Chronic Fluoxetine Microdialysis into the Medullary Raphe Nuclei of the Rat, but not Systemic Administration, Increases the Ventilatory Response to CO2 Running Head: Fluoxetine and Medullary Raphe Chemosensitivity

In conscious rats, focal CO2 stimulation of the medullary raphe increases ventilation, while interference with serotonergic function here decreases the ventilatory response to systemic hypercapnia. We sought to determine whether repeated administration of a selective serotonin reuptake inhibitor in this region would increase the ventilatory response to hypercapnia in unanaesthetized rats. In rats instrumented with EEG/EMG electrodes, 250 or 500 μM fluoxetine or artificial cerebrospinal fluid (aCSF) was microdialyzed into the medullary raphe for 30 minutes daily over 15 days. To compare focal and systemic treatment, two additional groups of rats received 10 mg*kg *d fluoxetine or vehicle systemically. Ventilation was measured in normocapnia and in 7% CO2 before treatment (Day 0), acutely (Days 1 or 3), on Day 7, and Day 15. There was no change in normocapnic ventilation in any treatment group. Rats that received 250 μM fluoxetine microdialysis showed a significant 13% increase in ventilation in wakefulness during hypercapnia on Day 7, due to an increase in tidal volume. In rats microdialyzed with 500 μM fluoxetine, there were 16% and 32% increases in minute ventilation during hypercapnia in wakefulness and sleep on Day 7, and 20% and 28% increases on Day 15; again due to increased tidal volume. There was no change in the ventilatory response to CO2 in rats microdialyzed with aCSF, or in systemically treated rats. Chronic fluoxetine treatment in the medullary raphe increases the ventilatory response to hypercapnia in an unanaesthetized rat model, an effect that may be due to facilitation of chemosensitive serotonergic neurons.