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).

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 animals’ 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 animals’ performance. FBM-treated animals display no adverse effects of drug treatment.

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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