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Differential effects of low and high doses of topiramate on consolidation and retrieval of novel object recognition memory in rats
Epilepsy & Behavior 10 (2007) 32–37 www.elsevier.com/locate/yebeh
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. 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 antiepileptic drugs in the treatment of epilepsy and indications other than epilepsy, including migraine prophylaxis, neuropathic 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 receptorgated channels, and blockade of voltage-gated ion channels [3]. Topiramate is a new antiepileptic agent initially introduced 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 *
Corresponding author. Fax: +55 51 33203612. E-mail address: [email protected] (N. Schro¨der).
1525-5050/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2006.09.007
for other neurological and psychiatric disorders including migraine [2,4–9]. Patients with epilepsy may have impaired cognitive abilities, 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, assessment of the potential adverse cognitive effects of new antiepileptic drugs using animal models may have implications for the clinical use of topiramate in the treatment of epilepsy and other conditions such as migraine. For instance, topiramate has been reported to produce a dose-related impairment in working memory assessed by spatial alternation 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
M.N. Martins de Lima et al. / Epilepsy & Behavior 10 (2007) 32–37
in a water maze in sham- but not brain-injured animals [16]. As mentioned above, proposed mechanisms mediating the actions of topiramate include sodium channel blockade; positive modulation of c-aminobutyric acid (GABA) type A (GABAA) receptors; and inhibition of the aminohydroxymethylisoxazole propionic acid (AMPA) and kainate non-N-methyl-D-aspartate (NMDA) glutamate receptor subtypes [1,3,4,6,17–19]. GABA and glutamate receptors and sodium channels have been implicated in memory formation and recall. The novel object recognition memory (NOR) task is based on the spontaneous tendency of rodents to explore a novel object in preference to a familiar object. It is a nonspatial and non-rewarded task that might depend on both the hippocampus and the nigrostriatal dopaminergic pathway [20–22]. Studies performed by Winters and Bussey [23–25] have indicated participation of the perirhinal cortex in recognition memory and have suggested that, as in the hippocampus, AMPA and NMDA glutamate receptors mediate synaptic transmission and activity-dependent synaptic plasticity, respectively, in several stages of memory processing (encoding, retrieval, and consolidation). Thus, the NOR procedure may be a useful preclinical model with which to characterize the effects of new antiepileptic drugs on cognitive function. The aim of the present study was to evaluate the effects of topiramate on consolidation and retrieval of NOR. The first experiment examined the effects of topiramate on consolidation in rats systemically administered topiramate immediately after NOR training. A second experiment examined the effects of topiramate on retrieval in animals given topiramate 1 hour before an NOR 24-hour retention test trial. 2. Method 2.1. Subjects Adult female Wistar rats were obtained from the State Health Research Foundation (FEPPS-RS, Porto Alegre, Brazil). The rats were maintained in groups of five animals in a plastic cage with sawdust bedding at a room temperature of 22 ± 1 C and on a 12-hour light/12-hour dark cycle. The animals were supplied with standardized pellet food and tap water ad libitum. Behavioral testing started when animals reached the age of 3 months. All experimental procedures were performed in accordance with the NIH Guide for Care and Use of Laboratory Animals (NIH Publication No. 80-23 Revised 1996).
2.2. Drugs and injection procedures For the first experiment, topiramate (Janssen–Cilag Pharmaceuticals, Sa˜o Paulo, Brazil; 0.01, 0.1, 1.0, 10.0, or 100.0 mg/kg body weight) or saline (0.9% NaCl) was administered intraperitoneally (1.0 ml/kg injection volume) immediately after the NOR training trial. For the second experiment, topiramate (0.01, 0.1, 1.0, 10.0, or 10.00 mg/kg) or saline was administered intraperitoneally 1 hour before the NOR long-term retention test trial.
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2.3. Novel object recognition The NOR task apparatus and procedures have been described elsewhere [22,26,27]. Briefly, an open-field apparatus (45 · 40 · 60 cm) made of plywood with sawdust covering its floor was used in the NOR task. On the first day, rats were submitted to a habituation session during which they were placed in the empty open field for 5 minutes. On the following day, rats were given one 5-minute training trial in which they were exposed to two identical objects (A1 and A2). All objects were made of Duplo Lego Toys and were similar in texture, color, and size, but had distinctive shapes. The objects were positioned in two adjacent corners, 9 cm from the walls. On a short-term memory (STM) retention test trial given 1.5 hour after the training session, rats were allowed to explore the open field for 5 minutes in the presence of two objects: the familiar object A and a novel object B. These were placed in the same locations as in the training trial. On a long-term memory (LTM) retention test trial carried out 24 hours after the training trial, rats were allowed to explore the open field for 5 minutes in the presence of the familiar object A and a third novel object C. The same animals were used for the STM and LTM retention tests as previously described [22,26,27]. Object exploration was measured using two stopwatches to record the time spent exploring the objects during the experimental sessions. Exploration was defined as sniffing or touching the object with the nose. Sitting on the object was not considered exploration. A recognition index for each animal was calculated as the ratio TN/(TF + TN), where TF = time spent exploring the familiar object (A), TN = time spent exploring the novel object (B or C). For the training trial, the index was the ratio of time spent exploring object A2 to time spent exploring both objects [TA2/(TA1 + TA2)].
2.4. Statistics Groups were compared using Kruskal–Wallis analysis of variance followed by the Mann–Whitney U test when necessary. Comparisons between sessions within the same group were made using the Wilcoxon test [26,27]. P values less than 0.05 were considered to indicate statistical significance.
3. Results The first experiment examined the effects of posttraining systemic administration of topiramate on consolidation of short- and long-term object recognition memory. Administration of topiramate at 10.0 and 100.0 mg/kg induced STM deficits, as recognition indexes of these groups were significantly lower than the recognition index of the saline-treated group (both P’s < 0.01) (Fig. 1, top). In the LTM test, results indicated that topiramate 0.1 mg/kg induced enhancement of recognition memory (P < 0.05 compared with saline-treated animals), whereas topiramate 10.0 or 100.0 mg/kg caused impairment of LTM (both P 0 s < 0.01 compared with saline-treated animals) (Fig. 1, bottom). Moreover, statistical analysis comparing recognition indexes obtained in training and long-term retention sessions within groups indicated that the group that received the highest dose of topiramate (100.0 mg/kg) had a complete memory blockade, as the animals showed no significant preference toward the novel object in the testing session (P = 0.17). There was no significant difference among groups in the total time spent exploring both objects during the training trial: mean ± SE time spent exploring both objects was 24.1 ± 4.6 in the saline-treated group, 20.7 ± 3.8 in the group treated with topiramate
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Fig. 1. Effects of posttraining administration of topiramate on recognition memory. Top: Short-term retention (STM) test 1.5 hours after training. Bottom: Long-term retention (LTM) test 24 hours after training. The proportion of the total exploration time that the animal spent investigating the novel object was the ‘‘recognition index’’ for the retention test trials, expressed by the ratio TN/(TF + TN), where TF = time spent exploring the familiar object (A), and TN = time spent exploring the novel object (B or C). For the training trial, the index was obtained as the ratio of time spent exploring object A2 to the time spent exploring both objects, TA2/(TA1 + TA2). Data are expressed as medians (interquartile ranges); n = 10 per group. Differences between saline- and topiramate-treated groups are indicated: *P < 0.05, **P < 0.01.
Fig. 2. Effects of administration of topiramate 1hour before the long-term retention (LTM) test on recognition memory. Top: Short-term retention (STM) test 1.5 hours after training. Bottom: Long-term retention (LTM) test 24 hour after training. The proportion of the total exploration time that the animal spent investigating the novel object was the ‘‘recognition index’’ for the retention test trials, expressed by the ratio TN/(TF + TN), where TF = time spent exploring the familiar object (A), and TN = time spent exploring the novel object (B or C). For the training trial, the index was obtained as the ratio of time spent exploring object A2 to the time spent exploring both objects, TA2/(TA1 + TA2). Data are expressed as medians (interquartile ranges); n = 10 per group. Differences between saline- and topiramate-treated groups are indicated: *P < 0.05, **P < 0.01.
0.01 mg/kg, 16.1 ± 1.7 in the group treated with topiramate 0.1 mg/kg, 24.3 + 1.8 in the group treated with topiramate 1.0 mg/kg, 26.0 ± 2.2 in the group treated with topiramate 10.0 mg/kg, and 30.8 ± 5.9 in the group treated with topiramate 100.0 mg/kg (F (5,52) = 1.87, P = 0.12). The second experiment examined the effect of pretest systemic administration of topiramate on retrieval of long-term object recognition memory. Results for the second experiment indicated that administration of topiramate 0.01 and 0.1 mg/kg induced enhancement of retrieval of LTM (both P 0 s < 0.05). In contrast, topiramate 10.0 mg/kg (P < 0.05) and 100.0 mg/kg (P < 0.01) caused significant impairment of LTM (Fig. 2, bottom). Again, statistical analysis comparing training and long-term memory session recognition indexes within groups indicated that the group that received topiramate 100.0 mg/kg had a complete memory blockade, as the animals showed no significant preference toward the novel object in the LTM retention test trial, although this fell short of significance (P = 0.07). There was no significant difference among groups in either STM retention (P = 0.69) (Fig. 2, top) or
total time spent exploring both objects during the training trial (mean ± SE time spent exploring both objects was 40.9 ± 9.3 in the saline-treated group, 44.4 ± 7.1 in the group treated with topiramate 0.01 mg/kg, 48.2 ± 6.2 in the group treated with topiramate 0.1 mg/kg, 44.9 ± 7.2 in the group treated with topiramate 1.0 mg/kg, 53.1 ± 8.4 in the group treated with topiramate 10.0 mg/ kg, and 38.0 ± 3.8 in the group treated with topiramate 100.0 mg/kg: F (5,53) = 0.61, P = 0.70), and pretest injections of topiramate did not affect total exploration time during the LTM test trial (P = 0.27). 4. Discussion The present results can be summarized as follows: rats that received a posttraining injection of topiramate 0.1 mg/kg exhibited improved LTM for the NOR task, whereas those that received 10.0 and 100.0 mg/kg had severe deficits in both STM and LTM. In animals given topiramate prior to the LTM retention test trial, low doses (0.01 and 0.1 mg/kg) enhanced and high doses (10.0 and
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100.0 mg/kg) impaired NOR retrieval. The use of posttraining injections rules out the possibility that the effects of topiramate on retention involve encoding, motivation, anxiety, or locomotion during training. In addition, pretest administration of topiramate did not affect exploration during the retention test trial. However, additional experiments investigating the effects of topiramate on open-field behavior or other locomotion and anxiety tests would be required to rule out the possibility that the effects of posttraining and pretest injections of topiramate on STM and LTM are attributable to altered anxiety or sensorimotor function. In addition, although we have demonstrated in previous studies that testing animals 1.5 hours after training does not affect performance in a second retention trial carried out 24 hours after training [22,26], we cannot rule out the possibility that drug-induced effects on information processing during the STM test trials interfered with performance during the LTM test trial. Our findings thus suggest that different doses of topiramate can have differential effects on memory consolidation and retrieval. Previous studies on the effects of topiramate on memory in rodent models have reported that topiramate can induce either memory impairment or enhancement in different experimental paradigms (for a review, see [28]). Thus, systemic administration of topiramate induces discrete impairment of working memory assessed by a spatial alternation task in rats [15]. In contrast, multiple systemic pretraining injections of topiramate (30 mg/ kg) induced enhancement of long-term spatial memory assessed in a Morris water maze [16]. It is remarkable that in our study, even very low doses of topiramate (0.01 and 0.1 mg/kg) produced significant effects on memory. Previous studies have evaluated the effects of higher doses (from 3 to 100.0 mg/kg) on memory in rats [15]. The ED50 for topiramate on seizures assessed by the maximal electroconvulsive shock test in rats is 14.9 mg/kg 1 hour after oral administration (reviewed in [18]). Additional studies are required to examine pharmacokinetic parameters after administration of low doses of topiramate in rats. A number of possible mechanisms mediating the anticonvulsant activity of topiramate have been proposed (for recent reviews, see [3,4,29]). Evidence has shown that topiramate exerts an attenuating effect on voltage-dependent sodium channels in cultured rat cerebellar granule cells [30]. In contrast, the study by McLean et al. [31] in cultured mouse spinal cord neurons did not support the view that sodium channel blockade is the primary mechanism mediating the anticonvulsant activity of topiramate. Another proposed mechanism of action of topiramate suggests that the drug enhances GABAergic activity by binding to a newly described site at the GABAA receptor complex [32]. Moreover, a recent study has demonstrated that topiramate also inhibits excitatory pathways through blockade of the AMPA and kainate subtypes of glutamate receptor [33], and NMDA glutamate receptors may be involved in the protective effect of topiramate against electroshock-induced seizures in mice [19]. At concentrations
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of 10–100 lM, topiramate induces both an increase in GABA-induced chloride influx into cerebellar granule cells and a blockade of glutamate receptor-mediated inward currents in hippocampal neurons (reviewed in [6]). It is widely known that GABAA receptors, as well as ionotropic glutamate receptors, are significantly involved in regulating memory. For instance, previous studies investigating the effects of micro-infusions of specific agonists and antagonists of neurotransmitter receptors on aversively motivated conditioning and habituation to a novel environment have demonstrated that the GABAA antagonists picrotoxin and bicuculline enhance, whereas benzodiazepines and the GABAA agonist muscimol impair, memory formation [34,35]. With respect to recognition memory, a recent study revealed that mice overexpressing GABA transporter 1 displayed cognitive deficits in the NOR task [36]. Both NMDA and non-NMDA ionotropic glutamate receptors are crucially involved in mediating synaptic plasticity and memory (for recent reviews, see [37–39]). A recent study has shown that the transient blockade of AMPA receptor-mediated synaptic transmission within the perirhinal cortex disrupted encoding of both short- and long-lasting memory, as well as retrieval and consolidation of NOR [23]. Furthermore, genetic studies have implicated hippocampal NMDA receptors in NOR formation [20], and we have recently demonstrated that NMDA receptor antagonism impairs consolidation of memory for the NOR task [27]. This evidence is consistent with the possibility that both NMDA and non-NMDA ionotropic glutamate receptors are involved in the topiramate-induced alterations in NOR. However, electrophysiological studies have shown that topiramate did not alter the induction of long-term potentiation (LTP), a cellular model of memory [40]. As most forms of LTP are triggered by calcium influx through NMDA receptor channels and maintained by non-NMDA receptor activity, this finding suggests that ionotropic glutamate receptors may not be crucial in mediating the effects of topiramate on synaptic plasticity. Despite the observed detrimental effects of topiramate on cognition, it has been proposed that topiramate also acts as a neuroprotective agent. Several studies indicate that epilepsy may lead to neuronal death and lesions in diverse brain regions [41,42]. Consistent with this view, Maragakis et al. [43] have suggested that topiramate can have anti-excitotoxic properties, because it protects against motor neuron degeneration. In addition, in a recent study topiramate improved survival and also improved CA1 and CA3 pyramidal cell survival in a dose-dependent manner in the pilocarpine rat model of chronic epilepsy [44]. Topiramate has also proved to be neuroprotective in an animal model of hypoxia–ischemia, as topiramate treated newborn piglets had reduced neuronal loss [45]. The present study suggests that acute administration of topiramate at low doses may improve memory. This would be consistent with the findings of Hoover et al. [16] showing that topiramate produced facilitation of spatial learning,
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thus indicating that topiramate may have cognition-enhancing properties. However, the doses of topiramate that induced memory facilitation in the present study were very low, and it is unclear what plasma levels of topiramate are reached with those doses. Although low doses of topiramate have been clinically used in humans [7–9,46–50], further research is necessary to clarify the pharmacological mechanisms mediating the effects of such low doses of topiramate. Acknowledgments This research was supported by CNPq-MCT Grants 474663/2004-3 and 307265/2003-0 (to N.S.) M.N.M.L. and A.D. are recipients of CAPES-MEC fellowships. References [1] LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA 2004;291:605–14. [2] Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy. Epileptic Disord 2004;6:57–75. [3] Czapinski P, Blaszczyk B, Czuczwar SJ. Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 2005;5:3–14. [4] White HS. Molecular pharmacology of topiramate: managing seizures and preventing migraine. Headache 2005;45(Suppl. 1): S48–S56. [5] Willmore LJ. Antiepileptic drugs and neuroprotection: current status and future roles. Epilepsy Behav 2005;7(Suppl. 3):S25–8. [6] Perucca F. A pharmacological and clinical review on topiramate, a new antiepileptic drug. Pharmacol Res 1997;35:241–56. [7] Chen CK, Shiah IS, Yeh CB, Mao WC, Chang CC. Combination treatment of clozapine and topiramate in resistant rapid-cycling bipolar disorder. Clin Neuropharmacol 2005;28:136–8. [8] De Bernardi C, Ferraris S, D’Innella P, Do F, Torre E. Topiramate for binge eating disorder. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:339–41. [9] Silberstein SD, Ben-Menachem E, Shank RP, Wiegand F. Topiramate monotherapy in epilepsy and migraine prevention. Clin Ther 2005;27:154–65. [10] Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001;357:216–22. [11] Fritz N, Glogau S, Hoffmann J, Rademacher M, Elger CE, Helmstaedter C. Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy Behav 2005;6:373–81. [12] Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52:321–7. [13] Meador KJ, Loring DW, Ray PG, et al. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia 1999;40:1279–85. [14] Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol 2004;3:618–21. [15] Shannon HE, Love PL. Effects of antiepileptic drugs on working memory as assessed by spatial alternation performance in rats. Epilepsy Behav 2004;5:857–65. [16] Hoover RC, Motta M, Davis J, et al. Differential effects of the anticonvulsant topiramate on neurobehavioral and histological outcomes following traumatic brain injury in rats. J Neurotrauma 2004;21:501–12. [17] Meldrum BS. Update on the mechanism of action of antiepileptic drugs. Epilepsia 1996;37(Suppl. 6):S4–S11. [18] Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2001;41(Suppl. 1):S3–9.
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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. 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 antiepileptic drugs in the treatment of epilepsy and indications other than epilepsy, including migraine prophylaxis, neuropathic 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 receptorgated channels, and blockade of voltage-gated ion channels [3]. Topiramate is a new antiepileptic agent initially introduced 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 *
Corresponding author. Fax: +55 51 33203612. E-mail address: [email protected] (N. Schro¨der).
1525-5050/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2006.09.007
for other neurological and psychiatric disorders including migraine [2,4–9]. Patients with epilepsy may have impaired cognitive abilities, 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, assessment of the potential adverse cognitive effects of new antiepileptic drugs using animal models may have implications for the clinical use of topiramate in the treatment of epilepsy and other conditions such as migraine. For instance, topiramate has been reported to produce a dose-related impairment in working memory assessed by spatial alternation 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
M.N. Martins de Lima et al. / Epilepsy & Behavior 10 (2007) 32–37
in a water maze in sham- but not brain-injured animals [16]. As mentioned above, proposed mechanisms mediating the actions of topiramate include sodium channel blockade; positive modulation of c-aminobutyric acid (GABA) type A (GABAA) receptors; and inhibition of the aminohydroxymethylisoxazole propionic acid (AMPA) and kainate non-N-methyl-D-aspartate (NMDA) glutamate receptor subtypes [1,3,4,6,17–19]. GABA and glutamate receptors and sodium channels have been implicated in memory formation and recall. The novel object recognition memory (NOR) task is based on the spontaneous tendency of rodents to explore a novel object in preference to a familiar object. It is a nonspatial and non-rewarded task that might depend on both the hippocampus and the nigrostriatal dopaminergic pathway [20–22]. Studies performed by Winters and Bussey [23–25] have indicated participation of the perirhinal cortex in recognition memory and have suggested that, as in the hippocampus, AMPA and NMDA glutamate receptors mediate synaptic transmission and activity-dependent synaptic plasticity, respectively, in several stages of memory processing (encoding, retrieval, and consolidation). Thus, the NOR procedure may be a useful preclinical model with which to characterize the effects of new antiepileptic drugs on cognitive function. The aim of the present study was to evaluate the effects of topiramate on consolidation and retrieval of NOR. The first experiment examined the effects of topiramate on consolidation in rats systemically administered topiramate immediately after NOR training. A second experiment examined the effects of topiramate on retrieval in animals given topiramate 1 hour before an NOR 24-hour retention test trial. 2. Method 2.1. Subjects Adult female Wistar rats were obtained from the State Health Research Foundation (FEPPS-RS, Porto Alegre, Brazil). The rats were maintained in groups of five animals in a plastic cage with sawdust bedding at a room temperature of 22 ± 1 C and on a 12-hour light/12-hour dark cycle. The animals were supplied with standardized pellet food and tap water ad libitum. Behavioral testing started when animals reached the age of 3 months. All experimental procedures were performed in accordance with the NIH Guide for Care and Use of Laboratory Animals (NIH Publication No. 80-23 Revised 1996).
2.2. Drugs and injection procedures For the first experiment, topiramate (Janssen–Cilag Pharmaceuticals, Sa˜o Paulo, Brazil; 0.01, 0.1, 1.0, 10.0, or 100.0 mg/kg body weight) or saline (0.9% NaCl) was administered intraperitoneally (1.0 ml/kg injection volume) immediately after the NOR training trial. For the second experiment, topiramate (0.01, 0.1, 1.0, 10.0, or 10.00 mg/kg) or saline was administered intraperitoneally 1 hour before the NOR long-term retention test trial.
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2.3. Novel object recognition The NOR task apparatus and procedures have been described elsewhere [22,26,27]. Briefly, an open-field apparatus (45 · 40 · 60 cm) made of plywood with sawdust covering its floor was used in the NOR task. On the first day, rats were submitted to a habituation session during which they were placed in the empty open field for 5 minutes. On the following day, rats were given one 5-minute training trial in which they were exposed to two identical objects (A1 and A2). All objects were made of Duplo Lego Toys and were similar in texture, color, and size, but had distinctive shapes. The objects were positioned in two adjacent corners, 9 cm from the walls. On a short-term memory (STM) retention test trial given 1.5 hour after the training session, rats were allowed to explore the open field for 5 minutes in the presence of two objects: the familiar object A and a novel object B. These were placed in the same locations as in the training trial. On a long-term memory (LTM) retention test trial carried out 24 hours after the training trial, rats were allowed to explore the open field for 5 minutes in the presence of the familiar object A and a third novel object C. The same animals were used for the STM and LTM retention tests as previously described [22,26,27]. Object exploration was measured using two stopwatches to record the time spent exploring the objects during the experimental sessions. Exploration was defined as sniffing or touching the object with the nose. Sitting on the object was not considered exploration. A recognition index for each animal was calculated as the ratio TN/(TF + TN), where TF = time spent exploring the familiar object (A), TN = time spent exploring the novel object (B or C). For the training trial, the index was the ratio of time spent exploring object A2 to time spent exploring both objects [TA2/(TA1 + TA2)].
2.4. Statistics Groups were compared using Kruskal–Wallis analysis of variance followed by the Mann–Whitney U test when necessary. Comparisons between sessions within the same group were made using the Wilcoxon test [26,27]. P values less than 0.05 were considered to indicate statistical significance.
3. Results The first experiment examined the effects of posttraining systemic administration of topiramate on consolidation of short- and long-term object recognition memory. Administration of topiramate at 10.0 and 100.0 mg/kg induced STM deficits, as recognition indexes of these groups were significantly lower than the recognition index of the saline-treated group (both P’s < 0.01) (Fig. 1, top). In the LTM test, results indicated that topiramate 0.1 mg/kg induced enhancement of recognition memory (P < 0.05 compared with saline-treated animals), whereas topiramate 10.0 or 100.0 mg/kg caused impairment of LTM (both P 0 s < 0.01 compared with saline-treated animals) (Fig. 1, bottom). Moreover, statistical analysis comparing recognition indexes obtained in training and long-term retention sessions within groups indicated that the group that received the highest dose of topiramate (100.0 mg/kg) had a complete memory blockade, as the animals showed no significant preference toward the novel object in the testing session (P = 0.17). There was no significant difference among groups in the total time spent exploring both objects during the training trial: mean ± SE time spent exploring both objects was 24.1 ± 4.6 in the saline-treated group, 20.7 ± 3.8 in the group treated with topiramate
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Fig. 1. Effects of posttraining administration of topiramate on recognition memory. Top: Short-term retention (STM) test 1.5 hours after training. Bottom: Long-term retention (LTM) test 24 hours after training. The proportion of the total exploration time that the animal spent investigating the novel object was the ‘‘recognition index’’ for the retention test trials, expressed by the ratio TN/(TF + TN), where TF = time spent exploring the familiar object (A), and TN = time spent exploring the novel object (B or C). For the training trial, the index was obtained as the ratio of time spent exploring object A2 to the time spent exploring both objects, TA2/(TA1 + TA2). Data are expressed as medians (interquartile ranges); n = 10 per group. Differences between saline- and topiramate-treated groups are indicated: *P < 0.05, **P < 0.01.
Fig. 2. Effects of administration of topiramate 1hour before the long-term retention (LTM) test on recognition memory. Top: Short-term retention (STM) test 1.5 hours after training. Bottom: Long-term retention (LTM) test 24 hour after training. The proportion of the total exploration time that the animal spent investigating the novel object was the ‘‘recognition index’’ for the retention test trials, expressed by the ratio TN/(TF + TN), where TF = time spent exploring the familiar object (A), and TN = time spent exploring the novel object (B or C). For the training trial, the index was obtained as the ratio of time spent exploring object A2 to the time spent exploring both objects, TA2/(TA1 + TA2). Data are expressed as medians (interquartile ranges); n = 10 per group. Differences between saline- and topiramate-treated groups are indicated: *P < 0.05, **P < 0.01.
0.01 mg/kg, 16.1 ± 1.7 in the group treated with topiramate 0.1 mg/kg, 24.3 + 1.8 in the group treated with topiramate 1.0 mg/kg, 26.0 ± 2.2 in the group treated with topiramate 10.0 mg/kg, and 30.8 ± 5.9 in the group treated with topiramate 100.0 mg/kg (F (5,52) = 1.87, P = 0.12). The second experiment examined the effect of pretest systemic administration of topiramate on retrieval of long-term object recognition memory. Results for the second experiment indicated that administration of topiramate 0.01 and 0.1 mg/kg induced enhancement of retrieval of LTM (both P 0 s < 0.05). In contrast, topiramate 10.0 mg/kg (P < 0.05) and 100.0 mg/kg (P < 0.01) caused significant impairment of LTM (Fig. 2, bottom). Again, statistical analysis comparing training and long-term memory session recognition indexes within groups indicated that the group that received topiramate 100.0 mg/kg had a complete memory blockade, as the animals showed no significant preference toward the novel object in the LTM retention test trial, although this fell short of significance (P = 0.07). There was no significant difference among groups in either STM retention (P = 0.69) (Fig. 2, top) or
total time spent exploring both objects during the training trial (mean ± SE time spent exploring both objects was 40.9 ± 9.3 in the saline-treated group, 44.4 ± 7.1 in the group treated with topiramate 0.01 mg/kg, 48.2 ± 6.2 in the group treated with topiramate 0.1 mg/kg, 44.9 ± 7.2 in the group treated with topiramate 1.0 mg/kg, 53.1 ± 8.4 in the group treated with topiramate 10.0 mg/ kg, and 38.0 ± 3.8 in the group treated with topiramate 100.0 mg/kg: F (5,53) = 0.61, P = 0.70), and pretest injections of topiramate did not affect total exploration time during the LTM test trial (P = 0.27). 4. Discussion The present results can be summarized as follows: rats that received a posttraining injection of topiramate 0.1 mg/kg exhibited improved LTM for the NOR task, whereas those that received 10.0 and 100.0 mg/kg had severe deficits in both STM and LTM. In animals given topiramate prior to the LTM retention test trial, low doses (0.01 and 0.1 mg/kg) enhanced and high doses (10.0 and
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100.0 mg/kg) impaired NOR retrieval. The use of posttraining injections rules out the possibility that the effects of topiramate on retention involve encoding, motivation, anxiety, or locomotion during training. In addition, pretest administration of topiramate did not affect exploration during the retention test trial. However, additional experiments investigating the effects of topiramate on open-field behavior or other locomotion and anxiety tests would be required to rule out the possibility that the effects of posttraining and pretest injections of topiramate on STM and LTM are attributable to altered anxiety or sensorimotor function. In addition, although we have demonstrated in previous studies that testing animals 1.5 hours after training does not affect performance in a second retention trial carried out 24 hours after training [22,26], we cannot rule out the possibility that drug-induced effects on information processing during the STM test trials interfered with performance during the LTM test trial. Our findings thus suggest that different doses of topiramate can have differential effects on memory consolidation and retrieval. Previous studies on the effects of topiramate on memory in rodent models have reported that topiramate can induce either memory impairment or enhancement in different experimental paradigms (for a review, see [28]). Thus, systemic administration of topiramate induces discrete impairment of working memory assessed by a spatial alternation task in rats [15]. In contrast, multiple systemic pretraining injections of topiramate (30 mg/ kg) induced enhancement of long-term spatial memory assessed in a Morris water maze [16]. It is remarkable that in our study, even very low doses of topiramate (0.01 and 0.1 mg/kg) produced significant effects on memory. Previous studies have evaluated the effects of higher doses (from 3 to 100.0 mg/kg) on memory in rats [15]. The ED50 for topiramate on seizures assessed by the maximal electroconvulsive shock test in rats is 14.9 mg/kg 1 hour after oral administration (reviewed in [18]). Additional studies are required to examine pharmacokinetic parameters after administration of low doses of topiramate in rats. A number of possible mechanisms mediating the anticonvulsant activity of topiramate have been proposed (for recent reviews, see [3,4,29]). Evidence has shown that topiramate exerts an attenuating effect on voltage-dependent sodium channels in cultured rat cerebellar granule cells [30]. In contrast, the study by McLean et al. [31] in cultured mouse spinal cord neurons did not support the view that sodium channel blockade is the primary mechanism mediating the anticonvulsant activity of topiramate. Another proposed mechanism of action of topiramate suggests that the drug enhances GABAergic activity by binding to a newly described site at the GABAA receptor complex [32]. Moreover, a recent study has demonstrated that topiramate also inhibits excitatory pathways through blockade of the AMPA and kainate subtypes of glutamate receptor [33], and NMDA glutamate receptors may be involved in the protective effect of topiramate against electroshock-induced seizures in mice [19]. At concentrations
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of 10–100 lM, topiramate induces both an increase in GABA-induced chloride influx into cerebellar granule cells and a blockade of glutamate receptor-mediated inward currents in hippocampal neurons (reviewed in [6]). It is widely known that GABAA receptors, as well as ionotropic glutamate receptors, are significantly involved in regulating memory. For instance, previous studies investigating the effects of micro-infusions of specific agonists and antagonists of neurotransmitter receptors on aversively motivated conditioning and habituation to a novel environment have demonstrated that the GABAA antagonists picrotoxin and bicuculline enhance, whereas benzodiazepines and the GABAA agonist muscimol impair, memory formation [34,35]. With respect to recognition memory, a recent study revealed that mice overexpressing GABA transporter 1 displayed cognitive deficits in the NOR task [36]. Both NMDA and non-NMDA ionotropic glutamate receptors are crucially involved in mediating synaptic plasticity and memory (for recent reviews, see [37–39]). A recent study has shown that the transient blockade of AMPA receptor-mediated synaptic transmission within the perirhinal cortex disrupted encoding of both short- and long-lasting memory, as well as retrieval and consolidation of NOR [23]. Furthermore, genetic studies have implicated hippocampal NMDA receptors in NOR formation [20], and we have recently demonstrated that NMDA receptor antagonism impairs consolidation of memory for the NOR task [27]. This evidence is consistent with the possibility that both NMDA and non-NMDA ionotropic glutamate receptors are involved in the topiramate-induced alterations in NOR. However, electrophysiological studies have shown that topiramate did not alter the induction of long-term potentiation (LTP), a cellular model of memory [40]. As most forms of LTP are triggered by calcium influx through NMDA receptor channels and maintained by non-NMDA receptor activity, this finding suggests that ionotropic glutamate receptors may not be crucial in mediating the effects of topiramate on synaptic plasticity. Despite the observed detrimental effects of topiramate on cognition, it has been proposed that topiramate also acts as a neuroprotective agent. Several studies indicate that epilepsy may lead to neuronal death and lesions in diverse brain regions [41,42]. Consistent with this view, Maragakis et al. [43] have suggested that topiramate can have anti-excitotoxic properties, because it protects against motor neuron degeneration. In addition, in a recent study topiramate improved survival and also improved CA1 and CA3 pyramidal cell survival in a dose-dependent manner in the pilocarpine rat model of chronic epilepsy [44]. Topiramate has also proved to be neuroprotective in an animal model of hypoxia–ischemia, as topiramate treated newborn piglets had reduced neuronal loss [45]. The present study suggests that acute administration of topiramate at low doses may improve memory. This would be consistent with the findings of Hoover et al. [16] showing that topiramate produced facilitation of spatial learning,
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thus indicating that topiramate may have cognition-enhancing properties. However, the doses of topiramate that induced memory facilitation in the present study were very low, and it is unclear what plasma levels of topiramate are reached with those doses. Although low doses of topiramate have been clinically used in humans [7–9,46–50], further research is necessary to clarify the pharmacological mechanisms mediating the effects of such low doses of topiramate. Acknowledgments This research was supported by CNPq-MCT Grants 474663/2004-3 and 307265/2003-0 (to N.S.) M.N.M.L. and A.D. are recipients of CAPES-MEC fellowships. References [1] LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA 2004;291:605–14. [2] Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy. Epileptic Disord 2004;6:57–75. [3] Czapinski P, Blaszczyk B, Czuczwar SJ. Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 2005;5:3–14. [4] White HS. Molecular pharmacology of topiramate: managing seizures and preventing migraine. Headache 2005;45(Suppl. 1): S48–S56. [5] Willmore LJ. Antiepileptic drugs and neuroprotection: current status and future roles. Epilepsy Behav 2005;7(Suppl. 3):S25–8. [6] Perucca F. A pharmacological and clinical review on topiramate, a new antiepileptic drug. Pharmacol Res 1997;35:241–56. [7] Chen CK, Shiah IS, Yeh CB, Mao WC, Chang CC. Combination treatment of clozapine and topiramate in resistant rapid-cycling bipolar disorder. Clin Neuropharmacol 2005;28:136–8. [8] De Bernardi C, Ferraris S, D’Innella P, Do F, Torre E. Topiramate for binge eating disorder. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:339–41. [9] Silberstein SD, Ben-Menachem E, Shank RP, Wiegand F. Topiramate monotherapy in epilepsy and migraine prevention. Clin Ther 2005;27:154–65. [10] Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001;357:216–22. [11] Fritz N, Glogau S, Hoffmann J, Rademacher M, Elger CE, Helmstaedter C. Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy Behav 2005;6:373–81. [12] Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52:321–7. [13] Meador KJ, Loring DW, Ray PG, et al. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia 1999;40:1279–85. [14] Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol 2004;3:618–21. [15] Shannon HE, Love PL. Effects of antiepileptic drugs on working memory as assessed by spatial alternation performance in rats. Epilepsy Behav 2004;5:857–65. [16] Hoover RC, Motta M, Davis J, et al. Differential effects of the anticonvulsant topiramate on neurobehavioral and histological outcomes following traumatic brain injury in rats. J Neurotrauma 2004;21:501–12. [17] Meldrum BS. Update on the mechanism of action of antiepileptic drugs. Epilepsia 1996;37(Suppl. 6):S4–S11. [18] Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2001;41(Suppl. 1):S3–9.
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