In the hypoglossal nucleus, DSI of glycinergic inhibition to principal cells has been reported, suggesting that it

is not ZD1839 ic50 confined to GABAergic synapses (Mukhtarov et al., 2005). Although DSI generally lasts less than 5 min, eCBs have also been implicated in LTD of GABAergic inhibitory transmission (“iLTD”). In the lateral amygdala, low-frequency stimulation at 1 Hz, designed to release glutamate at synapses on the target neuron, was followed by a persistent depression of inhibitory transmission, which was sensitive to blocking either mGluR1 or CB1 receptors (Marsicano et al., 2002). The effect was potentiated by blocking anandamide degradation, implying that this eCB, rather than 2-AG, is involved (Azad et al., 2004). In contrast, iLTD in hippocampal pyramidal neurons is sensitive to blocking diacylglycerol lipase (Chevaleyre and Castillo, 2003), implicating 2-AG. Roles for presynaptic adenylate cyclase, inhibited by the αi/o limb of the CB1 signaling cascade, and for the active zone protein RIM1α, discriminate iLTD from DSI (Chevaleyre et al., 2007). This brief summary of CB1 receptor-mediated plasticity of inhibition focuses exclusively on activity-dependent eCB signaling. Signaling by eCBs may also be tonically active. For example, a CB1 antagonist was shown to increase GABA release from a subset of hippocampal CCK-positive interneurons (Losonczy et al., 2004), and similar results have been

reported in the hypothalamus (Oliet et al., 2007). These reports raise the possibility that CB1 receptor-mediated control of GABA release can be Small molecule library mw modulated up or down. However, most of the available CB1 antagonists act as inverse agonists (Kirilly et al., 2012). The observation that these compounds can increase GABA release could therefore be explained as relief from constitutive G protein-coupled receptor activity and therefore falls short of demonstrating basal occupancy of CB1 receptors by continued synthesis of eCBs. Several other retrograde factors have been reported to modulate GABA release

and lead to long-term changes because in inhibitory transmission. In the ventral tegmental area, nitric oxide can be synthesized in response to high-frequency stimulation of glutamatergic afferents innervating dopaminergic cells. Nitric oxide in this system appears to trigger LTP of GABAergic transmission (Nugent et al., 2007). This phenomenon coexists with eCB-mediated iLTD in the same dopaminergic neurons (Pan et al., 2008), and these long-term changes in GABAergic signaling are modulated by drugs of abuse and D2 dopamine receptors (Nugent et al., 2007; Pan et al., 2008). In the neonatal hippocampus, high-frequency stimulation of afferent fibers can lead to a presynaptic form of LTD of GABAergic transmission (McLean et al., 1996). The induction of this phenomenon has been attributed to GABAA receptor-mediated depolarization, leading to NMDA receptor-mediated Ca2+ influx.