Behavioural Brain Research 153 (2004) 377–381 Research report Chronic hyperhomocysteinemia provokes a memory deficit in rats in the Morris water maze task Emilio Luiz Streck, Caren Serra Bavaresco, Carlos Alexandre Netto, Angela Terezinha de Souza Wyse ∗ Departamento de Bioqu´ ımica, Instituto de Ciˆ encias Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil Received 14 July 2003; received in revised form 8 December 2003; accepted 16 December 2003 Available online 5 February 2004 Abstract Homocystinuria is an inherited metabolic disease biochemically characterized by tissue accumulation of homocysteine. Affected patients present mental retardation and other neurological symptoms whose mechanisms are still obscure. In the present study, we investigated the effect of chronic hyperhomocysteinemia on rat performance in the Morris water maze task. Chronic treatment was administered from the 6th to the 28th day of life by s.c. injection of homocysteine, twice a day at 8-h intervals; control rats received the same volume of saline solution. Animals were left to recover until the 60th day of life. Morris water maze tasks were then performed, in order to verify any effect of early homocysteine administration on reference and working memory of rats. Results showed that chronic treatment with homocysteine impaired memory of the platform location and that homocysteine treated animals presented fewer crossings to the place where the platform was located in training trials when compared to saline-treated animals (controls). In the working memory task, homocysteine treated animals also needed more time to find the platform. Our findings suggest that chronic experimental hyperhomocysteinemia causes cognitive dysfunction and that might be related to the neurological complications characteristic of homocystinuric patients. © 2004 Elsevier B.V. All rights reserved. Keywords: Homocystinuria; Homocysteine; Memory; Morris water maze 1. Introduction Homocystinuria is an inborn error of metabolism caused by severe deficiency of cystathionine -synthase activity, re- sulting in tissue accumulation of homocysteine (Hcy) and methionine. Affected patients present alterations in various organs and systems, specially the central nervous and the vascular systems. Homocystinuric patients usually present mental retardation, seizures and atherosclerosis; the under- lying mechanisms of those symptoms are not clearly under- stood [6,15]. Evidence from literature indicates a neurotoxic potential of Hcy. In this context, it has been demonstrated that Hcy is citotoxic for some human neuronal cell lines [18] and causes neuronal death by free radical formation and by overstimu- lation of NMDA receptors [8,11]. Moreover, Kubová et al. ∗ Corresponding author. Tel.: +55-51-3316-5573; fax: +55-51-3316-5535. E-mail address: wyse@ufrgs.br (A.T.S. Wyse). [9] showed that injections of Hcy induce seizures in young rats. Recent reports indicate that Hcy is considered an impor- tant risk factor for cognitive dysfunction [13] and for the development of some diseases that affect the central nervous system, such as Alzheimer, Huntington and Parkinson dis- ease and brain ischemia [3,10,20,28]. On the other hand, it is believed that Hcy might play a role in the physiopatho- logical mechanisms in these diseases [12]. Animal models are useful to better understand the patho- physiology of diseases. We have recently developed a chem- ical experimental model of hyperhomocysteinemia [21], in which the Hcy levels are similar to those found in human homocystinuria [15]. Rats subjected to this experimental model of hyperhomocysteinemia presented a reduction of Na + ,K + -ATPase activity [21] and a diminution of some pa- rameters of brain energy metabolism [23] in hippocampus. Additionally, Reis et al. [19] showed that acute Hcy adminis- tration caused memory impairment on step-down inhibitory avoidance task, and that pretreatment with Vitamins E and C prevented such effect. 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2003.12.013