INHIBITION OF FIRING OF RAPHE NEURONS BY TRYPTOPHAN AND 5-HYDROXYTRYPTOPHAN - BLOCKADE BY INHIBITING SEROTONIN SYNTHESIS WITH RO-4-4602

The serotonergic neuronal activity was monitored by extracellular recording from identified cells in the rat midbrain dorsal raphe nucleus. The systemic administration of L-tryptophan, the initial precursor in the biosynthesis of brain serotonin [5-hydroxytryptamine (5-HT)], depressed the firing of serotonergic neurons. The systemic administration of L-5-hydroxytryptophan, the immediate precursor of 5-HT, in combination with a low dose of Ro4-4602 benserazide (50 mg/kg, which inhibits mainly peripheral decarboxylase) also depressed raphe firing. The tryptophan-induced depression of raphe activity was prevented by pretreatment of the animal with an L-aromatic amino acid decarboxylase inhibitor, Ro4-4602, in a dose (800 mg/kg) sufficient to block the formation of 5-HT in raphe neurons. p-Chlorophenylalanine, another 5-HT synthesis inhibitor, was ineffective in preventing the depression of raphe firing by tryptophan. p-Chlorophenylalanine did not prevent the accumulation of 5-HT within the raphe perikarya following loading doses of tryptophan (Aghajanian, Kuhar and Roth, 1973). Raphe neurons were also inhibited by the local (microiontophoretic) administration of L-tryptophan or L-5-hydroxytryptophan. Both 5-HT precursors (tryptophan and 5-hydroxytryptophan) inhibited raphe firing through their enzymatic conversion to 5-HT. A local increase in 5-HT within the raphe perikarya was sufficient to lead to a decrease in raphe cellular activity.