Cocaine-taking and cocaine-seeking behaviors in rats remain stable after systemic administration of GYKI 52466: a non-competitive AMPA receptor antagonist

Abstract

Given the posited role of enhanced AMPA-mediated synaptic transmission in relapse to drug seeking, we investigated whether systemic administration of the AMPA receptor antagonist GYKI 52466 inhibits cocaine-taking and cocaine-seeking behavior in rats. Rats were trained to self-administer cocaine until stable self-administration was achieved. Effects of GYKI 52466 (1, 3, or 10mg/kg, i.v.) on cocaine self-administration were assessed. Animals were allowed to re-establish stable cocaine self-administration and were then behaviorally extinguished from drug taking. The effects of GYKI 52466 (3, 10mg/kg, i.v.) on cocaine-induced reinstatement of drug-seeking behavior were assessed. We found that GYKI 52466 failed to inhibit cocaine-taking and cocaine-seeking in both the self-administration and reinstatement paradigms. We suggest that although AMPA receptors may be involved in cocaine reward and addiction, the AMPA receptor antagonist GYKI 52466 has low therapeutic potential for cocaine addiction treatment.

Figure 1. Effects of GYKI 52466 on total number of self-administered cocaine infusions

Data are presented as total number of cocaine infusions after different doses of GYKI 52466 or vehicle (means ± SEM). Across all subjects, GYKI 52466 at 1, 3, or 10 mg/kg (i.v.) did not significantly alter cocaine-self-administration under FR2 reinforcement.

Figure 2. Effects of GYKI 52466 on cocaine-triggered reinstatement of drug-seeking behavior

Lever press responses during the last day of cocaine self-administration, the last day of extinction, and the reinstatement test day are shown. During reinstatement, each dose of GYKI 52466 or vehicle was followed by a 10 mg/kg (i.p.) priming injection of cocaine to assess cocaine-induced drug-seeking behavior. Values are presented as means ± SEM. 2A: Active lever-presses. Cocaine-priming (10 mg/kg, i.p.) significantly increased active lever press responding during reinstatement testing (*p < 0.05, when compared to extinction levels). GYKI 52466 (3, 10 mg/kg, i.v.) pretreatment did not alter cocaine-triggered reinstatement of drug-seeking behavior as compared to vehicle control group (p = .96). 2B: Inactive lever-presses. GYKI 52466 and/or cocaine priming had no effect on inactive lever responses as compared to vehicle control group (p = .86).