Role of ß4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice.

ABSTRACT

Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. ß4-containing (ß4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of ß4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive ß4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 µg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that ß4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of ß4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of ß4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that ß4* nAChRs in the IPN have a role in maintaining nicotine IVSA.