European Journal of Pharmacology, 240 ( 1993 ) 107 - 109 Elsevier Science Publishers B.V. EJP 213111 Short communication The atypical antipsychotic drug amperozide enhances rat cortical and striatal dopamine efflux Elizabeth A. Pehek, Herbert Y. Meltzer and Bryan K. Yamamoto Department of Psychiatry. Case Western Resert,e Unit'ersity School of Medicine, Clet~eland, OH 44106, USA Received 14 June 1993, accepted 22 June 1993 Previous behavioral, biochemical, and electrophysiological studies have indicated that amperozide, a putative atyl antipsychotic drug with potent 5-HT, receptor antagonist potency, preferentially affects mesocorticolimbic, as compare mesostriatal dopamine neurons. The present experiment utilized in vivo microdialysis to compare the effects of amperozid dopamine effiux in medial prefrontal cortex versus caudate-putamen in the freely moving rat. The results demonstrated amperozide produced a greater elevation of cortical dopamine. These results were similar to those observed with clozapine not haloperidol. Prefrontal cortex; Microdialysis; Dopamine; Schizophrenia; Amperozide; Clozapine 1. Introduction the pathophysiology of schizophrenia (Weinbel 1987). Therefore, antipsychotic drugs which incr. The putative atypical antipsychotic drug amperozide dopaminergic activity in the cortex might be predi (N-ethyl-4-[4',4'-bis(p-fluoro-phenyl)butyl]-I-piperazi- to be more effective than those drugs which do no~ necarboxamide) has been reported to alleviate both vivo microdialysis studies in the anesthetized rat I positive and negative symptoms of schizophrenia with- shown that clozapine preferentially enhances cort out producing extrapyramidal side effects (Axelsson et as opposed to striatal, dopamine concentrat al., 1991; Christensson and Bjork, 1990). Behavioral, (Moghaddam and Bunney, 1990). In contrast, the 1 biochemical, and electrophysiological studies with rats cal neuroleptic haloperidol displayed an opposite have shown that amperozide preferentially affects file of action with relatively slight effects on cor mesocorticolimbic, as opposed to nigrostriatal, dopa- dopamine. mine neurons (see Christensson and Bjork, 1990, for It was therefore of interest to determine the eft review). Unlike typical neuroleptics such as halopcri- of amperozide administration on dopamine effiu dol, amperozide possesses a low affinity for dopamine the prefrontal cortex and the caudate-putamcn. D 2 receptors, while, similar to the atypical antipsy- present study thus compared the dose-response ell chotic clozapine, possessing a high affinity for 5-HT 2 of systemic amperozide administration on extracell receptors (Meltzer et al., 1992). In vitro and in vivo dopamine concentrations in these two structures in studies of the rat striatum have shown that amperozide unanesthetized rat. These results were then contra blocks dopamine uptake and amphetamine-stimulated with the effects of clozapinc and haloperidol adm dopamine release, and increases extracellular concen- tration on prefrontal dopamine. trations of dopamine (Eriksson and Christensson, 1990; Ichikawa and Meltzer, 1991; Yamamoto and Meltzer, 1992). 2. Materials and methods Hypofunction of the dopaminergic input to the pre- frontal cortex has been posited to underlie aspects of 2.1. Experiment 1 Male Sprague-Dawley rats (250-400 g; 5-6 rats Correspondence to: Elizabeth A. Pehek, Department of Psychiatry, group) were stereotaxically implanted, under ane., University ILlospitals, 21140 Abington Road, Cleveland, OH 44106, sia (150 mg/kg chloral hydrate and 100 mg/kg USA. Tel. 1216) 844-5848, fax (216) 844-8758. This work was presented in preliminary form at the 21st Annual tamine), with microdialysis probes 18-24 h before Meeting of the Society for Neuroscience. New Orleans, LA, U S A , experiment in either the medial prefrontal cortex November 10-15, 1991. = 2.7, ML = 0.8, DV = -5.5 from dura) or the anl