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

• N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers have antidepressant activity.
• The antidepressant effect is observed in β4+/+, but not in β4−/−, mice.
• β4-Containing nicotinic receptors are targets for antidepressants.
• The observed antidepressant activity is gender-dependent.

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 (1.0 mg/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.