EFFECT OF SERTINDOLE ON RAISED MESOLIMBIC DOPAMINERGIC ACTIVITY IN THE RAT

The effect of sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057-0.011 mu mol/kg = 2.5-5 mu g/kg, sc) and haloperidol (0.13-0.27 mu mol/kg = 50-100 mu g/kg, ip) inhibited the hyperactivity caused by the acute intra-accumbens injection of amphetamine (20 mu g). The administration of sertindole (0.0057-2.8 mu mol/kg = 2.5 mu g-1.25 mg/kg, sc daily), haloperidol (0.027-0.40 mu mol/kg = 10-150 mu g/kg, ip bd) or clozapine (15-31 mu mol/kg = 5-10 mg/kg, ip, bd) during a 13-day period of dopamine infusion (25 mu g/24 h) into the nucleus accumbens reduced the dopamine-induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 mu mol/kg = 2.5 mu g/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra-accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 mu mol/kg = 2.5 mu g/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 mu g/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity response to control levels. (C) 1994 Wiley-Liss, Inc.