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Behavioural Neuroscience Poster Session






Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References




Discussion
Board

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Appetitive-to-Aversive Instrumental Transfer: A Behavioral Paradigm Useful for Evaluation of the Relative Negative Learning/Memory Side-Effects of Antiepileptics.


Contact Person: Melissa K Banks (mebanks@indiana.edu)


Introduction

The appetitive-to-aversive transfer task (Steinmetz et al., 1993) provides a good means to measure relative cognitive impairments. We have used the paradigm to detect the learning and/or memory effects of a number of antiepileptic drugs, to include phenytoin, carbamazepine, valproic acid and felbamate (Banks et al., 1996, 1997, 1998). The transfer paradigm has demonstrated sufficient sensitivity to detect differential impairments arising from drug treatment. Performance in the transfer paradigm has suggested relative deficits for phenytoin- and carbamazepine-treated animals; however, valproic acid- and felbamate-treated animals demonstrated spared terminal performance in the avoidance task after transfer.

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Materials and Methods

Subjects

Data are reported for controls (water- or no treatment; CON), and for rats treated with phenytoin (DPH), carbamazepine (CBZ), valproic acid (VPA), or felbamate (FBM). All subjects were female Sprague-Dawley rats (approximately 90-150 days of age).

Task

Animals were trained in a sound-attenuated Skinner box to barpress for food reinforcement in the presence of a tone signal. Following the 21st daily training session, the drug-treated animals began treatment with one of four antiepileptic medications (DPH: N= 9, CBZ: N= 13, VPA: N= 7, FBM: N= 8) or water. For the respective drug regimens, either a loading dose (DPH) or gradual increases in dosage (CBZ, VPA, and FBM) were administered until the final maintenance dose was reached. The oral suspension or syrup was administered via gavage two to three times daily in divided doses, totaling approximately ten times the human therapeutic dose per unit weight (to reach therapeutic drug plasma levels). After assessing the extent to which the antiepileptics might impair the appetitive response in the drug-treated rats, all animals were transferred to the aversive context in which the tone signaled an impending shock rather than the availability of food. The shock could be avoided by a barpress within the first 3 seconds after tone onset, or escaped with a barpress during the subsequent 3 seconds. Control animals are presented for comparison (N= 18).

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Results

We have treated a number of control animals with water to assess for any effects of the gavage procedure, per se. We found no significant differences between H2O- and no-treatment controls; these data, therefore, are collapsed for presentation in the following graphs.

Appetitive Context Performance

Figure 1: Percent Reinforcement Performance.

Appetitive performance is relatively maintained after the initiation of drug treatment in the animals (compare performance across the last five days prior to drug treatment to the last five days of appetitive training during drug treatment). The percentage of reinforcements obtained appears to demonstrate no adverse effects of drug treatment.

Figure 2: Efficiency Ratios.

The relative efficiency of the animalsí behavior (# of reinforcements obtained / total # of barpresses) demonstrates no adverse effects of drug treatment.

Aversive Context Performance

Figure 3: Percent Avoidance Performance.

The drug-treated animals demonstrate differential impairments in acquisition of the avoidance response. DPH-treated animals show a pronounced inability to perform the avoidance response, showing little improvement over the first five days of training. CBZ-treated animals perform comparatively well in the acquisition of the avoidance response, but still show a moderate impairment in terminal performance as compared to CON. While VPA-treated animals display a slight impairment in avoidance acquisition, neither VPA- nor FBM- treated animals demonstrate impaired terminal performance of the avoidance response.

Figure 4: Efficiency Ratios.

The efficiency ratios (# of avoidances / total # of barpresses) during avoidance performance parallel the data for avoidance. DPH-treated animals demonstrate severe impairment. CBZ-treated animals do not appear affected, while VPA-treated animals show only moderate initial difficulties as compared to control animalsí performance. FBM-treated animals display no adverse effects of drug treatment.

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Discussion and Conclusion

Phenytoin, carbamazepine, valproic acid and felbamate treatment yield little to no effect in the performance of the appetitive task.

Carbamazepine- and phenytoin-treated animals, however, demonstrate relative impairments when transferred to the aversive context. Valproic acid-treated animals, on the other hand, showed a slight retardation in the acquisition of the avoidance response, but their asymptotic performance was equal that of controls. Felbamate-treated animals demonstrated no difficulties with the transfer task.

We will continue to evaluate other clinically available and experimental anticonvulsants in this behavioral paradigm with the goal of identifying those drugs or families of drugs that produce the smallest performance deficits.

Control versions of the paradigm, such as exposure to only the appetitive or aversive context, and the reverse transfer task (aversive-to-appetitive) will also be utilized.

Additionally, we will add other behavioral paradigms to our tools for the systematic assessment of the effects of these medications.

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References

  1. Banks, M.K., Fang, P.C., Germani, J.J., Goodpaster, C.J., Riccardi, M.F. and Garraghty, P.E. (1998) A Comparison of the effects of phenytoin, carbamazepine, and valproic acid on avoidance acquisition in adult rats with or without prior appetitive training. Society for Neuroscience Abstracts, 24, 1938.
  2. Banks, M.K., Mayer, J., Phipps, E.J., Besheer, J., Barrera, H.E., & Garraghty, P.E. (1997) A comparison of the effects of valproic acid, phenytoin, and carbamazepine on transfer from appetitive to avoidance contexts in adult rats. Society for Neuroscience Abstracts, 23, 2166.
  3. Banks, M. K., Besheer, J., Szypczak, J.R., Goodpaster, L.L., Steinmetz, J.E., & Garraghty, P.E. (1996) A comparison of the effects of carbamazepine and phenytoin on transfer from appetitive to avoidance contexts in adult rats. Society for Neuroscience Abstracts, 22, 2108.
  4. Steinmetz, J.E., Logue, S.F., & Miller, D.P. (1993) Using signalled bar-pressing tasks to study the neural substrates of appetitive and aversive learning in rats: Behavioral manipulations and cerebellar lesions. Behavioral Neuroscience, 107, 941-954.

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Banks, M.K.; Garraghty, P.E.; (1998). Appetitive-to-Aversive Instrumental Transfer: A Behavioral Paradigm Useful for Evaluation of the Relative Negative Learning/Memory Side-Effects of Antiepileptics.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/behavneuro/banks0749/index.html
© 1998 Author(s) Hold Copyright