5-HT-1A RECEPTOR-MEDIATED MODULATION OF MEDULLARY EXPIRATORY NEURONS IN THE CAT

1. The involvement of the 5-HT-1A receptor in serotoninergic responses of stage 2 expiratory (E-2) neurones was investigated in pentobarbito ne-anaesthetized, mechanically ventilated cats. 2. The specific agonis t of the 5-HT-1A receptor, 8-hydroxy-diproplaminotetralin (8-OH-DPAT), administered systemically or by ionophoresis directly on to the neuro nes, had a clear depressant effect. 3. Administration of 8-OH-DPAT at doses of 10-50 mu g kg(-1) (I.V.) increased the membrane hyperpolariza tions of E-2 neurones during the inspiratory and postinspiratory phase s, and shortened their duration of activity in association with shorte ning of phrenic nerve activity. Discharges of E-2 neurones were also l ess intense. At doses of 50-90 mu g kg(-1), 8-OH-DPAT reduced or aboli shed inspiratory hyperpolarizations, and reduced expiratory depolariza tions of membrane potential and discharge in parallel with inhibition of phrenic nerve discharges. The effects of the larger doses mere reve rsed by I.V. injection of NAN-190, an antagonist at the 5-HT-1A recept or. 4. Dose-dependent effects on the membrane potential and discharge of E-2 neurones, but not on phrenic nerve activity, were also seen by ionophoretic administration of 8-OH-DPAT on to E-2 neurones. At low cu rrents, ejection of 8-OH-DPAT hyperpolarized the neurones without affe cting the duration of inspiratory hyperpolarization and expiratory dep olarization. This hyperpolarization depressed the intensity and the du ration of expiratory discharges. Ejection with larger currents hyperpo larized the E-2 neurones further, and depressed expiratory depolarizat ion leading to blockade of expiratory discharges. 5. The effects on me mbrane potential were accompanied by decreased neuronal input resistan ce. This depressed the excitability of E-2 neurones as tested by disch arges evoked by intracellular current injection. The amplitudes of act ion potentials decreased in parallel with the changes in input resista nce. The effects were attributed to a postsynaptic effect of 8-OH-DPAT leading to a gradually developing inhibition by activation of 5-HT-1A receptors. 6. Hyperventilatory apnoea depressed on-going synaptic act ivity and unmasked the effect of ionophoretically applied 8-OH-DPAT. T he responses of the E-2 neurone were enhanced, as evidenced by increas ed membrane hyperpolarization and greater reduction of input resistanc e. Both responses faded appreciably, indicating receptor desensitizati on. The degree and rate of apparent desensitization depended on the do se/ejecting current. The greater sensitivity and faster desensitizatio n to 8-OH-DPAT were attributed to the hyperventilatory alkalinization of the extracellular fluid, which might influence agonist binding to 5 HT-1A receptors and/or receptor properties.