Comparison of the impact of melatonin on chronic ethanol-induced learning and memory impairment between young and aged rats Introduction An increasing number of reports suggest that aging is accompanied by cognitive deficits [1, 2]. Although neuro- genesis occurs throughout the brain during development, in the adult brain it only occurs in the hippocampus. Hippocampal neurogenesis is involved in hippocampal- mediated learning and memory formation. It has been proposed that changes in neurogenesis in the hippocampus may be involved in some of the alterations of cognitive function observed during aging [1]. One of the mechanisms which cause cognitive deficits in aged animal is the loss of the pyramidal neurons of the hippocampal formation [3]. Another mechanism involves the loss of hippocampal synapses [4]. Increased brain oxidative stress seems to have an important role in cognitive impairment caused by normal aging and neurodegenerative diseases [5]. Further- more, it has been suggested that several indices of antioxidant protection may be reduced in aging [6, 7]. The generation and accumulation of reactive oxygen species (ROS) and reduction in antioxidant defense in aging results in oxidative damage which is thought to be a contributory factor to the decrements in cognitive performance seen in aging. Ethanol administration also interferes with performance of spatial learning tasks via its influence on hippocampal functioning [8]. Chronic alcohol exposure causes cell loss in hippocampal structures [9], decreases cerebral cholinergic activity [10] and generates ROS [11] which are all associated with learning and memory impairments. Moreover, it has been suggested that ethanol exposure during brain devel- opment alters the pattern of neural cell adhesion molecules (NCAM) expression [12]. NCAM are likely candidate molecules which participate in synaptogenesis in neuronal plasticity. Furthermore, recent evidence strongly suggests that they also participate in synaptic changes underlying memory formation in the adult brain [13]. Three major forms of NCAM generated by alternative splicing are found, NCAM 120, 140 and 180 kDa. These molecules are also involved in cellular migration, axonal growth, and regeneration of peripheral axons [14]. Alcohol may alter the expression pattern of NCAM to impair learning and Abstract: Chronic alcohol exposure causes functional and structural changes in nervous system which have all been associated with learning and memory impairments. Furthermore, alcohol consumption has been shown to alter the pattern of neural cell adhesion molecules (NCAM) which are involved in memory processes. In the current work, we investigated the effects of melatonin on learning and memory deficits induced by alcohol exposure in young and aged rats. A group of young rats (3 months old) were administered ethanol for 45 days and half of them were co-treated with melatonin. Similar treatments were performed in the aged (19 months old) rats. Morris water maze test and passive avoidance task were used to assess cognitive performance. Lipid peroxidation (LPO) and glutathione (GSH) levels were determined to characterize the level of oxidative stress in the hippocampus and cortex. NCAM levels were determined by Western blotting in the hippocampal homogenates. There was a significant elevation in LPO levels and a reduction in GSH levels in aged and alcohol-exposed rats. Furthermore, both young and aged rats displayed some cognitive impairment when given with alcohol for 45 days. Co-administration of melatonin with ethanol significantly reduced LPO and elevated GSH levels while improving the learning and memory deficits induced by ethanol; the aged rats exhibited a greater response to melatonin supplementation. Moreover, melatonin modulated NCAM expression in hippocampus. Present findings indicate that exposure to ethanol induces learning and memory deficits probably by generating reactive oxygen species and downregulating NCAM 180 in hippocampus of aged rats. Melatonin improves learning and memory deficits and the behavioral responses of rats to melatonin supplementation are age dependent. Giyasettin Baydas 1 , Abdullah Yasar 1 and Mehmet Tuzcu 2 1 Department of Physiology, Faculty of Medicine and 2 Department of Biology, Faculty of Science, Firat University, Elazig, Turkey Key words: glutathione, learning, lipid peroxidation, melatonin, neural cell adhesion molecules Address reprint requests to Giyasettin Baydas, Department of Physiology, Faculty of Medi- cine, Firat University, Elazig 23119, Turkey. E-mail: gbaydas@firat.edu.tr Received Febraury 11, 2005; accepted May 19, 2005. J. Pineal Res. 2005; 39:346–352 Doi:10.1111/j.1600-079X.2005.00257.x Copyright Ó Blackwell Munksgaard, 2005 Journal of Pineal Research 346