Behavioral effects of chronic buspirone administration in the pigeon: Comparison to midazolam

Abstract

The effects of acute and chronic administration of buspirone and midazolam were examined in White Carneau pigeons (N = 5) responding under a fixed-ratio 30 (FR 30) schedule of food presentation. Each drug was studied in all pigeons. For three pigeons, buspirone was studied before midazolam, while the order was reversed for the other two subjects. For each drug, a dose-response curve was determined before (prechronic) and two weeks after (postchronic) discontinuation of chronic administration. Prior to chronic drug administration, buspirone (0.3–5.6 mg/kg) and midazolam (0.1–3.0 mg/kg) decreased response rates in all subjects, in a dose-dependent manner. Midazolam was more potent than buspirone; midazolam's ED 50 (95% C.I.) was 0.53 (0.41–0.69) mg/kg compared to 2.55 (1.48–4.41) mg/kg for buspirone. For each subject, the lowest dose that decreased responding by at least 50% was administered daily, immediately before the session, for up to 6 weeks. At the lowest daily dose of buspirone, complete recovery of baseline rates was observed in 3 pigeons. However, when the buspirone dose was increased, responding remained below control rates in all but one pigeon. During chronic midazolam administration, tolerance developed to the rate-decreasing effects of midazolam in 4 subjects. When saline was substituted for buspirone or midazolam, suppressed responding returned to predrug rates in all subjects. When the dose-response curves were redetermined, the postchronic ED 50 for buspirone was 3.79 (2.10–6.82) mg/kg, which was not significantly different from the prechronic ED 50, suggesting that tolerance did not develop to buspirone's rate-decreasing effects. However, the midazolam dose-response curve was shifted to the right after chronic midazolam administration, with an ED 50 of 1.18 (0.81–1.72) mg/kg. Thus, while the behavioral effects of acute administration of buspirone and midazolam were similar, the development of tolerance, as determined from shifts in acute dose-response curves and recovery of drug-free response rates during daily administration, was substantially less for buspirone compared to midazolam. Further, consistent with clinical reports, no evidence of withdrawal was seen when daily buspirone treatments were discontinued.