Central cholinergic regulation of respiration: nicotinic receptors

Abstract

Nicotinic acetylcholine receptors (nAChRs) are expressed in brainstem and spinal cord regions involved in the control of breathing. These receptors mediate central cholinergic regulation of respiration and effects of the exogenous ligand nicotine on respiratory pattern. Activation of alpha4* nAChRs in the preBötzinger Complex (preBötC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBötC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic alpha4* nAChRs on hypoglossal (XII) motoneurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity. As perinatal nicotine exposure may contribute to the pathogenesis of sudden infant death syndrome (SIDS), we discuss the effects of perinatal nicotine exposure on development of the cholinergic and other neurotransmitter systems involved in control of breathing. Advances in understanding of the mechanisms underlying central cholinergic/nicotinic modulation of respiration provide a pharmacological basis for exploiting nAChRs as therapeutic targets for neurological disorders related to neural control of breathing such as sleep apnea and SIDS.

Figure 1

Unilateral microinjection of nicotine into the preBötC increases frequency and decreases amplitude of respiratory-related rhythmic activity. Rhythmic activity was recorded from hypoglossal nerve roots (XIIn) in the medullary slice preparation in vitro and the signal was integrated. Left panel: Microinjection (↑) of 10 nL 20 μmol/L nicotine into: 1, ipsilateral preBötC; 2, contralateral preBötC; 3, ipsilateral hypoglossal (XII) nucleus and 4, contralateral XII nucleus respectively. Injection pipettes were inserted into the loci 100−200 μm below the surface of the slice. Right panel: bath applied 1 μmol/L mecamylamine (Meca) blocked nicotine-induced responses. Reproduced from reference .

Figure 2

Nicotine (5 nmol/L, bath applied) depolarizes preBötC inspiratory neurons and increases respiratory frequency in L9'A mouse slices; the effects are blocked by DHβE (0.2 μmol/L). Simultaneous whole-cell current-clamp recording from an inspiratory neuron (upper trace) in the preBötC and respiratory-related rhythmic activity from the XIIn (∫XII: integrated nerve activity) in medullary slice from L9'A mice. The neuron fired bursts of action potentials on top of rhythmic inspiratory depolarization synchronized with the rhythmic motor activity of XIIn. Insets: activities of both channels on an expanded time scale at time sections indicated. Time scales for all insets are equivalent. Y-scales for the continuous recordings and all the insets are equivalent for corresponding channels. Reproduced, with permission of J Neurosci, from reference .

Figure 3

1,1-dimethyl-4-phenylpiperazinium iodide (DMPP, a nicotinic agonist) produces inward currents that are dose-dependent and associated with an increase in membrane conductance in XII motoneurons. (A) An inward current in a voltage-clamped (-60 mV) XII motoneuron induced by bath-applied 25 μmol/L DMPP (bar). ^*I/V curve was measured during the break in record. (B) Peak amplitudes of DMPP-induced current (I_DMPP) as a function of concentration. Atropine (1 μmol/L) was presence in the bath solution for (A) and (B). Reproduced from reference .

Figure 4

Prenatal nicotine exposure reduces response to nicotine receptor activation in hypoglossal (XII) nucleus. (A) Respiratory-related rhythmic activity from the XIIn (∫_XII, integrated nerve activity) in control and prenatally nicotine-exposed medullary slices from P3 mice showing activity before, during and after 30 s local application of 10 μmol/L nicotine onto ipsilateral XII nucleus. Nicotine-mediated potentiation of XIIn inspiratory burst amplitude and tonic activity was diminished in slices from prenatally nicotine-exposed mice. (B) Respiratory-related rhythmic activity of XIIn from a control slice illustrates response to a 30 s application of 100 μmol/L nicotine before, during and after addition of 500 μmol/L nAChR antagonist hexamethonium bromide to the bathing solution. Reproduced, with permission of Blackwell Publishing Ltd, from reference .