ROLE OF N-METHYL-D-ASPARTIC ACID AND CHOLECYSTOKININ RECEPTORS IN APOMORPHINE-INDUCED AGGRESSIVE-BEHAVIOR IN RATS

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days) , in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 m g/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0. 1 mg/kgi.p.) and clozapine (10 mg/kgi.p.). An antagonist of N-methyl-D -aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked t he aggressive behaviour at 0.25 and 0.5 mg/kgi.p. but caused ataxia. W hen dizocilpine (0.25 mg/kgi.p.) and apomorphine were coadministered f or 10 days, aggressive behaviour did not develop. At 0.025 mg/kgi.p., dizocilpine even accelerated the appearance of apomorphine-induced agg ressive behaviour, which manifested on the 3rd day in all rats. In a s eparate study, a 7-day treatment with dizocilpine (0.25-1 mg/kgi.p.) o f rats, sensitized by a prior 10-day apomorphine treatment, did not re verse the established aggressive behaviour. The coadministration of ap omorphine and cholecystokinin (CCK) -A or -B antagonists, devazepide o r L-365,260 (0.01-2.5 mg/kgi.p.) respectively, neither affected develo pment of apomorphine-induced aggressive behaviour nor intensity of agg ressiveness in the sensitized rats. In binding studies neither density nor affinity of striatal dopamine D-2 receptors was changed by acute or chronic apomorphine treatment. The number of [H-3]pCCK-8 binding si tes in the frontal cortex increased already after a single injection o f apomorphine. After 10-day administration of apomorphine, a significa nt upregulation of [H-3]pCCK-8 binding sites occurred in the frontal c ortex and striatum, but a downregulation was observed in the hippocamp us. A challenge dose of apomorphine (0.5 mg/kgs.c.) on the 11th day of experiment, normalized the upregulated CCK receptors in the frontal c ortex and striatum. Acute apomorphine did not change [H-3]-MK-801 bind ing in the rat brain. However, in rats treated for 10 days with apomor phine, the number of NMDA-gated channels in open state was increased i n the frontal cortex and hippocampus. In these rats, a challenge dose of apomorphine (0.5 mg/kgs.c.) normalized also the increased number of [H-3]-MK-801 binding sites in the frontal cortex. In conclusion, repe ated treatment with apomorphine seems to modify the function of dopami ne D-2 receptors without affecting their number or affinity. The incre ased number of NMDA-gated channels in open state appears to be related to this alteration of dopamine D-2 receptors. The increased density o f [H-3]pCCK-8 binding sites in the frontal cortex may reflect anxiety and fear due to chronic exposure of rats to apomorphine.