Activation of α5, α3, β4 Acetylcholine Receptors in the Medial Habenula - Interpeduncular Nucleus Complex Inhibits Nicotine Intake.
- The MHb extends projections via the fasciculus retroflexus almost exclusively to the IPN and there is a high density of α5, α3, β4 receptors in the MHb-IPN complex.
- A null mutation in the α5 subunit and α5 subunit knockdown in the MHb increases nicotine intake. β4 subunit overexpression decreases nicotine intake, which is reversed by expression of a less active α5 subunit variant that increases nicotine intake. There is decreased IPN activation in α5 subunit knockout mice and disruption of MHb and IPN signaling increases nicotine intake in rats.
- Knockdown of the α5 subunit in the MHb does not alter the rewarding effects of nicotine.
- In humans, the less active α5 subunit variant that increases nicotine intake increases vulnerability to tobacco addiction and interacts with risk factors to increase tobacco addiction.
- Therefore, both the α5 and β4 subunits in the α5, α3, β4 receptors in the MHb-IPN complex play an important role in limiting excessive nicotine intake and impairment in this pathway can increase the risk of tobacco addiction.
