T215. THE ANTIPSYCHOTIC ACTION OF HALOPERIDOL IN PSYCHOTIC-LIKE RATS REQUIRES PRESYNAPTIC VESICULAR ACCUMULATION

BACKGROUND: The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their post synaptic inhibitory functions on the dopamine D2 receptor, which however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation remained unclear. Here we show that the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats. METHODS: We designed a haloperidol (HAL) analogue compound (HAL-F), which lacks the accumulation property of HAL, but retains its antagonist action at dopamine D2 receptors. RESULTS: By perfusing lysotracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an AMPH-hypersensitization psychosis-like model in rats, we found that subchronic i.c.v. delivered HAL, but not HAL-F attenuates psychotic-like behavior in rats in an amphetamine-induced hyperlocomotion test and the a pre-puls inhibition of an acustic startle response. DISCUSSION: These findings suggest the presynaptic accumulation of HAL as an essential prerequisite for its full antipsychotic action and may better explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action.