L-745,870, A SUBTYPE-SELECTIVE DOPAMINE-D4 RECEPTOR ANTAGONIST, DOES NOT EXHIBIT A NEUROLEPTIC-LIKE PROFILE IN RODENT BEHAVIORAL-TESTS

This study examined the high-affinity, selective dopamine D-4 receptor antagonist, L-745,870 )piperatin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridi ne) in rodent behavioral models used to predict antipsychotic potentia l and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-7 45,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selecti vely blocking D-4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding indu ced by the nonselective dopamine D-2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D-2/3 recep tor antagonist, raclopride (0.2 mg/kg s.c.), L-745,870 had no effect o n apomorphine-induced stereotypy in the rat but did induce catalepsy i n the mouse, albeit at a high dose of 100 mg/kg, which is likely to oc cupy dopamine D-2 receptors in vivo. High doses also impaired motor pe rformance; in rats L-745,870 significantly reduced spontaneous locomot or activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effe ctive dose = 100 mg/kg). Altogether these results suggest that dopamin e D-4 receptor antagonism is not responsible for the ability of clozap ine to attenuate amphetamine-induced hyperactivity and conditioned avo idance responding in rodents. Furthermore, the lack of effect of L-745 ,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.