Spinal AMP kinase activity differentially regulates phrenic motor plasticity.

Acute intermittent hypoxia (AIH) elicits phrenic motor plasticity via multiple distinct cellular mechanisms. With moderate AIH, phrenic motor facilitation (pMF) requires G(q) protein-coupled serotonin type 2 receptor activation, ERK MAP kinase activity, and new synthesis of brain-derived neurotrophic factor. In contrast, severe AIH elicits pMF by an adenosine-dependent mechanism that requires exchange protein activated by cAMP, Akt, and mammalian target of rapamycin (mTOR) activity, followed by new tyrosine receptor kinase B protein synthesis; this same pathway is also initiated by G(s) protein-coupled serotonin 7 receptors (5-HT(7)). Because the metabolic sensor AMP-activated protein kinase (AMPK) inhibits mTOR-dependent protein synthesis, and mTOR signaling is necessary for 5-HT(7) but not 5-HT(2) receptor-induced pMF, we hypothesized that spinal AMPK activity differentially regulates pMF elicited by these distinct receptor subtypes. Serotonin type 2A receptor [5-HT(2A); (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride] or 5-HT(7) (AS-19) receptor agonists were administered intrathecally at C(4) (3 injections, 5-min intervals) while recording integrated phrenic nerve activity in anesthetized, vagotomized, paralyzed, and ventilated rats. Consistent with our hypothesis, spinal AMPK activation with 2-deoxyglucose or metformin blocked 5-HT(7), but not 5-HT(2A) receptor-induced pMF; in both cases, pMF inhibition was reversed by spinal administration of the AMPK inhibitor compound C. Thus, AMPK differentially regulates cellular mechanisms of serotonin-induced phrenic motor plasticity.NEW & NOTEWORTHY Spinal AMP-activated protein kinase (AMPK) overactivity, induced by local 2-deoxyglucose or metformin administration, constrains serotonin 7 (5-HT(7)) receptor-induced (but not serotonin type 2A receptor-induced) respiratory motor facilitation, indicating that metabolic challenges might regulate specific forms of respiratory motor plasticity. Pharmacological blockade of spinal AMPK activity restores 5-HT(7) receptor-induced respiratory motor facilitation in the presence of either 2-deoxyglucose or metformin, showing that AMPK is an important regulator of 5-HT(7) receptor-induced respiratory motor plasticity.