CHARACTERIZATION OF THE IN-VIVO ACTION OF (R)-SALSOLINOL, AN ENDOGENOUS METABOLITE OF ALCOHOL, ON SEROTONIN AND DOPAMINE METABOLISM - A MICRODIALYSIS STUDY

Using a microdialysis-HPLC technique in conscious rats, we examined th e action of (R)-1-methyl-6,7-dihydroxy-1,2,3,4-tetra hydroisoquinoline , (R)-salsolinol (R-Sal), a possible endogenous metabolite of alcohol, on serotonin (5-HT) and dopamine (DA) metabolism in four regions of t he brain: the striatum, the substantia nigra, the hippocampus and the hypothalamus. Following 1 mM R-Sal perfusion, the dialysate level of 5 -HT in the striatum markedly increased from non-detectable levels to 4 259.2 +/- 617.5 nM, while DA increased from 3.4 +/- 0.9 nM to 206.0 +/ - 56.5 nM. This increase was one order of magnitude larger in 5-HT tha n in DA. Conversely, the output of 5-hydroxyindoleacetic acid decrease d markedly to non-detectable levels, while 3,4-dihydroxyphenylacetic a cid and homovanillic acid outputs decreased below 40% of basal levels. These effects were dose-related to R-Sal (1 mu M to 1 mM) and were co nfirmed also in 3 other brain regions. The R-Sal-induced responses in the striatum were observed even after pretreatment of 2 mu M tetrodoto xin, a blocker of nerve-firing activity, via the dialysis membrane. Th e repetitive perfusion with 1 mM R-Sal into the striatum induced the r eproducible response of 5-HT and DA. Furthermore, the potencies of 1 m M R-Sal to increase the output of 5-HT and DA were approximately 783.0 -fold and 2.6-fold stronger, respectively, than those of the same dose of methamphetamine. The results suggest that R-Sal acts to stimulate a release of monoamines, 5-HT preferentially, with inhibition of monoa mine oxidase and catechol-O-methyltranseferase activities.