In addition to direct modulation of EPSCs by cannabinoids within the LA, Huang et al. have demonstrated a role for eCB signaling in amphetamine-induced LTD of EC-evoked EPSPs in LA principal neurons (Huang et al., 2003). Application of amphetamine caused a rapid, dose-dependent reduction in eEPSP slope with an early component (acute depression) and late component (LTD). Interestingly, the CB1 receptor antagonist, AM251, blocked the amphetamine-induced acute depression and LTD, while having no effect on eEPSP slope alone. In this preparation, Win 5512-2 produced an initial depression and LTD similar to amphetamine, an effect abolished by AM 251. A presynaptic mechanism of action for both amphetamine and Win 55212-2 was demonstrated by showing an increase in PPR and a reduction in mEPSPs frequency, but not amplitude, for both compounds. Furthermore, Win 55212-2 occluded amphetamine-induced LTD, while amphetamine occluded Win 55212-2-induced LTD. Similarly, blockade of eCB transport with AM404, at low concentrations, mimicked amphetamine and Win 55212-2 induced LTD, while at high concentrations occluded amphetamine-induced LTD. eCB-mediated amphetamine LTD was dependent upon postsynaptic calcium influx and P/Q-type calcium channel activity. Taken
