A variety of agents that modulate glutamate receptor activity are also being studied as potential treatments against substance abuse. Reagents that increase basal extracellular levels of glutamate are also effective at preventing relapse and several forms of cocaine-induced plasticity (Baker et al., 2003; Knackstedt et al., 2009; Madayag et al., 2007; Martínez-Raga et al., 2008; Moran et al., 2005). Increased basal glutamate is thought to act on generally high-affinity autoreceptors to reduce the cue-, drug-, or stress-primed glutamate that acts through AMPAR to drive relapse (Baker et al., 2003). Accordingly, activation of receptors that can act as glutamate autoreceptors reduce cocaine seeking (Adewale et al, 2006; Peng et al., 2009; Peters and Kalivas, 2006; but see Bauzo et al., 2009). Thus, it is plausible to hypothesize a scenario where inhibiting excessive AMPA signaling while also promoting the diminished basal glutamatergic signaling that is often observed following repeated exposure to cocaine would represent a very effective way to prevent relapse. Indeed, other agents that weakly elevate activity of other glutamate receptors such as NMDARs, have shown some efficacy to reduce cocaine
