THE SELECTIVE SIGMA-LIGAND LU-28-179 HAS POTENT ANXIOLYTIC-LIKE EFFECTS IN RODENTS

The anxiolytic potential of the selective sigma(2) ligand (4-fluorophe nyl)-1-piperidinyl]-1-butyl]-1H-indole (Lu 28-179) was assessed in var ious animal models of anxiety in rodents. Lu 28-179 facilitated the ex ploratory behavior of mice and rats in the black and white two-compart ment box over a large dose range. In the rat, the minimal effective do se (MED) was 0.18 nmol/kg (0.1 mu g/kg), and in the mouse, the MED was 0.00018 nmol/kg (0.1 ng/kg). The anxiolytic-like effect was maintaine d after treatment with 1 mu g/kg/day for up to 14 days, and no anxioge nic-like effects were seen upon withdrawal from repeated treatment. Lu 28-179 increased the time that pairs of rats spent in active social i nteraction (unfamiliar high-light conditions), MED = 0.1 ng/kg. Daily treatment with Lu 28-179 (1.8 nmol/kg = 1 mu g/kg/day) for up to 4 wee ks increased the social interaction time significantly compared with c ontrols, and no anxiogenic-like effects were seen upon withdrawal. Fur thermore, Lu 28-179 reversed shock-induced suppression of drinking in the rat (MED = 18,000 nmol/kg = 10 mg/kg). Lu 28-179 did not inhibit f oot-shock-induced ultrasonic vocalization in the rat or isolation-indu ced aggressive behavior in the mouse. Lu 28-179 was over 100 times mor e potent than diazepam in the rat and mouse black and white test box a nd the rat social interaction test, whereas the potency of Lu 28-179 w as comparable to that of lorazepam in reversal of shock-induced suppre ssion of drinking, Lu 28-179 neither induced sedation nor impaired mot or coordination, even at high doses (70,000 nmol/kg = 40 mg/kg). In co nclusion, Lu 28-179 exerts potent and long-lasting anxiolytic-like eff ects in rodents without inducing sedation and withdrawal anxiogenesis.