Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement
Open Access
- 14 April 2010
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 30 (15), 5311-5325
- https://doi.org/10.1523/jneurosci.5095-09.2010
Abstract
α6* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of α6* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition and in vivo functional role of α6* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of α6* nAChR in the mesostriatal system is heterogeneous, with (non-α4)α6β2* being predominant in the mesolimbic pathway and α4α6β2* in the nigrostriatal pathway. We verified whether α6* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists α-conotoxin MII (CntxMII) (α3/α6β2* selective) or α-conotoxin PIA (CntxPIA) (α6β2* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicited DA release in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the α6β2* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that α6β2*-selective compounds capable of crossing the blood–brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence.Keywords
This publication has 62 references indexed in Scilit:
- α-Conotoxin MII-Sensitive Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Shell Regulate Progressive Ratio Responding Maintained by NicotineNeuropsychopharmacology, 2009
- Rodent Habenulo–Interpeduncular Pathway Expresses a Large Variety of Uncommon nAChR Subtypes, But Only the α3β4 and α3β3β4 Subtypes Mediate Acetylcholine ReleaseJournal of Neuroscience, 2009
- Crucial Role of α4 and α6 Nicotinic Acetylcholine Receptor Subunits from Ventral Tegmental Area in Systemic Nicotine Self-AdministrationJournal of Neuroscience, 2008
- In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity α6∗ Nicotinic Acetylcholine ReceptorsNeuron, 2008
- Long-Term Nicotine Treatment Differentially Regulates Striatal α6α4β2*and α6(Nonα4)β2*nAChR Expression and FunctionMolecular Pharmacology, 2008
- The neuronal nicotinic acetylcholine receptors α4* and α6* differentially modulate dopamine release in mouse striatal slicesJournal of Neurochemistry, 2008
- Exposure to nicotine and sensitization of nicotine-induced behaviorsProgress in Neuro-Psychopharmacology and Biological Psychiatry, 2007
- The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatumBiochemical Pharmacology, 2007
- Oral absorption and in vivo biodistribution of α-conotoxin MII and a lipidic analogueBiochemical and Biophysical Research Communications, 2007
- Expression of Nigrostriatal α6-Containing Nicotinic Acetylcholine Receptors Is Selectively Reduced, but Not Eliminated, by β3 Subunit Gene DeletionPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2005