An evaluation of the mechanism by which serotonergic activation depresses respiration

The present investigation attempted to determine if the previously reported depression of respiration by serotonergic agonists was a result of peripheral or central nervous system drug effects. Systemic administration of 5-hydroxytryptophan (5-HTP) to pargyline-treated animals and 5-methoxy-N,N-di-methyltryptophan (5-MDMT) probably depress respiration secondary to central penetration of these drugs, since: 1) adult rats with biochemical evidence of partial destruction of central serotonergic neurons after neonatal intracisternal 5,7-dihydroxytryptamine were supersensitive to the respiratory depressing effect of 5-HTP and 5-MDMT; 2) the ventilatory effect of the serotonergic agonists was not reduced by surgical deafferentiation induced by bilateral transection of the glossopharyngeal nerves; 3) after sectioning of the vagus nerve, the absolute change produced by serotonergic agonists was less; however, the relative change was unaltered; and 4) inhibition of peripheral aromatic amino acid decarboxylase by RO-4-4602 significantly blunted the respiratory depressant activity of 5-HTP observed at 15 min but not that present 30 min after 5-HTP. The present fidings thus suggest that the cenvel by the activity of central serotonergic neurons.