Some antiepileptic compounds impair learning by rats in a Morris water maze

Churchill, James D.; Fang, Pei Chun; Voss, Steven E.; Besheer, Joyce; Herron, A; Garraghty, Preston E.

doi:10.1007/bf02688828

Cited by 15 publications

(10 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VPA adversely affects many measures of cognition in healthy humans . In rodents, VPA has been shown to disrupt spatial working memory in the eight‐arm radial maze, but not in other models . Furthermore, in several studies, approximately 500–1,000 μ m of VPA impaired HFS‐LTP in area CA1 of the rat hippocampus .…”

Section: Discussionmentioning

confidence: 98%

“…24 When examined in rodents, PHT has been shown to disrupt spatial memory, 25 whereas CBZ's effects on memory have been mixed. 25,26 Some of these discrepancies might be explained by differences in the concentrations employed. Consistent with its benign profile in humans, LTG has been shown to have no negative effect on learning and memory in rodents.…”

Section: Sodium Channel Blocking Asdsmentioning

confidence: 99%

See 1 more Smart Citation

Antiseizure drugs differentially modulate theta‐burst induced long‐term potentiation in C57BL/6 mice

et al. 2014

View full text Add to dashboard Cite

Summary Objective Cognitive comorbidities are increasingly recognized as an equal (or even more disabling) aspect of epilepsy. Additionally, the actions of some antiseizure drugs (ASDs) can impact learning and memory. Accordingly, the NINDS epilepsy research benchmarks call for the implementation of standardized protocols for screening ASDs for their amelioration or exacerbation of cognitive comorbidities. Long-term potentiation (LTP) is a widely used model for investigating synaptic plasticity and its relationship to learning and memory. While the effects of some ASDs on LTP have been examined, none of these studies employed physiologically relevant induction stimuli such as theta-burst stimulation (TBS). To systematically evaluate the effects of multiple ASDs in the same preparation using physiologically relevant stimulation protocols, we examined the effects of a broad panel of existing ASDs on TBS-induced LTP in area CA1 of in-vitro brain slices, prepared in either normal or sucrose-based ACSF, from C57BL/6 mice. Methods Coronal brain slices containing the dorsal hippocampus were made using either standard or sucrose-based ACSF. Recordings were obtained from four slices at a time using the Scientifica Slicemaster high throughput recording system. Slices exposed to ASDs were paired with slices from the opposite hemisphere that served as controls. Field excitatory post-synaptic potentials (fEPSPs) were recorded, and all ASDs were applied to slices by bath perfusion for 20 minutes prior to the induction stimulus. LTP was induced by TBS or by high-frequency stimulation (HFS). The following ASDs were examined: 100 µM phenobarbital (PB), 80 µM phenytoin (PHT), 50 µM carbamazepine (CBZ), 600 µM valproate (VPA), 60 µM topiramate (TPM), 60 µM lamotrigine (LTG), 100 µM levetiracetam (LEV), 10 µM ezogabine (EZG), and 30 µM tiagabine (TGB). Results Among voltage-gated sodium channel inhibitors, CBZ significantly attenuated TBS-induced LTP, PHT attenuated both TBS-induced LTP and post-tetanic potentiation (PTP), and LTG failed to affect LTP but did attenuate PTP. ASDs that modulate GABAergic synaptic transmission, such as PB and TGB, significantly attenuated LTP in brain slices prepared in sucrose-based ACSF but not standard ACSF. Third generation ASDs, such as LEV and TPM, did not affect LTP in ACSF- or sucrose-prepared brain slices. While EZG failed to affect LTP, it did significantly attenuate PTP under both slicing conditions. VPA failed to affect LTP in area CA1, both in C57BL/6 mice and Sprague Dawley rats, using TBS or HFS. However, VPA did attenuate TBS-induced LTP in the dentate gyrus (DG).

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Sodium Channel Blocking Asdsmentioning

confidence: 99%

Antiseizure drugs differentially modulate theta‐burst induced long‐term potentiation in C57BL/6 mice

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Conflicting reports of cognitive deficits in patients maintained on AEDs have motivated our ongoing evaluation of these drugs using a variety of behavioral paradigms (Churchill et al, 1998, 2003; Banks et al, 1999, 2001; McDowell et al, 2004; Samuelson et al, 2005). The present study expands our efforts to VPA, using the same well-defined instrumental learning and memory paradigm used to investigate phenytoin and carbamazepine in previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…One of the two daily dosages was delivered 2 h before training. This regimen has been previously shown to produce plasma levels within the human therapeutic range during the training period (Churchill et al, 2003). …”

Section: Methodsmentioning

confidence: 99%

“…Population estimates suggest that 0.5–7.1 in 1000 people are affected by epilepsy in any given year (Sander, 2003; Hirtz et al, 2007). Pharmacological intervention with antiepileptic drugs (AEDs) is the treatment of choice, but is not without cognitive side effects in animal models (Banks et al, 1999, 2001; Churchill et al, 2003; Samuelson et al, 2005; Umka et al, 2010) and human patients (Loring and Meador, 2001; Meador et al, 2003; Hamed, 2009). Our laboratory has previously shown that phenytoin, a commonly prescribed AED, blocked the acquisition of an avoidance response in the second part of an instrumental appetitive-to-aversive conditioning task (Banks et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The effects of valproic acid on appetitive and aversive instrumental learning in adult rats

Orczyk

Banks

Garraghty

2014

Front. Behav. Neurosci.

Self Cite

View full text Add to dashboard Cite

Antiepileptic medications are the frontline treatment for seizure conditions. However, these medications are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin and carbamazepine-treated rats. In the experiment reported here, the effects of valproic acid (VPA) have been studied using the same instrumental training tasks. VPA-treated rats displayed a severe deficit in acquiring a tone-signaled avoidance response. This deficit was attenuated in animals that had prior training in an appetitive context. Thus, this deficit is specific to learning in an aversive context, and does not result from difficulties in transferring associations from an appetitive to aversive context. Learning transfer deficits were previously observed in rats treated with phenytoin, and to a lesser extent, carbamazepine. On the other hand, rats treated with VPA fail to suppress inappropriate responsiveness across aversive training whether they had undergone prior appetitive training or not.

show abstract

Discrete and contextual cue alterations eliminate the instrumental appetitive-to-aversive transfer impairment in phenytoin-treated rats

McDowell

Samuelson

Dina

et al. 2004

Integr. psych. behav.

View full text Add to dashboard Cite

We have shown previously that the antiepileptic phenytoin impairs transfer in an instrumental learning task (Banks et al., 1999). The present study examined the effects of contextual alterations on appetitive-to-aversive transfer performance of rats treated with either phenytoin or tang. Adult rats were tested in tone-signaled appetitive and aversive instrumental tasks, where the animal bar-pressed to obtain a food reward (sugar pellet) or to avoid shock. Rats were trained on the appetitive task for 31 days. Beginning on the twenty-first day, rats were gavaged with either phenytoin or tang twice daily. Animals were then transferred to aversive training, with the phenytoin or tang treatment continuing throughout the 25 testing days. For some animals, contextual changes were introduced as they shifted from appetitive to aversive training, while for other animals these changes were not made. Phenytoin-treated rats that were presented with changes in context as they transferred from the appetitive to the aversive task learned the avoidance response to levels substantially higher than drug-treated rats not presented with the contextual changes. These results indicate that phenytoin impairs avoidance learning following transfer from the appetitive task, and that this impairment can be eliminated by introducing changes in context at the point of transfer. In the tang-treated control subjects, on the other hand, there was no improvement in transfer learning performance associated with the changes in contextual cues. This pattern of results suggests that contextual encoding processes in rats being trained in an instrumental appetitive-to-aversive paradigm are dramatically affected by phenytoin.

show abstract

Some antiepileptic compounds impair learning by rats in a Morris water maze

Cited by 15 publications

References 31 publications

Antiseizure drugs differentially modulate theta‐burst induced long‐term potentiation in C57BL/6 mice

Antiseizure drugs differentially modulate theta‐burst induced long‐term potentiation in C57BL/6 mice

The effects of valproic acid on appetitive and aversive instrumental learning in adult rats

Discrete and contextual cue alterations eliminate the instrumental appetitive-to-aversive transfer impairment in phenytoin-treated rats

Contact Info

Product

Resources

About