PSNCBAM-1 has recently been described as a CB1 allosteric antagonist and associated with hypophagic effects in vivo; this study also suggested that PSNCBAM-1 actions were agonist-dependent in a yeast reporter assay (Horswill et al., 2007). The effects of PSNCBAM-1 (and other CB1 allosteric antagonists) on neuronal excitability remain unknown. Therefore, we investigated the action of PSNCBAM-1 on the well-characterised presynaptic CB1 receptor-mediated pathway at inhibitory interneurone-Purkinje cell (IN-PC) synapses. Patch-clamp electrophysiology was used to record miniature inhibitory postsynaptic currents (mIPSCs) at IN-PC synapses in acute parasagittal cerebellar slices from male, 3-5-week-old C57Bl/6 mice. The effects of PSNCBAM-1 (10 μM) alone and upon responses to the standard synthetic cannabinoid receptor agonists WIN55,2-212 (WIN55; 5 μM) and CP55,940 (5 μM) and the CB1 receptor antagonist AM251 (2 μM) were investigated. Application of PSNCBAM-1 alone did not affect mIPSC frequency (99 ± 6 % of CTL; n=12; P=0.8; paired t-test). WIN55 (74 ± 6 % of CTL; n=8; P<0.01; paired t-test) and CP55,940 (62 ± 6 % of CTL; n=6; P<0.01; paired t-test) both reduced mIPSC frequency, with no effect on mIPSC amplitude. Pretreatment with PSNCBAM-1 had no clear effect on WIN55-induced reduction in mIPSC frequency (76 ± 4 %; n=7; P<0.01; paired t-test). In contrast, pretreatment with PSNCBAM-1 abolished the CP55,940-induced reduction in mIPSC frequency (97 ± 11 %; n=5; P=0.83; paired-test). Application of AM251 increased mIPSC frequency beyond basal levels (117 ± 4 % of CTL; n = 7; P<0.01; paired t-test); interestingly, subsequently applied PSNCBAM-1 reduced mIPSC frequency (decrease to 104 ± 3% of CTL; n=7; P<0.01; repeated measures one-way ANOVA followed by Tukey’s HSD). Furthermore, pretreatment with PSNCBAM-1 attenuated the degree to which AM251 reversed WIN55 effects (reversal to 97 ± 6 % of CTL by AM251 pre-treated with PSNCBAM-1; n=8; P<0.01; vs reversal to 115 ± 7 % of CTL by AM251 alone; n=7; P<0.001; repeated measures one-way ANOVA followed by Tukey’s HSD). The observed effects of synthetic CB1 ligands confirmed the presence of a functional (endo)cannabinoid inhibitory pathway at IN-PC synapses in C57Bl/6 mice. The ability of PSNCBAM-1 to block CP55,940-induced, but not WIN55-induced decreases in inhibitory transmission are consistent with ligand-dependent PSNCBAM-1 effects. PSNCBAM-1 also attenuated the action of the CB1 antagonist AM251. Moreover, PSNCBAM-1 lacked properties associated with conventional CB1 receptor antagonists by failing to increase inhibitory transmission. Consequently, these data justify further investigation of ligand-dependent PSNCBAM-1 effects in modulating excitability in the cerebellum.