In the present experiments, we investigated the effects of several commonly employed antiepileptic drugs on the performance of adult rats in a Morris water maze task. We found that phenytoin treatment produced the most deleterious performance impairments across all days of training, and that these performance deficits are not likely due to any general sensorimotor impairments. Carbamazepine had milder, but detectable negative effects, as carbamazepine-treated animals exhibited initial acquisition deficits, but rapidly achieved escape levels comparable to controls. In marked contrast, valproate and ethosuximide had no detectable effects on learning in the water maze. These results parallel previous findings in rats treated with these compounds and tested in an instrumental learning task, and are in general agreement with the human clinical literature. To the extent that one might wish to minimize learning deficits associated with maintenance on antiepileptic drugs, phenytoin is definitely not the treatment of choice, while valproate or ethosuximide are apparently much less disruptive.
In the present study we examined the effects of the specific NMDA receptor antagonist CPP on discrimination reversal learning in rabbits. We report two primary findings. First, the institution of NMDA receptor blockade had no effect on a learned discrimination. Second, after stimulus reversal, CPP treatment impaired acquisition of the discrimination reversal. This impairment manifested itself early in training as a retardation in acquisition of a CR to the new CS+ and late in training as an inability to suppress responsiveness to the new CS-. Given the comparability of the present results with previously published results for phenytoin-treated rabbits, we suggest that the effects of phenytoin on learning in this paradigm is at least in part mediated by its effects on NMDA receptors. We further suggest that these findings emphasize the need to better define the role of NMDA receptor activation and hippocampally-mediated circuits in a variety of associative learning paradigms.
Summary: Purpose: Cognitive deficits associated with chronic treatment with phenytoin (PHT) have been reported. PHT blocks transfer from a signaled appetitive bar press to an active avoidance response in rats. We investigated the effects of PHT and the prodrug fosphenytoin in rabbits required to learn a discrimination and reversal of a classical eyeblink conditioning paradigm.Methods: Before drug treatment was started, rabbits were trained to produce a discriminated eyeblink response. PHT (n = 7) was administered centrally or the prodrug fosphenytoin (n = 2) was given systemically. Control animals were similarly treated centrally with either saline (n = 3) or no drug treatment (n = 13). Rabbits were then challenged with a stimulus reversal while being maintained on the respective drug.Results: On the first day of reversal training, control animals typically displayed high response rates to both tones, followed by a reduction in responsiveness to the new conditioned stimulus (CS-) in the ensuing days. In contrast, PHT-treated animals failed to suppress responsiveness to the new CS-.Conclusions: The response patterns observed are similar to those observed in rabbits with hippocampal ablations, leading us to suggest that the adverse effects of phenytoin may be due to actions in the hippocampus. Key Words: PhenytoinFosphenytoin-Prodrug-Antiepileptic-AnticonvulsantEpilepsy.The prevalent therapy for the treatment of seizure disorders is antiepileptic drugs (AEDs). Phenytoin (PHT) is an AED that has played a major role in the treatment of seizures since its anticonvulsant properties were reported by Merritt and Putnam (1). While the control of abnormal seizure activity is the primary goal of this class of drugs, the side effects of these drugs have not been adequately investigated. Aldenkamp et al. (2) and Pullainen and Jokelainen (3) reported that cognitive deficits were associated with chronic PHT treatment. Wilder et al. (4) have shown that all major antiepileptic drugs, particularly at high blood levels, can cause such deficits in cognition. These results stress the need for a systematic analysis of the ways in which chronic treatment with AEDs may affect learning and memory. We previously reported that chronic PHT treatment in rats impaired their acquisition of an avoidance response to a tone that had previously signaled the availability of a food reinforcement doses of PHT that suppress seizures in rats also decrease schedule-controlled responding in an operant paradigm.The classically conditioned eyeblink response has been extensively characterized and is often used as a model by which the neurobiological substrates of associative learning are analyzed (7). This model has been used to study associative learning in a wide variety of species to include humans, rats, rabbits and chickens. The rabbit eyeblink preparation provides an array of well-accepted behavioral tests for psychopharmacological manipulations (8) and has proven to be an exemplar of associative learning (9). Specifically, the discrimination and rev...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.