Systemic vs. Central administration of common hypnotics reveals opposing effects on genioglossus muscle activity in rats

Study Objectives: To determine if systemic administration of selected sedative-hypnotics that modulate the function of the y-amino-butyric acid-A (GABA(A)) receptor can: (i) delay arousal thereby allowing genioglossus (GG) activity to increase more in response to respiratory stimulation during sleep, (ii) also cause the robust increase in GG activity during undisturbed sleep recently observed with barbiturates. We also determined effects on GG activity with local application to the hypoglossal motor nucleus (HMN). Design, Participants, and Interventions: Sleep-wake states, GG and diaphragm activities were recorded in freely-behaving rats after systemic administration of lorazepam (0.5 mg/kg and 1 mg/kg, n = 9 and 5 mg/kg, n = 7), zolpidem (5 mg/kg and 10 mg/kg, n = 6) and the antihistamine diphenhydramine (20 mg/kg, n = 9). Rats were also exposed to ramp increases in inspired CO2 in NREM sleep. The effects of lorazepam and zolpidem applied directly to the HMN were also determined in 37 anesthetized rats. Measurements and Results: Lorazepam, zolpidem and diphenhydramine all increased arousal threshold, consistent with their sedative action. GG activity before arousal in response to hypercapnia was increased with lorazepam and zolpidem only, an effect mainly due to increased baseline activity before CO2 stimulation. Lorazepam and zolpidem applied directly to the HMN, however, decreased GG activity. Conclusions: Lorazepam and zolpidem have an inhibitory effect on GG activity via local effects at the HMN. Following systemic administration, however, this inhibitory effect can be outweighed both by a delay in arousal (allowing greater CO2-mediated respiratory stimulation in sleep) and excitatory influences on baseline GG activity via mechanisms operating outside the HMN.