AMPA-receptor GluR1 subunits are involved in the control over behavior by cocaine-paired cues

The learning processes underlying the formation of drug-cue associations involve changes in synaptic transmission mediated by AMPA receptors. Here, we examine the consequences of targeted deletion of the gene encoding GluR1 subunits of AMPA receptors (gria1 knockouts (KO)) on cocaine self-administration and on the ability of cocaine-paired cues to affect cocaine-seeking in mice. Cocaine self-administration was unaffected by gria1 deletion, as was the ability of a cocaine-paired cue to reinstate responding following extinction, following either a 3 or a 66 day delay. However, gria1 KOs over-responded during extinction. The KOs were unable initially to learn a new response to access a cue previously conditioned to cocaine (conditioned reinforcement (CR)), although a second test 2 months later revealed that this was a transient deficit. These studies indicate that GluR1-containing AMPA-receptors are not involved in cocaine self-administration, cue-induced reinstatement of cocaine seeking, or incubation of the cocaine seeking response. In order to understand the specificity of the deficits in CR responding, a parallel study was performed with food reward. As with cocaine, there were no effects of gria1 deletion on food self-administration or cue-induced reinstatement, and KOs over-responded during extinction. However, even immediately after instrumental training for food, KO mice demonstrated responding for CR, suggesting that the CR deficit observed with a cocaine cue is specific to drug reward. These data indicate that GluR1-containing AMPA receptors are important in stimulus reward learning, though the method of cue-reward association formation, the reward class, and the behavioral end point are critical variables in determining their involvement.