Cannabinoids, whether naturally occurring (Δ9-THC), synthetic (WIN55212-2) or endogenous (anandamide, 2-AG) have all been shown to disrupt hippocampal LTP (Terranova et al. 1995; Stella et al. 1997). Oleamide (cOA) is a brain lipid with sleep-inducing properties that are blocked by the CB1 receptor antagonist SR141716A (Mendelson & Basile, 1999). Here we examine the effects of the putative endocannabinoid on the induction of LTP in rat brain slices.

Male Wistar rats (150Ð200 g) were humanely killed and transverse slices (400 mm) containing the hippocampus were obtained. After 1 h recovery, slices were perfused (2Ð3 ml min^-1) with ACSF (composition (mM): NaCl 124, KCl 3, MgCl₂ 1, CaCl₂ 2, NaHCO₃ 26, NaH₂PO₄ 1.25 and D-glucose 10, equilibrated with carbogen) at 35 °C. ACSF was supplemented with 0.1 % BSA and 0.1 % DMSO in all experiments to aid drug dissolution. Extracellular field potentials (fEPSP) were obtained from the stratum radiatum in response to stimulation of the Schaffer’s collaterals (0.1 ms pulses, 0.05 Hz). We assessed synaptic modulation as changes in the initial slope (20Ð80 % of maximum amplitude of the fEPSP) of the recorded signal. fEPSP values are expressed as % mean ± S.E.M. (normalised to pretreatment). Statistical tests are as stated below. A P value of < 0.05 was judged significant.

HFS (high frequency stimulation, 100 Hz for 1 s repeated after 20 s) predictably increased the slope of the fEPSP 30 min after stimulation in the absence of drugs (191 ± 24 vs. control baseline, P < 0.01, paired t test, n = 5), while u-burst (10 trains of 4 bursts at 100 Hz delivered 200 ms apart), given 30 min post-HFS, caused a smaller further incremental increase in fEPSP slope measured a further 30 min later (132 ± 5 vs. pre-u baseline, paired t test, P > 0.05, n = 5). Neither 32 µM cOA nor 10 µM anandamide significantly altered the fEPSP slope during pre-incubation in ACSF, prior to high frequency stimulation, but WIN55212-2 (5 mM) depressed fEPSP amplitude and slope (59 ± 4.5 of control, n = 4, P < 0.01, paired t test). WIN55212-2 (5 mM) reliably, and potently, inhibited both HFS and u-burst LTP induction (HFS 104.5 ± 4.856, u-burst 105.0 ± 5.845, n = 4, unpaired t tests, P < 0.001). Anandamide (10 mM), significantly attenuated responses to HFS-induced LTP, but failed to block u-burst-LTP (HFS 130.0 ± 13.05, P < 0.05, u-burst 139.8 ± 13.92, P > 0.05, n = 5, unpaired t tests). Oleamide (32 mM) did not block HFS-LTP but attenuated u-burst-LTP (HFS 174.5 ± 22.91 P < 0.05, u-burst 109.5 ± 4.406, P > 0.05, n = 4, unpaired t tests).

Oleamide does not profoundly and indiscriminately occlude LTP as seen with synthetic cannabinoid agonists. The different profiles observed with endocannabinoids may reflect mechanisms of action, but differential lipophilicity, permeation and metabolism within the slice complicate this issue.

This work was supported by The Wellcome Trust, College of Pharmacy Practice, RPharm Soc GB and NI.

All procedures accord with UK legislation.