Cyclic nucleotides modulate genioglossus and hypoglossal responses to excitatory inputs in rats

Previous studies modulating pharyngeal muscle activity with pharmacologic approaches have targeted membrane receptors on pharyngeal motoneurons. Whether modulation of intracellular pathways can increase pharyngeal muscle activity, however, has not been investigated but is relevant to pharmacologic treatments of obstructive sleep apnea.

To determine if modulating the second messenger cyclic adenosine-3'-5'-monophosphate (cAMP) at the hypoglossal motor nucleus (HMN) will increase genioglossus activity across sleep- wake states.

Forty-eight rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states and genioglossus and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN to perfuse artificial cerebrospinal fluid and (1) forskolin (500 microM, adenylyl cyclase activator to increase cAMP), (2) a cAMP analog (500 microM), (3) iso-butyl-methylxanthine (IBMX; 300 microM, phosphodiesterase inhibitor), or (4) a cyclic guanosine-3'-5'-monophosphate (cGMP) analog (500 microM, 8-Br-cGMP).

Forskolin and the cAMP analog at the HMN increased respiratory-related and tonic genioglossus activities in wakefulness and non-REM sleep but not REM sleep. IBMX did not affect genioglossus activity in awake or sleeping rats. However, IBMX abolished the robust excitatory responses to serotonin and phenylephrine at the HMN, but responses to non-N-methyl-D-aspartate receptor activation remained. These effects of IBMX were mimicked by 8-Br-cGMP.

Genioglossus responses to manipulation of cAMP at the HMN are differentially modulated by sleep-wake state. Selective abolition of serotonin and phenylephrine responses after IBMX suggests that under conditions of nonspecific phosphodiesterase inhibition the HMN is unresponsive to certain, otherwise potent, excitatory inputs. Similar responses with 8-Br-cGMP suggest this effect is likely mediated by cGMP pathways.