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The Journal of Neuroscience, February 18, 2009, 29(7):2272-2282; doi:10.1523/JNEUROSCI.5121-08.2009

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Cellular/Molecular
Rodent Habenulo–Interpeduncular Pathway Expresses a Large Variety of Uncommon nAChR Subtypes, But Only the 3β4^* and 3β3β4^,* Subtypes Mediate Acetylcholine Release

Sharon R. Grady,^1 * Milena Moretti,^2 * Michele Zoli,^3 * Michael J. Marks,¹ Alessio Zanardi,³ Luca Pucci,² Francesco Clementi,² and Cecilia Gotti²

¹Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80301, ²Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology Center, Department of Medical Pharmacology, University of Milan, 20129 Milan, Italy, and ³Department of Biomedical Sciences, Section of Physiology, University of Modena and Reggio Emilia, 41100 Modena, Italy

Correspondence should be addressed to Cecilia Gotti, Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology Center, Department of Medical Pharmacology, University of Milan, 20129 Milan, Italy. Email: c.gotti{at}in.cnr.it

Recent studies suggest that the neuronal nicotinic receptors (nAChRs) present in the habenulo–interpeduncular (Hb–IPn) system can modulate the reinforcing effect of addictive drugs and the anxiolytic effect of nicotine. Hb and IPn neurons express mRNAs for most nAChR subunits, thus making it difficult to establish the subunit composition of functional receptors. We used immunoprecipitation and immunopurification studies performed in rat and wild-type (+/+) and β2 knock-out (–/–) mice to establish that the Hb and IPn contain significant β2* and β4* populations of nAChR receptors (each of which is heterogeneous). The β4* nAChR are more highly expressed in the IPn. We also identified novel native subtypes (2β2*, 4β3β2*, 3β3β4*, 6β3β4*). Our studies on IPn synaptosomes obtained from +/+ and 2, 4, 5, 6, 7, β2, β3, and β4^–/– mice show that only the 3β4 and 3β3β4 subtypes facilitate acetylcholine (ACh) release. Ligand binding, immunoprecipitation, and Western blotting studies in β3^–/– mice showed that, in the IPn of these mice, there is a concomitant reduction of ACh release and 3β4* receptors, whereas the receptor number remains the same in the Hb. We suggest that, in habenular cholinergic neurons, the β3 subunit may be important for transporting the 3β4* subtype from the medial habenula to the IPn. Overall, these studies highlight the presence of a wealth of uncommon nAChR subtypes in the Hb–IPn system and identify 3β4 and 3β3β4, transported from the Hb and highly enriched in the IPn, as the subtypes modulating ACh release in the IPn.

Key words: habenula; nucleus interpeduncularis; nicotinic receptor subtypes; acetylcholine release; subunit composition; knock-out mice

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Received Oct. 23, 2008; revised Jan. 7, 2009; accepted Jan. 12, 2009.

Correspondence should be addressed to Cecilia Gotti, Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology Center, Department of Medical Pharmacology, University of Milan, 20129 Milan, Italy. Email: c.gotti{at}in.cnr.it

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