Subsequent studies by the same authors shed considerable light on the molecular mechanisms subserving eCB-mediated LTDi in the BA. These authors found that LTDi was occluded by Win 55212-2 and did not depend upon post-synaptic elevations in intracellular calcium (Azad et al., 2004). A role for metabotropic glutamate receptors (mGluR) in LTDi was also suggested. The mGluR1/5 agonist, DHPG, suppressed eIPSC amplitude in a manner similar to LTDi in wild-type, but not CB1−/− mice. DHPG also occluded LFS-LTDi, and did not affect eIPSC amplitude after LTDi had been induced. A specific role for mGluR1, rather than mGluR5, was suggested based upon pharmacological evidence. LTDi was also found to be dependent upon post-synaptic G-protein activation and the adenylate cyclase (AC)-protein kinase A (PKA) pathway (Azad et al., 2004). However, LTDi was not dependent upon PLC or DAGL activity. Lastly, FAAH−/− mice (which exhibit elevated brain AEA levels) showed a more pronounced LTDi than wild-type mice. These authors suggest that the G-protein coupled mGluR1, acting via an AC-PKA pathway, is important for LTDi in the BA, and AEA rather than 2-AG may be the relevant eCB subserving this process (Azad et al., 2004).
