AMPA RECEPTORS AND MOTIVATION FOR DRUG - EFFECT OF THE SELECTIVE ANTAGONIST NBQX ON BEHAVIORAL SENSITIZATION AND ON SELF-ADMINISTRATION IN MICE

A series of experiments was carried out in which the potency of the se lective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)- receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinox aline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smalle st dose of NBQX significantly reducing spontaneous or cocaine-induced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomoto r response to a challenge dose of cocaine (16 mg/kg). NBQX reversed th e sensitized response at 30 and 100 mg/kg. The pattern of results obta ined leaves open the role that AMPA-receptors may have in the expressi on of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 mu g per reinforcer) via intra venous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 mu g) or halved (t o 15 mu g) the mice adapted lever pressing rates to maintain some cons tancy of self-dosing (but not at 7.5 mu g per reinforcer) and when sal ine was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-admini stration of 30 mu g reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifical ly antagonized the reinforcing effect of cocaine, as responding was si milarly reduced on both the reinforced and the non-reinforced lever, n or did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor expe riments and the self-administration experiments are discussed together , in terms of current hypotheses about glutamatergic mechanisms involv ed in motivation for drug. Behav Pharmacol 1998; 9:457-467 (C) 1998 Li ppincott Williams & Wilkins.