Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column

Abstract

Reverse dialysis of the muscarinic receptor antagonist, atropine (ATR, 50 mM), into the pre-Bötzinger Complex region of the ventral respiratory column (VRC) of awake and sleeping goats increases breathing frequency and serotonin (5-HT), substance P (SP), glycine, and GABA concentrations in the effluent dialysate. Herein, we report data from goats in which we reverse dialyzed 5 mM ATR or specific antagonists of M2 or M3 muscarinic receptors into the VRC. The effects on frequency of all three antagonists were not significantly different from time control studies. 5 mM ATR and the M3 antagonist increased SP seven-fold less than 50 mM ATR. The antagonists had no effect on 5-HT, glycine, and/or GABA, suggesting that the increases in glycine and GABA with 50 mM ATR were secondary to the larger increases in 5-HT and/or SP. These data are suggestive of neuromodulator interdependence, whereby attenuation of one neuromodulator is compensated for by local changes in other neuromodulators to stabilize breathing.

Blockade of neurokinin-1 receptors in the ventral respiratory column does not affect breathing but alters neurochemical release

“…As in past studies, in which we blocked cholinergic receptors (28,29), the most striking and consistent finding with dialysis of NK1R antagonists was an increase in SP concentration at the site of dialysis. While we previously speculated that atropine-induced increases in SP and/or 5-HT may have been due to presynaptic disinhibition of neurochemical release (28), the increase in extracellular SP with NK1R blockade may be due to accumulation of the peptide in the synaptic space, rather than enhanced release per se.…”

“…1 are the MT placements and corresponding NMDA responses for the animals studied herein. As in past studies (28,29), there is variation in both MT placement, as determined by histology, and NMDA responses. Thus neither index provides absolute confirmation of the exact site of dialysis, as previously discussed in greater detail (28,29).…”

“…As in past studies (28,29), there is variation in both MT placement, as determined by histology, and NMDA responses. Thus neither index provides absolute confirmation of the exact site of dialysis, as previously discussed in greater detail (28,29). Despite this limitation, we have historically found changes in +1-2 mm +5-7 mm SP with antagonist dialysis to be the most highly consistent between animals for a given treatment.…”

“…For example, we have previously shown that nonselective blockade of muscarinic receptors with 50 mM atropine in the VRC of intact goats can dramatically increase breathing frequency and 5-HT and SP concentrations (28). Conversely, a smaller dose of atropine (5 mM) does not affect breathing, but significantly increases SP concentration, albeit, to a much smaller degree (29). We were unable to measure acetylcholine/choline in these studies.…”

“…As in past reports (29), we compared daytime ventilatory data from the present study with established time control studies (28) we previously conducted, in which mCSF alone was dialyzed for Hours 1-3. The present studies were carried out by identical methodologies and under the same conditions as time control studies (28).…”