AMPA-Receptor GluR1 Subunits are Involved in the Control Over Behavior by Cocaine-Paired Cues

Abstract

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 selfadministration 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.

Incubation of Methamphetamine but not Heroin Craving After Voluntary Abstinence in Male and Female Rats

“…Based on their clinical observations, Gawin and Kleber (1986) proposed that cueinduced cocaine craving increases during early abstinence and remains elevated for extended time periods. An analogous phenomenon termed 'incubation of drug craving' has been observed in rats and mice trained to self-administer cocaine (Grimm et al, 2001;Mead et al, 2007;Neisewander et al, 2000) and rats trained to self-administer alcohol (Bienkowski et al, 2004), nicotine (Abdolahi et al, 2010;Funk et al, 2016), heroin (Fanous et al, 2012;Shalev et al, 2001), and methamphetamine (Li et al, 2015;Shepard et al, 2004). In animal models, incubation of drug craving refers to the time-dependent increase in drug seeking during forced abstinence (Pickens et al, 2011;Wolf, 2016).…”

Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure® and Corn-Oil Seeking in Mice

“…Whereas cue-induced reinstatement behavior has been extensively studied in rats, far fewer studies have assessed such behavior in mice (Highfield et al, 2002;Fuchs et al, 2003;Yan et al, 2006;Mead et al, 2007). Therefore, the present study examined the effect of SR141716A on cueinduced reinstatement behavior in mice trained to respond for the sweet reinforcer Ensure s .…”

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

“…These include extinction tests in the presence of the drugassociated cues (Conrad et al, 2008;Lee et al, 2006;Lu et al, 2004a), discrete cue-induced reinstatement after extinction (Grimm et al, 2001;Mead et al, 2007), and acquisition of a new conditioned response (Di Ciano and Everitt, 2004). A common feature of these studies and related studies (Pacchioni et al, 2011;Van den Oever et al, 2008;Van den Oever et al, 2010) is that abstinence is forced either by removing the rats from the drug self-administration environment or by conducting extinction training.…”