The tryptophan (TRP) depletion method has been used as a tool to investigate the effects of acute lowered serotonin levels in the brain. In the present study, the effects of this treatment were investigated in rat models of anxiety (open field test, home cage emergence test), depression (forced swimming test, sucrose preference test) and cognition (spatial discrimination learning, sustained attention). It was found that the repeated TRP depletion increased anxiety-related behaviour in the open field test and increased immobility in the forced swimming test. The other behavioural tests did not reveal effects of treatment. TRP levels were decreased in plasma (34%) and hippocampus (33%) but not in the cortex. Stress-induced corticosterone levels were not affected after TRP depletion. The present findings indicate that repeated moderate TRP depletion leads to anxiogenic and depressive-like behaviour in the rat and corroborates the notion of the involvement of serotonin in these behaviours.
Antagonists at serotonin type 6 (5-HT 6 ) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT 6 antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic-(tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT 6 receptor antagonists.
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