DIFFERENTIAL-EFFECTS OF PHENCYCLIDINE AND METHAMPHETAMINE ON DOPAMINEMETABOLISM IN RAT FRONTAL-CORTEX AND STRIATUM AS REVEALED BY IN-VIVO DIALYSIS

We have examined the effects of schizophrenomimetic drugs including ph encyclidine (PCP) and methamphetamine (MAP) on cortical and striatal d opamine (DA) metabolism using an in vivo dialysis technique in the rat . An acute systemic injection of PCP (2.5-10 mg/kg, intraperitoneally (i.p.)) dramatically increased concentrations of DA, 3,4-dihydroxy-phe nylacetic acid, and homovanillic acid in the dialysates from the media l frontal cortex in a dose-dependent fashion. However, PCP (2.5-10 mg/ kg, i.p.) caused a much lower augmentation of extracellular DA release , with a significant decrease in dialysate DOPAC levels in the striatu m. Moreover, continuous infusion of tetrodotoxin (TTX, 10(-5) M) into the prefrontal or striatal region through the microdialysis tube compl etely blocked the ability of PCP (10 mg/kg, i.p.) to alter the extrace llular release of DA and its metabolites in the respective areas. In c ontrast, MAP (4.8 mg/kg, i.p.) elicited a marked and tetrodotoxin-resi stant increase in DA levels with a significant loss of DOPAC contents in the extracellular space of both the frontal cortex and the striatum . The present results clearly demonstrate the differential effects of PCP on cortical and striatal DA transmission, suggesting that PCP may facilitate DA release in the medial frontal cortex by increasing impul se flow in the DA neurons projecting to the cortical area, whereas PCP -induced elevation of extracellular DA in the striatum may be caused m ainly by reuptake inhibition of DA liberated by basal activity of the striatal DA neurons. The regional variation in PCP-induced DA release would be due to the combination of NMDA (N-methyl-D-aspartate) recepto r blocking and DA reuptake inhibition by the drug. The uniform and TTX -resistant nature of MAP-induced changes in brain DA metabolism may re sult from the direct actions of MAP at DA nerve terminals. (C) 1996 Wi ley-Liss, Inc.