Central serotonergic responses and behavioural adaptation to repeated immobilisation: the effect of the corticosterone synthesis inhibitor metyrapone.

Rats were immobilised for 2 h/day. Twenty-four hours after the 1, 3 or 7 immobilisation periods they were injected with the 5HT agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT; 5 mg/kg i.p.) and behavioural responses (i.e. hind limb abduction, forepaw treading, head weaving, tremor, Straub tail) compared with those of a control group. As we have previously observed after 7 (but not after 1 or 3 immobilisations) forepaw treading and tremor were enhanced and the other responses unaffected. Pretreatment with metyrapone (a corticosterone synthesis inhibitor 150 mg/kg i.p., 3 h before each immobilisation) did not affect the above responses to 1 immobilisation, increased tremor after 3 immobilisations and also increased forepaw treading, hind limb abduction and Straub tail after 7 immobilisations but decreased head weaving under the latter conditions. Metyrapone without immobilisation had no effect on responses to 5MeODMT. Twenty four hours after 1 or 3 (but not 7) immobilisation periods, rats placed for the first time in an open field showed less locomotion and rearing and more defaecation than control animals. Rats also given metyrapone exhibited normal open field behaviour after only 3 immobilisations. The drug also accelerated the return to normal on repeated immobilisation of the impairment of food intake and growth rate which occurred after a single immobilisation. The results as a whole suggest that metyrapone promotes behavioural adaptation to repeated immobilisation and that this is associated with enhanced postsynaptic responses to 5HT. These findings suggest that immobilisation stress-induced changes might be relevant as an animal model for depression which incorporates reported biochemical abnormalities in the illness and is of relevance to proposals concerning its precipitation by stress.