SEROTONIN-MEDIATED INCREASE IN PREFRONTAL CORTEX DOPAMINE RELEASE - PHARMACOLOGICAL CHARACTERIZATION

Interactions between serotonin (5-HT) and dopamine (DA) neuronal syste ms in the prefrontal cortex (PFC) may be important in the pathophysiol ogy of cognitive disorders such as schizophrenia. We have examined the effect of 5-HT, applied locally through a microdialysis probe, on ext racellular DA in the PFC, and compared the response to that observed i n the striatum. 5-HT in concentrations of 1 to 10 mu M increased extra cellular DA dose-dependently to a greater extent in the PFC than in th e striatum. The PFC response was pharmacologically characterized to de termine the 5-HT receptor subtype mediating the increase in DA levels. The coperfusion of selective 5-HT2A and 5-HT, antagonists MDL 100,907 -1-[2(4-flourophenylethyl)]-4-piperidine-methanol} and MDL 72222 (3-t ropanyl-3,5-dichlorobenzoate), respectively, with 5-HT failed to signi ficantly attenuate the 5-HT induced increase of extracellular DA. Furt hermore, the local application of the 5-HT2A/2C agonist (+/-)-1-(2,5-d imethoxy-4-iodophenyl aminopropane did not yield an increase in extrac ellular DA. On the other hand, coperfusion of the selective 5-HT1B/1D antagonist GR 127935 {N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]- -(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4- carboxamide]} with 5-HT completely blocked the effect of 5-HT alone. Infusion of the sele ctive 5-HT1B agonists CP 93,129 ,6-tetrahydro-4-pyridyl)pyrrolo[3,2-b] pyrid-5-one} and CP 94,253 {3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxy pyrrolo [3,2-b]pyridine} resulted in a significant increase in extrace llular DA and the effect of CP 93,129 was attenuated by coperfusion of GR 127935. The results obtained demonstrate a functional interaction between DA and 5-HT pathways in the PFC, with evidence of potential me diation by the 5-HT1B receptor subtype.