Beiranvand_2014_Br.J.Pharmacol_171_5209

BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nACh receptors) play a central role in the habenulo-interpeduncular system. We studied nicotine-induced release of NA and ACh in the habenula and interpeduncular nucleus (IPN). EXPERIMENTAL APPROACH: The habenula and IPN were loaded with [(3) H]-choline or [(3) H]-NA and placed in superfusion chambers. [(3) H]-ACh release was also stimulated using nicotinic agonists, electrical pulses and elevated [KCl]o in hippocampal and cortical slices from rats, wild-type mice and mice lacking alpha5, alpha7, beta2, or beta4 nACh receptor subunits. Finally, we analysed nACh receptor subtypes in the IPN using immunoprecipitation. KEY
RESULTS: Nicotine induced release of [(3) H]-ACh in the IPN of rats and mice. This release was calcium-dependent but not blocked by tetrodotoxin (TTX); moreover, [(3) H]-ACh release was abolished in beta4-knockout mice but was unaffected in beta2- and alpha5-knockout mice. In contrast, nicotine-induced release of [(3) H]-NA in the IPN and habenula was blocked by TTX and reduced in both beta2-knockout and beta4-knockout mice, and dose-response curves were right-shifted in alpha5-knockout mice. Although electrical stimuli triggered the release of both transmitters, [(3) H]-ACh release required more pulses delivered at a higher frequency. CONCLUSIONS AND IMPLICATIONS: Our results confirm previous findings that beta4-containing nACh receptors are critical for [(3) H]-ACh release in the mouse IPN. Experiments using alpha5-knockout mice also revealed that unlike in the hippocampus, nicotine-induced [(3) H]-NA release in the habenulo-interpeduncular system is altered in this knockout model. As alpha5-containing nACh receptors play a key role in nicotine intake, our results add NA to the list of transmitters involved in this mechanism.