Actions of serotonergic agents on hypothalamic-pituitary-adrenal axis activity in the rat

1. The effects of ipsapirone, nefazodone, tiaspirone, BMS-20661, buspirone and gepirone on the hypothalamic-pituitary-adrenal (HPA) axis were studied. These drugs were selected because they have serontonin 1A (5-HT1A) receptor-binding capability and have the potential for therapeutic activity in the treatment of major affective or anxiety disorders or both. 2. Plasma corticosterone level was used as the end point for determining the effect of each drug on the HPA axis. Each drug increased the plasma corticosterone levels in a dose-dependent manner. The ED50 values were 0.8 mg/kg for BMS-20661, 3.5 mg/kg for gepirone, 3.9 mg/kg for buspirone, 5.3 mg/ kg for tiaspirone, 10.5 mg/kg for ipsapirone and 73.5 mg/kg for nefazodone. Ipsapirone and buspirone were more efficacious than the other four drugs. 3. The effect of a 10-mg/kg (35 mg/kg for nefazodone) test dose of each drug reached a peak between 30 min and 1 hr, and plasma corticosterone levels generally returned to control levels after 2 hr. 4. When the drugs were given 30 min before decapitation, in conjunction with a rotatory stress, BMS-20661 significantly inhibited the stress-induced rise, whereas ipsapirone and gepirone caused a significant increase in plasma corticosterone levels. However, when the drugs were given 2 hr before decapitation, nefazodone caused a significant decrease, whereas ipsapirone, BMS-20661 and gepirone produced significant increases in HPA axis activity. An 0800 hr dose of 0.1 mg/kg of dexamethasone suppressed the 1500 hr HPA activity by 73.1%. The 0.1-mg/kg dose of dexamethasone significantly reduced the drug-activated HPA axis activity of all of the drugs from their saline-control levels. The rank order, from least to greatest inhibitory effect, produced by this dexamethasone treatment on the drug-control levels was gepirone (-42.6%), tiaspirone (-48.9%), buspirone (-56.1%), nefazodone (-68.5%), insapirone (-70.0%), and BMS-20661 (-74.3%).