THE CHARACTERIZATION OF THE EFFECT OF LOCALLY APPLIED N-METHYLQUIPAZINE, A 5-HT3 RECEPTOR AGONIST, ON EXTRACELLULAR DOPAMINE LEVELS IN THE ANTERIOR MEDIAL PREFRONTAL CORTEX IN THE RAT - AN IN-VIVO MICRODIALYSIS STUDY

In this study, we examined the effect of n-methylquipazine (NMQ), whic h is a putative 5-hydroxytryptamine (5-HT3) receptor agonist, on the e xtracellular concentrations of dopamine (DA) and one of its metabolite s, dihydroxyphenylacetic acid (DOPAC), in the anterior medial prefront al cortex (AmPFc) of awake, freely moving rats. The administration of NMQ via the perfusion fluid produced a concentration-dependent (10-1,0 00 mu M) increase in extracellular DA levels in the AmPFc. In contrast , NMQ produced a decrease in the extracellular concentrations of DOPAC . The increase in extracellular DA levels returned to baseline after t he removal of NMQ from the perfusate. he increase in extracellular DA levels in the AmPFc produced by 100 mu M of NMQ was markedly attenuate d by either the coadministration of tetrodotoxin (1 mu M), which inhib its axonal impulse flow, or the depletion of extracellular Ca2+ by rem oving CaCl2 and adding EDTA to the perfusate. The intradialysate admin istration of the 5-HT3 antagonist BRL 46470A produced a concentration- dependent (10-1,000 mu M) decrease in extracellular DA levels, and thi s effect was reversible on removal from the perfusate. In contrast, on dansetron (500 and 1,000 mu M), which is another 5-HT3 receptor antago nist, produced a transient increase followed by a sustained decrease i n extracellular DA levels. The preinfusion of 10 mu M of BRL 46470 fol lowed by coperfusion of BRL 46470A with 50 or 100 mu M of NMQ via the dialysis probe did not significantly attenuate the increase of NMQ in extracellular DA levels in the AmPFc. The administration of the select ive 5-HT2 receptor MDL 100907 (1 mg/kg, i.p.) also did not alter the i ncrease in basal DA levels produced by 100 mu M Of NMQ. The pretreatme nt of rats with alpha-methyl-p-tyrosine produced a significant attenua tion in the NMQ-induced increase in extracellular DA levels, suggestin g that the elevation by NMQ of DA levels is dependent on newly synthes ized stores of DA. Overall, these results suggest that the increase in AmPFc DA levels by NMQ is probably not mediated by its interaction wi th the 5-HT3 receptor. (C) 1996 Wiley-Liss, Inc.