Cannabinoids cause an increase in synaptic transmission via gamma-aminobutyric acid (GABA) receptors and this may be the mechanism by which activation of CB1 receptors blocks the induction of long-term potentiation (LTP). To test this hypothesis, we used paired pulse depression (PPD) of CA1 population spike responses recorded in the rat hippocampal slice as an index of GABA-ergic feedback inhibition, to establish whether the effects of a stereoselective CB1 receptor agonist on GABA-ergic transmission and LTP were correlated. The active isomer, WIN55212-2, blocked the induction of LTP and suppressed PPD over the concentration range 250 nM-5 microM, whereas the inactive isomer, WIN55212-3, was inactive at 5 microM. The effects of 5 microM WIN55212-2 on both LTP and PPD were completely blocked by the CB1 receptor antagonist SR141716A (5 microM). The results show that the effects are correlated in that both suppression of PPD and blockade of induction of LTP are probably mediated by CBI receptors. However, the suppression in PPD suggests that WIN55212-2 caused a decrease in GABA-ergic feedback transmission which would be expected to facilitate, rather than block, the induction of LTP. We therefore conclude that the blockade of LTP by cannabinoids is not via upregulation of GABA-ergic synaptic transmission.