An Ethopharmacological Analysis of Selective Activation of 5-HT 1A Receptors: The Mouse 5-HT 1A Syndrome

Abstract

The behavioral effects of 8-OH-DPAT [0.5–10 mg/kg intraperitoneally (IP)] and (+) S-20499 (1–20 mg/kg IP), a recently synthesized 5-HT 1A receptor full agonist, were examined over a 2-h period in mice in a neutral cage and, during the peak period of effect, in a runway. 8-OH-DPAT (1 and 10 mg/kg) and (+) S-20499 (10 and 20 mg/kg) blocked vertical activity (i.e., rearing and hanging on the wire mesh) during the period postinjection when levels of activity of the control mice were high. In this initial period (0–30 min), mice treated with 8-OH-DPAT, but not those treated with (+) S-20499, displayed flat back rather than curve back locomotion (0.5–10 mg/kg). However, after about 50 min, marked hyperactivity emerged for 8-OH-DPAT at 0.5 and 1 mg/kg and for (+) S-20499 at all doses, including increases in rearing, hanging, grooming, and, for (+) S-20499, curve back locomotion. Both 8-OH-DPAT (10 mg/kg) and (+) S-20499 (>20 mg/kg) significantly enhanced eating responses. Both drugs rapidly induced straub tail responses at all doses, and this effect remained significant until the end of the experiment at the highest doses. Subjects treated with 0.5 mg/kg of 8-OH-DPAT and 10 mg/kg of (+) S-20499 displayed in the initial time period “ballistic-type” rapid forelimb movements targeted toward the side of the head. During peak drug effect periods, higher doses of both drugs produced significant increases in movement with a change of direction, including rotation around the hindlimbs, suggesting, as do the ballistic-type movements, particular involvement of the forelimbs. These findings provide evidence consonant with the view that selective activation of 5-HT 1A receptors in mice produces distinct behavioral changes in part associated with the 5-HT syndrome. Moreover, these changes differ, in the specific movements induced and in the drug parameters and time course of changes, from those reported in the laboratory rat.