The α5 nAChR subunit has a restricted distribution profile in the brain, with dense expression in the habenulo-interpeduncular pathway, deep layers of the cortex and hippocampus, and lower expression in the ventral tegmental area (VTA) and substantia nigra27. The medial habenula (MHb) projects almost exclusively to the interpeduncular nucleus (IPN) via the fasciculus retroflexus28. Functional α5* nAChRs are expressed on MHb afferents to the IPN29, and high but not low nicotine doses activate the habenulo-interpeduncular tract, as measured by an increased local glucose utilization in rats30. The habenulo-interpeduncular tract regulates avoidance of noxious substances31 and regulates somatic aspects of nicotine withdrawal32. However, little is known of its role in drug-taking behavior33. Intriguingly, the lateral habenula (LHb) has an inhibitory influence on VTA dopamine neurons34, is activated by aversive stimuli or omission of anticipated reward, and is considered a source of negative motivational signals in the brain34. We therefore hypothesized that nicotine-induced stimulation of α5* nAChRs in the habenulo-interpeduncular pathway triggers an inhibitory motivational signal that limits consumption of the drug. In knockout and wildtype mice that received injections of a
