the hippocampal slice.

Male Wistar rats (ca 150 g) were humanely killed and transverse hippocampal slices (400 mm) were isolated. After ▓ge│ 1 h, slices were perfused (2-3 ml min^-1) with ACSF (composition (mM): NaCl 124, KCl 3, MgCl₂ 1, CaCl₂ 2, NaHCO₃ 26, NaH₂PO₄ 1.25, D-glucose 10, equilibrated with carbogen) at 34.6 ± 0.2°C (n = 10). ACSF was supplemented with 0.1 % of DMSO and BSA to aid the dissolution of cOA. Extracellular fEPSPs were obtained from the stratum radiatum in response to stimulation of the Schaffer collaterals (0.1 ms pulses, 0.05 Hz). We quantified changes in the initial slope (20-80 % of maximum amplitude) 30 min after the conditioning protocols (all ligands were applied at least 60 min before the conditioning train was given at 100 Hz for 1 s). Values are expressed as % of mean ± S.E.M. (normalised to pretreatment). A P value of less than 0.05 was significant.

The HFS protocol caused a significant and sustained increase in the slope of the fEPSP compared with untreated controls. (159.8 ± 6.4 %, n = 4). TFNO (1 mM) did not block the induction of LTP when compared with the controls (171.3 ± 12.85 %, n = 4, P > 0.05, unpaired t tests). cOA (32 mM), in the presence of TFNO (1 mM), did not inhibit HFS-LTP(166.0 ± 12.9 %, P > 0.05, n = 4, unpaired t tests). On the contrary, AM404 (20 mM) significantly attenuated LTP after 30 min (137.0 ± 2.1 %, n = 4, P < 0.001, unpaired t test).

Selective inhibition of the metabolism of anandamide by TFNO does not block CA1 LTP, which is sensitive to exogenous anandamide (Terranova et al. 1995). Combination of TFNO and cOA did not block LTP either, which emphasises oleamide’s lack of CB1 agonist properties in our hands. The transport inhibitor AM404 does attenuate LTP. This has some parallels in vivo where systemically administered FAAH inhibitors or anandamide transport inhibitors potentiate the actions of the endocannabinoids, but only the latter increases anandamide titres in plasma (Giuffrida et al. 2000).

Thanks to The Wellcome Trust, College of Pharmacy Practice and The RPharmS for financial support.

All procedures accord with current UK legislation.