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The effects of the anxiolytic agents, buspirone and diazepam, on the hypothalamic-pituitary-adrenal axis (HPAA), indicated by changes in the concentration of corticosterone (CS) in plasma, were studied 1 2 , 1, 2, 4, 6, 8 and 24 hr after administration of the drug (i.p.). Samples of plasma were collected in the mid-morning (0930–1130 hr) when activity in the hypothalamic-pituitary-adrenal axis in the rat and control levels of corticosterone were low and were repeated in the afternoon (1400–1600 hr) when activity in the hypothalamic-pituitary-arenal axis and levels of corticosterone were higher. At small doses (1 mg/kg) buspirone had a greater facilitating effect on the hypothalamic-pituitary-adrenal axis than did diazepam. In addition, buspirone had a greater maximum facilitatory effect (477%) on levels of corticosterone than diazepam (345%). However, buspirone (ED 50 = 8.6 μ mol/kg) and diazepam (ED 50 = 8.7 μ mol/kg) were equipotent. Administration of I mg/kg of buspirone in the morning increased the combined 1 2 and 1 hr circulating levels of corticosterone 75% above control levels. Diazepam, at 1 mg/kg, did not produce any significant changes in levels of corticosterone. Large doses (10 mg/kg) of buspirone increased morning levels of corticosterone by 328% and diazepam increased levels of corticosterone by 265%. During the afternoon small doses of buspirone or diazepam did not significantly alter levels of corticosterone. Large doses of buspirone and diazepam significantly increased levels of corticosterone by 166% and 80%, respectively. Animals stressed by spinning for l min at 30–60 rpm, 15min before decapitation had levels of corticosterone that were 397% higher than the morning, and 238% higher than the afternoon control levels. The effects of spinning stress and the actions of buspirone on the hypothalamic-pituitary-adrenal axis were additive at large doses as buspirone increased levels of corticosterone above stressed controls by 20%.

It was found that gepirone and 1-(2-pyrimidinyl)-piperazine (1-PP) increased levels of corticosterone in plasma in the intact rat. Gepirone was more potent and more efficacious than its metabolite, 1-PP. The ED50 was 6.4 μmol/kg for gepirone and 65.4 μmol/kg for 1-PP. Forty-five min after intraperitoneal administration, gepirone and 1-PP produced maximum increases in corticosterone of 283% and 211 %, respectively, above control values. The amplitude and duration of the effects of the drugs were dependent on the ongoing activity in the hypothalamic-pituitary-adrenal axis. Consequently, the greatest absolute increases in corticosterone were produced during the afternoon when the activity in the hypothalamic-pituitary-adrenal axis was greatest. A single 10 mg/kg dose of gepirone significantly elevated levels of corticosterone in plasma (313 % after 1 hr) above control values for 2 hr during afternoon trials and for 1 hr (244%) during morning trials. In addition, it was found that the effects of the administration of gepirone and of stress on the levels of corticosterone in plasma were additive. In the light of other work on the hypothalamic-pituitary-adrenal axis, these results suggest that the increased levels of corticosterone, elicited by gepirone, were mediated through a serotonergic action rather than through noradrenergic activity.