QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.149609v1 329/1/377    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mineur, Y. S. Articles by Picciotto, M. R. Search for Related Content PubMed PubMed Citation Articles by Mineur, Y. S. Articles by Picciotto, M. R.

NEUROPHARMACOLOGY

Cytisine-Based Nicotinic Partial Agonists as Novel Antidepressant Compounds

Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut (Y.S.M., G.Y., C.K., M.R.P.); Pharmazeutisches Institut, Pharmazeutische Chemie I, Bonn, Germany (C.E., D.G.); and Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida (R.L.P.)

Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the β2 subunit (β2^*), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at 4/β2^* nAChRs, and a full agonist at 3/β4^* and 7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at 4/β2^* nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

Address correspondence to: Dr. Marina R. Picciotto, Department of Psychiatry, Yale School of Medicine, 34 Park Street, 3rd Floor Research, New Haven, CT 06508. E-mail: marina.picciotto{at}yale.edu