Pineal hormone melatonin has an important role in the ageing process as potential drug to relieve oxidative damage, a likely cause of age-associated brain dysfunction. As age advances, the nocturnal production of melatonin decreases suggesting physiological alterations in elderly. As serotonin (5-HT) plays a role in adult memory processing, present experiments were performed to study in vivo the effects of exogenously administered melatonin (1 mg/kg/day, diluted in drinking water, 4 weeks) on central serotonin (5-HT) and working memory task in aged rats (20 months, n=6). Animals were maintained under controlled conditions (22ordm;C, 70% humidity, 12/12LD). The accumulation of 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used as a measure of tryptophan hydroxylation rate in the brain in vivo. Also, spatial memory in 8-arm radial-maze test was tested. Modulation of tryptophan hydroxylation and working memory test were assessed in male Wistar young (3 months, n=6) and old (20 months, n=6) control rats for comparisons. After treatments, to test radial maze memory task, trials were judged complete when rats had chosen all 8 baited arms or spent 20 minutes in the trial. After that, rats were sacrificed by decapitation and hippocampus and striatum samples analyzed by HPLC with electrochemical detection to measure 5-HTP, 5-HT and the metabolite 5-HIAA. Tryptophan hydroxylation decreased significantly in the hippocampus (48%) and striatum (44%) of aged rats indicating an impairment in serotonin synthesis with age. However, when aged rats were repeatedly treated with melatonin, an important increase in tryptophan hydroxylation in hippocampus (53%) and striatum (83%) was observed. Similar results were obtained for 5-HT and 5-HIAA metabolite. All these neurochemical observations correlated well with an impairment of task performance in radial maze in aged controls and an improvement in the rats treated with melatonin. In conclusion these in vivo findings suggest that melatonin chronic treatment is able to improve 5-HT cerebral neurotransmission in aged rats, which might aid to improve the cognitive deficit that normally occurs as a consequence of aging.

Supported by SAF2007-66878-CO2-02 from MEC