Differential effects of low and high doses of topiramate on consolidation and retrieval of novel object recognition memory in rats Maria Noemia Martins de Lima a , Juliana Presti-Torres b , Arethuza Dornelles b , Elke Bromberg b , Nadja Schro ¨der a,b, * a Graduate Program in Biomedical Gerontology, Institute for Geriatrics and Gerontology, Sa ˜o Lucas Hospital, Pontifical Catholic University, 90619-900 Porto Alegre, RS, Brazil b Neurobiology and Developmental Biology Laboratory, Graduate Program in Cellular and Molecular Biology, Faculty of Biosciences, Pontifical Catholic University, 90619-900 Porto Alegre, RS, Brazil Received 20 June 2006; revised 9 September 2006; accepted 13 September 2006 Available online 27 October 2006 Abstract Topiramate is a new antiepileptic drug proposed to facilitate synaptic inhibition and block excitatory receptors. However, little is known about the effects of topiramate on memory. In the first experiment, intraperitoneal injection of topiramate at doses of 10.0 and 100.0 mg/kg, immediately after training, induced a deficit in short-term memory (STM) of a novel object recognition (NOR) task tested 1.5 hours after training in rats. In a long-term memory (LTM) test given to the same rats 24 hours after training, topiramate 0.1 mg/kg enhanced, whereas 10.0 and 100.0 mg/kg impaired, NOR retention. In the second experiment, administration of topiramate 0.01 and 0.10 mg/kg 1 hour prior to the LTM retention test improved NOR retention, whereas 10.0 and 100.0 mg/kg produced retrieval deficits. The results indicate that low doses of topiramate improve, whereas high doses impair, consolidation and retrieval of recognition memory in rats. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Topiramate; Anticonvulsant drugs; Epilepsy; Memory consolidation; Memory retrieval; Object recognition; Recognition memory 1. Introduction There has been growing interest in the use of new anti- epileptic drugs in the treatment of epilepsy and indications other than epilepsy, including migraine prophylaxis, neuro- pathic pain syndromes, and neuroprotection (for recent reviews, see [1–5]). Proposed molecular mechanisms of action of new antiepileptic drugs include stimulation of the GABAergic system, inhibition of glutamate receptor- gated channels, and blockade of voltage-gated ion channels [3]. Topiramate is a new antiepileptic agent initially intro- duced for the management of partial seizures and approved worldwide for the treatment of several types of epilepsy. Topiramate has also been proposed as a therapeutic agent for other neurological and psychiatric disorders including migraine [2,4–9]. Patients with epilepsy may have impaired cognitive abil- ities, and antiepileptic drug therapy may contribute to this impairment [10,11]. Several reports have suggested that newer antiepileptic drugs such as topiramate have fewer effects on cognition than older drugs [12–14]. Thus, assess- ment of the potential adverse cognitive effects of new anti- epileptic drugs using animal models may have implications for the clinical use of topiramate in the treatment of epilep- sy and other conditions such as migraine. For instance, topiramate has been reported to produce a dose-related impairment in working memory assessed by spatial alterna- tion behavior in rats [15]. Although antiepileptic drugs can impair neuropsychological functioning, their positive effect on seizure control may improve cognition and behavior. In addition, topiramate was reported to enhance performance 1525-5050/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2006.09.007 * Corresponding author. Fax: +55 51 33203612. E-mail address: nadja_s@terra.com.br (N. Schro ¨ der). www.elsevier.com/locate/yebeh Epilepsy & Behavior 10 (2007) 32–37