PT  - JOURNAL ARTICLE
AU  - Atsushi Doi
AU  - Jan-Marino Ramirez
TI  - State-Dependent Interactions between Excitatory Neuromodulators in the Neuronal Control of Breathing
AID  - 10.1523/JNEUROSCI.5361-09.2010
DP  - 2010 Jun 16
TA  - The Journal of Neuroscience
PG  - 8251--8262
VI  - 30
IP  - 24
4099  - http://www.jneurosci.org/content/30/24/8251.short
4100  - http://www.jneurosci.org/content/30/24/8251.full
SO  - J. Neurosci.2010 Jun 16; 30
AB  - All neuronal networks are modulated by multiple neuropeptides and biogenic amines. Yet, few studies investigate how different modulators interact to regulate network activity. Here we explored the state-dependent functional interactions between three excitatory neuromodulators acting on neurokinin1 (NK1), α1 noradrenergic (α1 NE), and 5-HT2 serotonin receptors within the pre-Bötzinger complex (pre-BötC), an area critical for the generation of breathing. In anesthetized, in vivo mice, the reliance on endogenous NK1 activation depended on spontaneous breathing frequency and the modulatory state of the animal. Endogenous NK1 activation had no significant respiratory effect when stimulating raphe magnus and/or locus ceruleus, but became critical when α1 NE and 5-HT2 receptors were pharmacologically blocked. The dependence of the centrally generated respiratory rhythm on NK1 activation was blunted in the presence of α1 NE and 5-HT2 agonists as demonstrated in slices containing the pre-BötC. We conclude that a modulator's action is determined by the concurrent modulation and interaction with other neuromodulators. Deficiencies in one neuromodulator are immediately compensated by the action of other neuromodulators. This interplay could play a role in the state dependency of certain breathing disorders.