Abstract
Nicotine's modulation of hippocampal noradrenergic neurotransmission may contribute to its mnemonic properties, but the nicotinic acetylcholine receptor (nAChR) subtypes that modulate terminal release of norepinephrine are unknown. In the present study, we used a number of subtype-selective α-conotoxins in combination with nicotinic receptor subunit-deficient mice to characterize nAChRs that modulate [3H]nore-pinephrine release from synaptosomes. The results indicate that at least two populations of nAChRs contribute to this release: a novel α6(α4)β2β3β4 subtype and an α6(α4)β2β3 subtype. These are distinct from subtypes that modulate synaptosomal norepinephrine release in the rat hippocampus in which an α6/β2 and/or α6/β4 ligand binding interface is not present. Whereas α-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 α-conotoxin BuIA, a toxin that kinetically distinguishes between β2- and β4-containing nAChRs, was partially reversible in mouse but irreversible in rat. This indicates that in contrast to rat, mouse nAChRs are made of both β4 and non-β4-containing populations. Results from β2 and β4 null mutant mice confirmed this conclusion, indicating the presence of the β2 subunit in all nAChRs and the presence of the β4 subunit in a subpopulation of nAChRs. In addition, both α4 and β3 subunits are essential for the formation of functional nAChRs on mouse noradrenergic terminals. Cytisine, a ligand formerly believed to be β4-selective, was a highly effective agonist for α6β2-containing nAChRs. The sum of these results suggests a possible novel nAChR subtype that modulates nor-adrenergic neurotransmission within the mouse hippocampus.
Footnotes
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This work was supported by National Institutes of Health grant DA016835 (to L.A.), DA015663 (Institute for Behavioral Genetics), and MH53631 (to J.M.M.).
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This work was previously presented in part at the 2003 Society for Neuroscience Annual Meeting, Program 248.12; Nov 8-12, 2003; New Orleans, LA.
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; CTX, conotoxin; DA, dopamine; LC, locus wild-type.
- Received March 15, 2006.
- Accepted May 30, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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