Inhibition of firing of raphe neurones by tryptophan and 5-hydroxytryptophan: Blockade by inhibiting serotonin synthesis with Ro-4-4602

Abstract

In these studies, serotonergic ncuronal activity was monitored by extracellular recording from identified cells in the midbrain dorsal raphe nucleus. The systemic administration of l-tryptophan. the initial precursor in the biosynthesis of brain serotonin (5-HT). was found to depress the firing of serotonergic neurones. The systemic administration of l-5-hydroxytryptophan, the immediate precursor of 5-HT. in combination with a low dose of Ro4-4602 (50 mg/kg, which inhibits mainly peripheral decarboxylase) was also found to depress 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 neurones. p-Chlorophenylalanine. another 5-HT synthesis inhibitor, was found to be ineffective in preventing the depression of raphe firing by tryptophan. However, previous studies have shown that p-chlorophenylalanine does not prevent the accumulation of 5-HT within the raphe perikarya following loading doses of tryptophan (Aghajanian, Kuhar and Roth. 1973). Raphe neurones were also inhibited by the local (microiontophoretic) administration of l-tryptophan or l-5-hydroxytryptophan. We conclude that (1) both 5-HT precursors (tryptophan and 5-hydroxytryptophan) inhibit raphe firing through their enzymatic conversion to 5-HT: (2) a local increase in 5-HT within the raphe perikarya is sufficient to lead to a decrease in raphe cellular activity.