Increased spinal adenosine impairs phrenic long-term facilitation in aging rats.

Moderate acute intermittent hypoxia (mAIH) elicits a form of spinal, respiratory motor plasticity known as phrenic long-term facilitation (pLTF). In middle-aged male and geriatric female rats, mAIH-induced pLTF is attenuated through unknown mechanisms. In young adults, mAIH activates competing intracellular signaling cascades, initiated by serotonin 2 and adenosine 2A (A2A) receptors, respectively. Since spinal A2A receptor inhibition enhances mAIH-induced pLTF, serotonin dominates, and adenosine constrains mAIH-induced plasticity in the daily rest phase, we hypothesized elevated basal adenosine levels in the ventral cervical spinal cord of aged rats shifts this balance, undermining mAIH-induced pLTF. A selective A2A receptor antagonist (MSX-3) or vehicle were delivered intrathecally at C4 in anesthetized young (3-6 months) and aged (20-22 months) Sprague-Dawley rats prior to mAIH (3,5-min episodes; arterial PO2 =45-55mmHg). In young males, spinal A2A receptor inhibition enhanced pLTF (119 ± 5%) versus vehicle (55 ± 9%), consistent with prior reports. In old males, pLTF was reduced (25 ± 11%), but A2A receptor inhibition increased pLTF to levels greater than in young males (186 ± 19%). Basal adenosine levels in ventral C3-C5 homogenates are elevated 2-3-fold in old versus young males. These findings advance our understanding of age as a biological variable in phrenic motor plasticity and will help guide translation of mAIH as a therapeutic modality to restore respiratory and non-respiratory movements in older populations afflicted with clinical disorders that compromise movement.