MODULATION OF RESPIRATORY RHYTHM BY 5-HT IN THE BRAIN-STEM-SPINAL CORD PREPARATION FROM NEWBORN RAT

Effects of 5-hydroxytryptamine (5-HT) on inspiration-related nerve act ivity and membrane potential of respiratory neurons in the ventrolater al medulla were studied in brainstem-spinal cord preparations isolated from newborn rats. Bath application of 5-100 mu M 5-HT induced a biph asic response in inspiratory nerve activity: a transient increase in r espiratory frequency followed by a decrease in the rate of discharge. The excitatory effect of 5-HT was particularly prominent in preparatio ns with a respiratory rate of less than 3 min(-1), whereas the inhibit ory effect was more pronounced in preparations with a higher respirato ry rate. In pre-inspiratory (Pre-I) and inspiratory (Insp) neurons, 20 mu M 5-HT induced a membrane depolarization of up to 10 mV accompanie d by a significant decrease in the input resistance. Membrane depolari zation by 5-HT was also evident in the presence of tetrodotoxin. In Pr e-I neurons, 5-HT caused an increase in the burst rate, which was foll owed by a decrease in the intraburst firing frequency and burst amplit ude, although the burst rate remained high. The burst rate in Insp neu rons first increased and subsequently decreased without significant ch ange in the intraburst firing frequency. Simultaneous intra-and extrac ellular recordings (in the contralateral medulla) of Pre-I/Pre-I neuro n or Pre-I/Insp neuron pairs revealed that 5-HT disturbed the correlat ion between these neuron bursts. Increase in the respiratory rate indu ced by 20 mu M 5-HT was completely blocked by pretreatment (5-15 min) with 5 mu M ketanserin or 1 mu M methysergide, but not by 10 mu M prop ranolol. None of these antagonists blocked the inhibitory effects of 5 -HT. A 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (D OI, 10-100 mu M) increased the respiratory rate. Perfusion with a 5-HT 1A agonist, 8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT, 2 0-100 mu M) induced an increase or a decrease in the respiratory rate. A 5-HT2C agonist, 1-(3-chlorophenyl)piperazine (m-CPP 2-10 mu M) indu ced an initial decrease in the respiratory rate followed by a further long-lasting decrease. Burst activity of Pre-I neurons was suppressed upon administration of 10 mu M m-CPP and enhanced with 20 mu M DOI. Th e results suggest that changes in the bursting properties of Pre-I and Insp neurons induced by 5-HT lead to modulation of the respiratory ne twork, thus causing biphasic modulation of the respiratory rhythm. In addition to effects via 5-HT1A receptors, activation of 5-HT2A and 5-H T2C receptor subtypes might be involved in excitatory effects and inhi bitory effects of 5-HT respectively.