Protective effects of 5‐HT 1A receptor agonists against emotional changes produced by stress stimuli are related to their neuroendocrine effects

The effects of the 11β‐hydroxylase inhibitor metyrapone on the protective effects of serotonin (5‐hydroxytryptamine; 5‐HT) 1A receptor agonists against emotional changes produced by acute restraint stress were examined in mice. Changes in the emotional state of mice were evaluated in terms of changes in exploratory activity, i.e. total locomotor activity, number and duration of rearing and head‐dipping behaviours, and latency to the first head‐dipping, using an automatic hole‐board apparatus. Treatment with the 5‐HT 1A receptor agonists flesinoxan (1 mg kg −1 , i.p.) and R(+)‐2‐di‐n‐propylamino‐8‐hydroxy‐1,2,3,4‐tetrahydronaphthalene hydrobromide (8‐OH‐DPAT; 1 mg kg −1 , i.p.) 24 h prior to exposure to stress significantly suppressed the decrease in various exploratory behaviours that was observed immediately after the exposure to acute restraint stress (60 min). The effects of flesinoxan (1 mg kg −1 , i.p.) and 8‐OH‐DPAT (1 mg kg −1 , i.p.) were antagonized by co‐injection with N‐{2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]ethyl}‐N‐(2‐pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635; 1 mg kg −1 , i.p.), a selective 5‐HT 1A receptor antagonist. Flesinoxan (1 mg kg −1 , i.p.) and 8‐OH‐DPAT (1 mg kg −1 i.p.) significantly increased the plasma corticosterone level, and these effects of 5‐HT 1A receptor agonists were dose‐dependently blocked by pretreatment with metyrapone (12.5 and 25 mg kg −1 , s.c.). Metyrapone (25 mg kg −1 , s.c.) alone did not modify the stress‐induced changes in exploratory behaviours. Pretreatment with metyrapone (12.5 and 25 mg kg −1 , s.c.) partly antagonized the protective effects of flesinoxan (1 mg kg −1 , i.p.) and 8‐OH‐DPAT (1 mg kg −1 , i.p.) with regard to only the number and duration of head‐dipping behaviours. These results suggest that activation of the adrenocortical system via 5‐HT 1A receptors may facilitate some adaptive mechanism(s) involved in the recognition of and/or ability to cope with stressful situations.British Journal of Pharmacology (2001) 134 , 585–595; doi: 10.1038/sj.bjp.0704276