The effect of CNQX on self-administration: present in nicotine, absent in methamphetamine model

Abstract

Objective: Addiction is a chronic disease with limited pharmacological options for intervention. Focusing on reducing glutamate levels in the brain seems to be a promising strategy in addiction treatment research. Our research aimed to evaluate the effects of CNQX, an antagonist that targets AMPA and kainate glutamatergic receptors while also exhibiting affinity for the NMDA receptor, especially by modulating its glycine site. We conducted this assessment on the self-administration of nicotine and methamphetamine via intravenous (IV) administration in rats.

Methods: An operant IV self-administration model was used in male Wistar rats. When animals maintained a stable intake of nicotine or methamphetamine, we administered a single injection of CNQX (in the dose of 3 or 6 mg/kg IV) to evaluate its effect on drug intake. Subsequently, the rats were forced to abstain by staying in their home cages for 2 weeks. The period of abstinence was followed by a context-induced relapse-like session before which animals were pretreated with the injection of CNQX (3 or 6 mg/kg IV) to evaluate its effect on drug seeking.

Results: CNQX significantly reduced nicotine intake during the maintenance phase, but no effect was revealed on nicotine seeking after forced abstinence. CNQX did not affect methamphetamine taking or seeking.

Conclusion: The effect of reducing nicotine taking but not seeking could be explained by different involvement of glutamatergic receptors in various stages of nicotine dependence.

Keywords: AMPA/kainate receptor; CNQX; methamphetamine; nicotine; relapse; self-administration.

Figure 1

Schematic timeline of both nicotine and methamphetamine study.

Figure 2

Maintenance of intravenous self-administration of nicotine (A) and methamphetamine (B). The line graphs show mean values ± SEM of active nose-pokes, inactive nose-pokes, and the number of infusions obtained daily during the IVSA maintenance period.

Figure 3

Depicts the effect of CNQX treatment in the nicotine study. The bar graphs on the top of the panel show mean values ± SEM of nicotine operant variables after CNQX treatment. Graphs indicate the effect of CNQX treatment at doses of 3 and 6 mg/kg during maintenance on active nose-pokes (A), the number of infusions (B), and nicotine dose in mg/kg (C). ^#(p = 0.042) indicates a significant difference between CNQX3 and CNQX6 groups in nicotine infusions (B) and ^#(p = 0.035) nicotine dose in mg/kg (C). Graphs at the bottom indicate the effect of CNQX treatment at doses of 3 and 6 mg/kg during the context-induced nicotine seeking after forced abstinence on active nose-pokes (D), inactive nose-pokes (E), and preference of the active operandum (F) - % of previously drug-paired responses over the total number of responses.

Figure 4

Depicts the effect of CNQX treatment in the METH study. The bar graphs show mean values ± SEM of methamphetamine operant variables after CNQX treatment. Graphs at the top indicate the effect of CNQX treatment at doses of 3 and 6 mg/kg during maintenance on active nose-pokes (A), the number of infusions (B), and METH dose in mg/kg (C). Graphs at the bottom indicate the effect of CNQX treatment at doses of 3 and 6 mg/kg during the context-induced methamphetamine seeking after forced abstinence on active nose-pokes (D), inactive nose-pokes (E), and preference of the active operandum (F) - % of previously drug-paired responses over the total number of responses. No significant differences were revealed.