Figure 1.

JWH018 decreases neurotransmitter release by activating presynaptic CB₁ receptors. (A) Chemical structure of JWH018. (B) JWH018 concentration-dependently decreased EPSC charge (n= 8 to 14 for each concentration tested). This inhibitory effect was reversed by 1 µM rimonabant (n= 12) and was absent in CB₁−/− neurons (n= 5). (C) A representative experiment showing a time course of EPSC inhibition by 1 nM JWH018 followed by 100 nM JWH018. 1 µM rimonabant reversed JWH018 inhibition. Inset shows representative traces for three indicated time points. JWH018 (100 nM) significantly increases the paired-pulse ratio (right: representative traces of paired pulses, numbers indicate order of pulses) (D) and decreases miniature EPSC frequency (E) without affecting miniature EPSC amplitude (F), indicative of decreasing the probability of neurotransmitter release by acting at a presynaptic site (n= 5 to 8 for each). Inset scale bars: 1 nA and 10 ms. (G) Coefficient of variation analysis demonstrating that r < π < 1, which is consistent with a presynaptic site for JWH018's action resulting in synaptic depression. Values are presented as mean ± SEM where applicable. *P < 0.05, **P < 0.01, ***P < 0.0001. CB₁, cannabinoid receptor 1; EPSC, excitatory postsynaptic current.