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

Abstract

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.

Chronic developmental exposure to phenytoin has long‐term behavioral consequences

“…We used an instrumental appetitive-to-aversive transfer paradigm (AP-AV) and an avoidance learning (AV) paradigm to test simple associative and higher-order learning and memory in the female offspring of these animals. Previous studies report that the appetitive to aversive transfer paradigm has hippocampal dependent components (Banks et al, 1999(Banks et al, , 2001McDowell et al, 2004). Because DPH administration has teratogenic effects that produce behavioral deficits in various spatial learning and memory paradigms (Vorhees, 1987a,b;Minck et al, 1991;McCartney et al, 1999;Schilling et al, 1999;Wolansky and Azcurra, 2005), this study was designed to comparatively investigate the behavioral effect of prenatal DPH exposure on a simple associative learning task (appetitive and aversive conditioning) and a hippocampal dependent associative learning task (AP-AV).…”

“…In this study two forms of a signaled bar pressing task were used that were designed to investigate the neural substrates of appetitive and aversive learning (Steinmetz et al, 1993). The transfer from the appetitive task to the aversive task has learning and memory components that are hippocampal-dependent (Banks et al, 1999(Banks et al, , 2001McDowell et al, 2004).…”

The Effects of Sex and Chronic Restraint on Instrumental Learning in Rats

“…Pavlovian instrumental learning requires the subject to make an association between two stimuli and subsequently volitionally manipulates an object as an indication of choice, typically a lever or barpress. The animals were restrained for 3 weeks and then tested in either an active avoidance task or in an appetitive-to-aversive transfer task, paradigms that we have previously employed in both male and female rats (e.g., [ 13 – 16 ]). This paradigm was selected because of its ability to test lower level associations (i.e., shaping and nontransfer-signaled learning) as well as the ability to test discrimination learning (i.e., appetitive-to-aversive transfer learning).…”

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

“…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.…”

“…This paradigm was developed to study appetitive and aversive learning in the same subjects, and has been used in past work to evaluate learning, memory, and impairments that accompany cerebellar, hippocampal, cingulate, and prefrontal cortex lesions (Steinmetz et al, 1993; Logue, 1994). We have used this behavioral paradigm to evaluate the effects of phenytoin and carbamazapine in adult rats (Banks et al, 1999, 2001; McDowell et al, 2004), rats exposed to phenytoin in utero (Mowery et al, 2008), rats with lesions of the basal nucleus of Meynart (Butt et al, 2003), ovariectomized female rats with or without estradiol replacement (Goodman et al, 2004), and rats undergoing chronic restraint (McDowell et al, 2013). …”