Nicotinic enhancement of the noradrenergic inhibition of sleep-promoting neurons in the ventrolateral preoptic area - PubMed (original) (raw)
Nicotinic enhancement of the noradrenergic inhibition of sleep-promoting neurons in the ventrolateral preoptic area
Benoît Saint-Mleux et al. J Neurosci. 2004.
Abstract
According to multiple lines of evidence, neurons in the ventrolateral preoptic area (VLPO) that contain GABA promote sleep by inhibiting neurons of the arousal systems. Reciprocally, transmitters used by these systems, including acetylcholine (ACh) and noradrenaline (NA), exert an inhibitory action on the VLPO neurons. Because nicotine, an agonist of ACh, acts as a potent stimulant, we queried whether it might participate in the cholinergic inhibition of these sleep-promoting cells. Indeed, we found that ACh inhibits the VLPO neurons through a nicotinic, as well as a muscarinic, action. As evident in the presence of atropine, the non-muscarinic component was mimicked by epibatidine, a nonselective nicotinic ACh receptor (nAChR) agonist and was blocked by dihydro-beta-erythroidine, a nonselective nAChR antagonist. It was not, however, blocked by methyllycaconitine, a selective antagonist of the alpha7 subtype, indicating that the action was mediated by non-alpha7 nAChRs. The nicotinic inhibition was attributed to a presynaptic facilitation of NA release because it persisted in the presence of tetrodotoxin and was blocked by yohimbine and RS 79948, which are both selective antagonists of alpha2 adrenergic receptors. Sleep-promoting VLPO neurons are thus dually inhibited by ACh through a muscarinic postsynaptic action and a nicotinic presynaptic action on noradrenergic terminals. Such dual complementary actions allow ACh and nicotine to enhance wakefulness by inhibiting sleep-promoting systems while facilitating other wake-promoting systems.
Figures
Figure 1.
Identified VLPO neurons are inhibited by both muscarinic and nicotinic agonists. A, B, Characterization of a neuron located in the VLPO by its complete inhibition by bath-applied NA. C, D, Effects of ACh application in control ACSF or in the presence of atropine. E, F, Effect of muscarine in control ACSF or in a condition of synaptic blockade by a high Mg2+-low Ca2+ ACSF. G, Effect of nicotine. H, Effect of epibatidine. 3V, Third ventricle; ac, anterior commissure; BF, basal forebrain; oc, optic chiasm; POA, preoptic area.
Figure 2.
Characterization of the receptor implicated in the nicotinic inhibition of VLPO neurons. A, Rate-meter recording of the response of a neuron to repeated applications of ACh in either a control ACSF or the presence of atropine. Timing of ACh applications is identified by black triangles and numbers (from 1 to 8). Numbered insets demonstrate the effects of some of the ACh applications. B-E, Effect of ACh applications (always in the presence of atropine) in control condition (B) or in the presence of MLA (C), DHβE (D), and after DHβE washout (E).
Figure 3.
The nicotinic inhibition of VLPO neurons is abolished by either synaptic transmission blockade or α2 noradrenergic antagonists. A, Application of ACh in the presence of atropine in a control ACSF (left panel), followed by application of ACh in a high Mg2+-low Ca2+ ACSF that abolished the response (middle panel). Right panel shows recovery of response after return to a control ACSF. B, C, Inhibitory action of ACh (left panels) is not blocked in the presence of either GABAA (bicuculline; right panel in B) or GABAB (saclofen; right panel in C) selective antagonists. D, E, Inhibitory action of ACh (left panels) is abolished by the α2 noradrenergic selective antagonists yohimbine (right panel in D) and RS 79948 (right panel in E).
Figure 4.
The nicotinic inhibition of VLPO neurons results from a presynaptic facilitation of NA release associated with an increase in a potassium conductance. A, B, Characterization of a VLPO neuron by its complete inhibition with bath application of NA in extracellular recordings (left panel in A) as well as its inhibitory response to ACh (right panel in A) and by the subsequent demonstration of a low-threshold spike (*, right panel in B) when the neuron is hyperpolarized from rest in whole-cell recordings (B). C, D, Application of ACh (in the presence of atropine and TTX) results in a short-lasting hyperpolarization (C) that is completely abolished by yohimbine, a selective α2 receptor antagonist (D). E, Bath-applied noradrenaline in the presence of TTX also induces a hyperpolarization. Note that it is accompanied by a decrease in membrane resistance, as revealed by comparing (inset) short hyperpolarizing pulses before (filled square) and during (filled dot) the effect. F, The noradrenaline-induced hyperpolarization (when the neuron is at rest; -61 mV) is abolished when it is held close to E K (-83 mV) and reverses below (-103 mV). G, The ACh-induced hyperpolarization in the presence of atropine is also abolished when the neuron is hold at -83 mV and reverses below.
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