The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not beta2- or alpha7-nicotinic acetylcholine receptor subunit knockout mice.
BACKGROUND
Increases in cholinergic transmission are linked to depression in human subjects and animal models. We therefore examined the effect of decreasing nicotinic acetylcholine receptor (nAChR) activity in tests of antidepressant efficacy using C57BL/6J mice.


OBJECTIVE
We determined whether the noncompetitive nAChR antagonist mecamylamine had antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). These experiments were repeated in mice lacking either the beta2- or alpha7-nAChR subunits to identify the nAChR subunits involved in mediating the antidepressant response to mecamylamine.


METHODS
Adult mice on the C57BL/6J background were acutely administered mecamylamine i.p. 30 min before testing in the FST or TST.


RESULTS
A dose-response study showed that mecamylamine significantly decreased immobility time in the TST at the 1.0-mg/kg dose but did not alter baseline locomotor activity. The competitive nAChR antagonist dihydro-beta-erythroidine, but not the blood-brain barrier impermeant antagonist hexamethonium, also decreased immobility in the TST. One milligram per kilogram of mecamylamine also significantly decreased time immobile in the FST whereas both beta2- and alpha7-knockout mice were insensitive to the effects of mecamylamine in the FST.


CONCLUSIONS
Decreased activity of central nAChRs has antidepressant-like effects in both the TST and FST and these effects are dependent on both beta2 and alpha7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans.
Rabenstein
R L
RL
Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT 06508, USA.
Caldarone
B J
BJ
Picciotto
M R
MR
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D005260:Female; D019417:Hindlimb Suspension; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000928:Antidepressive Agents; D008464:Mecamylamine; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse