Nicotinic acetylcholine receptors control acetylcholine and noradrenaline release in the rodent habenulo-interpeduncular complex

Background and purposeNicotinic 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 approachThe habenula and IPN were loaded with [H-3]-choline or [H-3]-NA and placed in superfusion chambers. [H-3]-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 5, 7, 2, or 4 nACh receptor subunits. Finally, we analysed nACh receptor subtypes in the IPN using immunoprecipitation. Key resultsNicotine induced release of [H-3]-ACh in the IPN of rats and mice. This release was calcium-dependent but not blocked by tetrodotoxin (TTX); moreover, [H-3]-ACh release was abolished in 4-knockout mice but was unaffected in 2- and 5-knockout mice. In contrast, nicotine-induced release of [H-3]-NA in the IPN and habenula was blocked by TTX and reduced in both 2-knockout and 4-knockout mice, and dose-response curves were right-shifted in 5-knockout mice. Although electrical stimuli triggered the release of both transmitters, [H-3]-ACh release required more pulses delivered at a higher frequency. Conclusions and implicationsOur results confirm previous findings that 4-containing nACh receptors are critical for [H-3]-ACh release in the mouse IPN. Experiments using 5-knockout mice also revealed that unlike in the hippocampus, nicotine-induced [H-3]-NA release in the habenulo-interpeduncular system is altered in this knockout model. As 5-containing nACh receptors play a key role in nicotine intake, our results add NA to the list of transmitters involved in this mechanism.