NEUROCHEMICAL AND NEUROPHARMACOLOGICAL STUDIES IN RATS FOLLOWING SINGLE AND REPEATED RESTRAINT STRESSES

A considerable body of evidence points to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) in the pathogenesis as well as treatment of depression. Stress life events precipitate depression. Parallel studies on experimental animals show that an uncontrollable stress situation increases brain 5-HT metabolism and precipitates behavioural deficits. Stress-induced behavioural changes in rats are often taken as an animal model of depression. It has been also reported that restraint induced behavioural deficits do not occur when the stress is given repeatedly suggesting adaptation to a stress schedule occurs. The present study concerns serotonergic functions in rat brain following adaptation to stress. Important findings of the study are as follows:\ud \ud 1 Single episode of 2h restraint decreased 24h cumulative food intake and growth rate. Open field activity monitored 24h after restraint also decreased. The behavioural deficits were not observed following 5 restraint periods of 2h/day. Restraint- induced increases of rectal temperature did not occur in rats restrained 2h/day for 5 days.\ud \ud 2.An episode of 2h restraint increased brain 5-HT metabolism in previously unrestrained rats but not in rats adapted to 5 restraint periods of 2h a day.\ud \ud 3.Injected tryptophan increased plasma levels of tryptophan more in unrestrained than restrained rats but injected tryptophan-induced increases of 5-HT and 5-HIAA were greater in the latter group.\ud \ud 4 Injected tryptophan increased plasma levels of tryptophan more in unrestrained than repeatedly restrained rats but injected tryptophan induced increases of 5-HT and 5-HIAA were comparable in the two groups.\ud \ud 5 An episode of 2h restraint increased 5-HT synthesis rate in the midbrain, hindbrain, hypothalamus, and cortex of previously unrestrained rats. Increases in the hippocampus and striatum were not significant. The episode of 2h restraint did not increase 5-HT synthesis rate in the midbrain, hindbrain, hypothalamus and cortex of repeatedly restrained, behaviourally adapted rats. On the other hand, 5-HT synthesis rate increased in the hippocampus and decreased in the striatum when rats adapted to 5 restraint periods of 2h/day were re-restrained on the 6th day.\ud \ud 6. 8-0H-DPAT, a 5-HT1A selective agonist, provoked greater 5-HT syndrome like behaviour in repeatedly restrained behaviourally adapted rats than in previously unrestrained rats. Conversely, 8-0H-DPA T-induced decreases of 5-HT metabolism were greater in the latter group.\ud \ud The results tend to suggest that at least two factors vis (1) increased availability of tryptophan to the brain and (2) enhanced activity of 5-HT synthesizing enzyme (tryptophan hydroxylase) are involved in the enhancement of 5-HT metabolism following an acute episode of restraint stress. Restraint-induced increases of brain 5-HT metabolism do not occur in repeatedly restrained behaviourally adapted rats because adaptive changes occur both in the availability of tryptophan to the brain and activity of tryptophan hydroxylase in general. In view of clinical evidences it is suggested that an increase in hippocampal 5-HT synthesis rate may be involved in adaptation. A role of somatodendritic and postsynaptic 5-HT 1 A receptors in adaptation to stress is also discussed. The findings imply that drugs modulating particularly hippocampal 5-HT function may prove better antidepressants