TY - JOUR
T1 - Role of the nicotinic receptor β4 subunit in the antidepressant activity of novel N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers
AU - Targowska-Duda, Katarzyna M.
AU - Jozwiak, Krzysztof
AU - Arias, Hugo R.
N1 - Funding Information:
This research was supported by a grant from the TEAM research subsidy from the Fundation for Polish Science, Poland (to K.J.). Dr. Targowska-Duda was supported by the TEAM program to work at Dr. Arias’ lab. The FST apparatus was purchased with a grant from Targacept, Inc. (to H.A.). The authors thank Dr. Mariella De Biasi (Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA) for her gift of wild-type (β4+/+) and mutant (β4−/−) mice.
PY - 2013/10/11
Y1 - 2013/10/11
N2 - The role of the nicotinic receptor β4 subunit in the antidepressant activity of N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers was investigated using wild-type (β4+/+) and knockout (β4-/-) mice. Mice were injected (i.p.) with saline (control) or with either enantiomer (1.0mg/kg base drug) daily for the first two weeks. Forced swim tests (FST) were performed on Day 1 to determine the acute effect of each enantiomer, and on Day 7 and 14, to determine the chronic activity. To examine the remnant effects after drug treatment, a withdrawal period of two more weeks was continued with FSTs performed on Day 21 and 28. Our results indicate that: (1) the acute antidepressant effect elicited by the (S,S)-enantiomer is observed in β4+/+ mice from both sexes, whereas the effect elicited by the (R,R)-enantiomer is only observed in male β4+/+ mice. There is no antidepressant effect for both novel compounds on male and female β4-/- mice, (2) the chronic antidepressant effect elicited by both enantiomers is observed in β4+/+, but not in β4-/-, mice from both sexes, and (3) the residual antidepressant effect mediated by each enantiomer after withdrawal was observed only in female β4+/+ mice. Our results clearly indicate that β4-containing AChRs are targets for the antidepressant activity of these compounds, and that this activity is gender-dependent.
AB - The role of the nicotinic receptor β4 subunit in the antidepressant activity of N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers was investigated using wild-type (β4+/+) and knockout (β4-/-) mice. Mice were injected (i.p.) with saline (control) or with either enantiomer (1.0mg/kg base drug) daily for the first two weeks. Forced swim tests (FST) were performed on Day 1 to determine the acute effect of each enantiomer, and on Day 7 and 14, to determine the chronic activity. To examine the remnant effects after drug treatment, a withdrawal period of two more weeks was continued with FSTs performed on Day 21 and 28. Our results indicate that: (1) the acute antidepressant effect elicited by the (S,S)-enantiomer is observed in β4+/+ mice from both sexes, whereas the effect elicited by the (R,R)-enantiomer is only observed in male β4+/+ mice. There is no antidepressant effect for both novel compounds on male and female β4-/- mice, (2) the chronic antidepressant effect elicited by both enantiomers is observed in β4+/+, but not in β4-/-, mice from both sexes, and (3) the residual antidepressant effect mediated by each enantiomer after withdrawal was observed only in female β4+/+ mice. Our results clearly indicate that β4-containing AChRs are targets for the antidepressant activity of these compounds, and that this activity is gender-dependent.
KW - β4 Subunit
KW - Antidepressants
KW - Forced swim test
KW - Knock-out mice
KW - Nicotinic acetylcholine receptors
UR - http://www.scopus.com/inward/record.url?scp=84884403721&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2013.08.036
DO - 10.1016/j.neulet.2013.08.036
M3 - Article
C2 - 23994392
AN - SCOPUS:84884403721
SN - 0304-3940
VL - 553
SP - 186
EP - 190
JO - Neuroscience Letters
JF - Neuroscience Letters
ER -