The selective sigma2-ligand Lu 28-179 has potent anxiolytic-like effects in rodents

The anxiolytic potential of the selective sigma2 ligand 1-[4-[1-(4-Fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4-piperidine] [corrected] (Lu 28-179) was assessed in various animal models of anxiety in rodents. Lu 28-179 facilitated the exploratory behavior of mice and rats in the black and white two-compartment box over a large dose range. In the rat, the minimal effective dose (MED) was 0.18 nmol/kg (0.1 microg/kg), and in the mouse, the MED was 0.00018 nmol/kg (0.1 ng/kg). The anxiolytic-like effect was maintained after treatment with 1 microg/kg/day for up to 14 days, and no anxiogenic-like effects were seen upon withdrawal from repeated treatment. Lu 28-179 increased the time that pairs of rats spent in active social interaction (unfamiliar high-light conditions), MED = 0.1 ng/kg. Daily treatment with Lu 28-179 (1.8 nmol/kg = 1 microg/kg/day) for up to 4 weeks increased the social interaction time significantly compared with controls, and no anxiogenic-like effects were seen upon withdrawal. Furthermore, 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 footshock-induced ultrasonic vocalization in the rat or isolation-induced aggressive behavior in the mouse. Lu 28-179 was over 100 times more potent than diazepam in the rat and mouse black and white test box and the rat social interaction test, whereas the potency of Lu 28-179 was comparable to that of lorazepam in reversal of shock-induced suppression of drinking. Lu 28-179 neither induced sedation nor impaired motor coordination, even at high doses (70,000 nmol/kg = 40 mg/kg). In conclusion, Lu 28-179 exerts potent and long-lasting anxiolytic-like effects in rodents without inducing sedation and withdrawal anxiogenesis.