Heterogeneity of nicotinic acetylcholine receptor expression in the caudal nucleus of the solitary tract

Abstract

The nucleus of the solitary tract (NTS) is the principal integrating relay in the processing of visceral sensory and gustatory information. In the present study, patch-clamp electrophysiological experiments were conducted using rat horizontal brainstem sections. Pre-synaptic and somatic/ dendritic nicotinic acetylcholine receptors (nAChRs) expressed in neurons of the caudal NTS (cNTS) were found to be randomly distributed between pre-synaptic and somatic/dendritic sites (χ 2 =0.72, df =3, p>0.87, n=200). Pre-synaptic nAChRs were detected by their facilitating effects on glutamatergic neurotransmission of a sub-population of cNTS neurons (categorized as "effectpositive") upon brief picospritzer applications of 0.1-0.5 mM nicotine. These effects were resistant to inhibition by 20 nM methyllycaconitine (MLA) and 4 μM dihydro-β-erythroidine (DHβE), and were replicated by brief picospritzer applications of 0.2-1 mM cytisine. Picospritzer applications of 0.2 mM RJR-2403, a potent agonist of α4β2 nAChRs, did not facilitate synaptic release of glutamate in effect-positive cNTS neurons. The population of somatic/dendritic nAChRs has been found to be heterogeneous and included nAChRs that were activated by RJR-2403 and/or cytisine; or insensitive to cytisine; or inhibited by MLA. The presented results are consistent with the expression of β4-containing (i.e., β4*) nAChRs, likely α3β4*, in presynaptic terminals of effectpositive cNTS neurons. Somatic/dendritic nAChRs appear to involve both α7 and non-α7 subunits. Heterogeneity in the subunit composition of pre-synaptic and somatic/dendritic nAChRs may underlie diverse roles that these receptors play in regulation of behavioral and visceral reflexes, and may reflect specific targeting by endogenous nicotinic agents and nicotine.

Mechanisms of facilitation of synaptic glutamate release by nicotinic agonists in the nucleus of the solitary tract

“…Electrophysiological recordings from the NTS in brainstem slices revealed that nAChRs and mAChRs are likely expressed by different NTS neurons (43, 55). Moreover, subsets of small (somal area, ϳ137 m 2 ), elongated (form factor, ϳ0.62) caudal NTS neurons have been found to express functional presynaptic ␣3␤4-containing (this will be referred to throughout as ␣3␤4*) nAChRs (44), whose activation by nicotine, a broad spectrum agonist of nAChRs, or cytisine, a potent agonist of ␤4*-nAChRs, was found to enhance synaptic release of glutamate via a presynaptic mechanism (44).The presence of presynaptic and/or preterminal nAChRs in the CNS has been previously documented (1,19,28,31,34,44,57). Several studies reported presynaptic and/or preterminal ␤2-containing (likely ␣4␤2*) nAChRs corresponding to high-affinity binding sites for nicotine (1,13,24,28,(32)(33)(34)42).…”

“…The NTS plays a key role in the maintenance of autonomic homeostasis and projects within the brainstem [e.g., to the dorsal motor nucleus of the vagus (DMV) and the ventrolateral medulla] that support parasympathetic and sympathetic visceral reflexes (e.g., gastrointestinal and baroreflex), as well as to higher brain regions (e.g., the thalamus and the hypothalamus) that support behavioral and endocrine functions (2, 46). Therefore, modulation of neuronal activity and synaptic transmission in the NTS by biologically active compounds such as nicotinic agonists can have potent effects on basic autonomic functions and visceral reflexes.The NTS contains a highly heterogeneous population of neurons characterized by a broad spectrum of morphological, electrophysiological, and cytochemical properties and multiple projection targets (3,6,12,17,20,23,44,55). Expression of nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) also varies across the NTS region (44, 55).…”

“…The NTS contains a highly heterogeneous population of neurons characterized by a broad spectrum of morphological, electrophysiological, and cytochemical properties and multiple projection targets (3,6,12,17,20,23,44,55). Expression of nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) also varies across the NTS region (44, 55).…”

“…Expression of nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) also varies across the NTS region (44,55). Electrophysiological recordings from the NTS in brainstem slices revealed that nAChRs and mAChRs are likely expressed by different NTS neurons (43,55).…”

“…Electrophysiological recordings from the NTS in brainstem slices revealed that nAChRs and mAChRs are likely expressed by different NTS neurons (43,55). Moreover, subsets of small (somal area, ϳ137 m 2 ), elongated (form factor, ϳ0.62) caudal NTS neurons have been found to express functional presynaptic ␣3␤4-containing (this will be referred to throughout as ␣3␤4*) nAChRs (44), whose activation by nicotine, a broad spectrum agonist of nAChRs, or cytisine, a potent agonist of ␤4*-nAChRs, was found to enhance synaptic release of glutamate via a presynaptic mechanism (44).…”