Intracerebroventricular administration of endothelin-1 impairs the habituation of rats to a novel environment in conjunction with brain serotonergic activation.

The effects of i.c.v. administration of endothelin-1, at a low dose that does not produce abnormal behaviors such as barrel-rolling, on the emotional state of rats exposed to a novel environment were examined. Changes in the emotional state of rats with a novel environment were evaluated in terms of changes in exploratory activity in the hole-board apparatus, i.e., locomotor activity as well as the number and duration of rearing and head-dipping behaviors. Rats treated with i.c.v. saline showed marked exploratory behaviors immediately after exposure to the hole-board apparatus, but these exploratory behaviors decreased rapidly with time. On the other hand, the habituation of rats to a novel environment was prolonged by the i.c.v. administration of endothelin-1 (0.3 and 1 pmol). Furthermore, we also found that i.c.v. administration of endothelin-1 (1 pmol) significantly increased the serotonin (5-hydroxytryptamine) turnover in some brain regions, i.e., the cerebral cortex, hippocampus and midbrain, and the inhibition of brain 5-hydroxytryptamine synthesis by treatment with p-chlorophenylalanine (200 mg/kg/day, s.c.) for 2 days suppressed the behavioral effects of endothelin-1 (1 pmol, i.c.v.). In addition, i.c.v. administration of endothelin-1 (1 pmol) did not affect the spontaneous motor activity of rats. The present study demonstrated that i.c.v. administration of low doses of endothelin-1 impairs the habituation of rats to a novel environment in conjunction with brain 5-hydroxytryptaminergic activation. These results suggest that the central endothelin system may play a significant role in mediating emotionality.