EFFECT OF SERTINDOLE ON RAISED MESOLIMBIC DOPAMINERGIC ACTIVITY IN THE RAT

The effect of sertindole in models of mesolimbic dopamine excess in th e rat was evaluated. Sertindole (0.0057-0.011 mu mol/kg = 2.5-5 mu g/k g, sc) and haloperidol (0.13-0.27 mu mol/kg = 50-100 mu g/kg, ip) inhi bited 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 m u 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/2 4 h) into the nucleus accumbens reduced the dopamine-induced hyperacti vity response to control levels, except at the highest dose which redu ced activity to below control levels. Locomotor activity remained at c ontrol levels after discontinuing the dopamine/sertindole treatment re gimen, whereas discontinuation of the dopamine/haloperidol treatment r egimen 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 preve nted 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 ha ving right hemispheric dominance (as measured in a turn preference tes t). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusio n, sertindole, like haloperidol and clozapine, can reduce raised mesol imbic dopaminergic activity in the rat. Sertindole differs from halope ridol by its ability to return the hyperactivity response to control l evels. (C) 1994 Wiley-Liss, Inc.