Pentobarbital More Potently Disrupts Learning in Females Than Males Compared to Other Allosteric Modulators of the GABAAReceptor Complex

Abstract

<b>Abstract ID 25346</b> <b>Poster Board 216</b> <b>Background:</b> Understanding sex differences in drug effects leads to improved clinical outcomes and a better understanding of drug mechanisms. For this reason, several positive allosteric modulators and a negative allosteric modulator of the GABA_A receptor complex were administered to male and female Long-Evans rats responding in a learning task. The positive allosteric modulators were ethanol, pentobarbital, and alprazolam, whereas the negative allosteric modulator was FG-7142. <b>Methods:</b> Learning was assessed using a repeated-acquisition procedure in which subjects responded on three response keys to acquire a different four-response sequence each session for food reinforcement. More specifically, sequence completions were reinforced under a second-order variable ratio 2 (VR-2) schedule, and incorrect responses resulted in a 5-sec timeout. Data were analyzed in terms of the overall response rate (responses/min, not including timeouts) and the percentage of errors ((incorrect responses/total responses) x 100). After responding under the repeated acquisition baseline stabilized, dose-effect curves were obtained for each of the drugs. ED50 values were calculated for each subject and the group by linear regression using two or more data points in the descending (response rate) and ascending (percent errors) portion of the dose-effect curves. <b>Results:</b> With a few exceptions, all of the drugs were equally potent in both males and females compared to their respective controls, and dose-dependently decreased the overall response rate and increased the percentage of errors as the dosage increased. Overall response rate and percent errors were both significantly affected at the same dose for FG-7142 (1.0-10 mg/kg) and ethanol (0.32-1.33 mg/kg). Alprazolam (1.0-18 mg/kg) more potently decreased response rate than it increased percent errors. In contrast, pentobarbital (1.0-18 mg/kg) was unlike the other drugs in that it more potently decreased response rate and increased errors in female rats compared to males by a quarter-log unit. This difference was also reflected in the ED50s calculated from individual animal data and ED50s from grouped data. Pentobarbital also significantly increased percent errors at a lower dose than the dose affecting response rate in males, while response rate and percent errors were significantly disrupted at the same dose in females. <b>Conclusions:</b> Whereas ethanol, pentobarbital, alprazolam, and FG-7142 all allosterically modulate the GABA_A receptor complex, they can produce very distinctive disruptions of rate and accuracy of responding under a repeated-acquisition procedure. Furthermore, these drugs can produce distinctive disruptions of these measures in males versus females. In this study pentobarbital decreased accuracy at doses lower than those that decreased response rate in males, whereas it decreased both measures at the same dose in females. These data, therefore, expand our understanding of allosteric GABA_A modulators and reveal sex differences in pentobarbital’s potency for disrupting learning.