Received for publication March 16, 2006.
Revised May 30, 2006.
Accepted for publication May 30, 2006.

Characterization of Nicotinic Acetylcholine Receptors that Modulate Nicotine-evoked [³H]Norepinephrine Release from Mouse Hippocampal Synaptosomes

Abstract

Nicotine's modulation of hippocampal noradrenergic neurotransmission may contribute to its mnemonic properties, but the nAChR subtypes that modulate terminal release of norepinephrine are unknown. In the present study, we have used a number of subtype selective -conotoxins in combination with nicotinic receptor subunit deficient mice to characterize nAChRs that modulate [³H]norepinephrine release from synaptosomes. The results indicate that at least 2 populations of nAChRs contribute to this release. These are a novel 6(4)234 subtype and an 6(4)23 subtype. These are distinct from subtypes that modulate synaptosomal norepinephrine release in the rat hippocampus where an 6/2 and/or 6/4 ligand-binding interface is not present. Whereas -conotoxin MII fully inhibits nicotine-evoked [³H]norepinephrine release in mouse, it is ineffective in blocking [³H]norepinephrine release in rat. Block of [³H]norepinephrine release by -conotoxin BuIA, a toxin that kinetically distinguishes between 2- and 4-containing nAChRs, was partially reversible in mouse but irreversible in rat. This indicates that in contrast to rat, mouse nAChRs are made of both 4 and non-4-containing populations. Results from 2 and 4 null mutant mice confirmed this conclusion, indicating the presence of the 2 subunit in all nAChRs, and the presence of the 4 subunit in a subpopulation of nAChRs. Additionally, both 4 and 3 subunits are essential for formation of functional nAChRs on mouse noradrenergic terminals. Cytisine, a ligand formerly believed to be 4-selective, was a highly efficacious agonist for 62-containing nAChRs. The sum of these results suggests a possible novel nAChR subtype that modulates noradrenergic neurotransmission within the mouse hippocampus.

Key words: Adrenergic, Nicotinic cholinergic

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