Prioleau C, Montague DM, Choksi NY, Southerland SB, Lawler CP, Mailman RB. Unusual neurochemical properties of the novel antipsychotic OPC-14597 in rat striatum. Poster presented at Society for Neuroscience Annual Meeting, 1995.
OPC-14597 (OPC} is a novel antipsychotic from a unique structural class. It binds with high affinity to rat striatal D2-like dopamine receptors, and exhibits functional antagonist properties at measures of postsynaplic receptor function. OPC also has nanomolar affinity for cloned D; receptors where it behaves functionally as an antagonist. Preliminary clinical data also indicate that this drug may be a new atypical antipsychotic having good efficacy, yet little tendency to induce extrapyramidal side effects. Thus, it was surprising that in rat brain slices OPC actually had, at high concentrations, a modest inhibitory effect on dopamine synthesis, suggesting possible agonist presynaptic actions. The present studies were aimed at investigating the actions of OPC on another measure of presynaptic function, dopamine release. The effects of OPC on dopamine release in rat striatum were compared to those of the D2 selective antagonist sulpiride using two distinct preparations. The first of these utilized in vivo cerebral microdialysis in freely moving animals We have previously shown that OPC (12 mg/kg) had little or no effect on the concentration of DA or its metabolites HVA and DOPAC, whereas haloperidol markedly increased all three. In the present studies, 1 pM OPC was infused directly into the dialysis cannula. Sulpiride, as expected, increased the efflux of dopamine and its metabolites DOPAC and HVA. Surprisingly, OPC increased dopamine overflow but, unlike sulpiride, had no effect whatsoever on the overflow of HVA and DOPAC. This was investigated further using superfused rat striatal slices preloaded with pHJ dopamine As expected, apomorphine inhibited pH] efflux, and this effect was blocked by sulpiride. Yet whereas sulpiride alone had no effect, OPC (1 pMj alone dramatically increased basal pHJ dopamine release. These data demonstrate that OPC has neurochemical functional effects distinct from those of other antipsychotic candidates, and that this may play a role in its actions in vivo