Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

Abstract

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 mg/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0.1 mg/kg i.p.) and clozapine (10 mg/kg i.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kg i.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25–1 mg/kg i.p.) of rats, sensitized by a prior 10-day apomorphine treatment, did not reverse the established aggressive behaviour. The coadministration of apomorphine and cholecystokinin (CCK)-A or -B antagonists, devazepide or L-365,260 (0.01–2.5 mg/kg i.p.) respectively, neither affected development of apomorphine-induced aggressive behaviour nor intensity of aggressiveness in the sensitized rats.

In binding studies neither density nor affinity of striatal dopamine D₂ receptors was changed by acute or chronic apomorphine treatment. The number of [³H]pCCK-8 binding sites in the frontal cortex increased already after a single injection of apomorphine. After 10-day administration of apomorphine, a significant upregulation of [³H]pCCK-8 binding sites occurred in the frontal cortex and striatum, but a downregulation was observed in the hippocampus. A challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day of experiment, normalized the upregulated CCK receptors in the frontal cortex and striatum. Acute apomorphine did not change [³H]-MK-801 binding in the rat brain. However, in rats treated for 10 days with apomorphine, the number of NMDA-gated channels in open state was increased in the frontal cortex and hippocampus. In these rats, a challenge dose of apomorphine (0.5 mg/kg s.c.) normalized also the in reased number of [³H]-MK-801 binding sites in the frontal cortex.

In conclusion, repeated treatment with apomorphine seems to modify the function of dopamine D₂ receptors without affecting their number or affinity. The increased number of NMDA-gated channels in open state appears to be related to this alteration of dopamine D₂ receptors. The increased density of [³H]pCCK-8 binding sites in the frontal cortex may reflect anxiety and fear due to chronic exposure of rats to apomorphine.