The Nicotinic Antagonist Mecamylamine Has Antidepressant-like Effects in Wild-type but Not Beta2- or Alpha7-nicotinic Acetylcholine Receptor Subunit Knockout Mice

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2006 Oct 4

PMID 17016705

Citations 66

Authors

R L Rabenstein

B J Caldarone

M R Picciotto

Affiliations

Soon will be listed here.

Abstract

Rationale: 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.

Objectives: 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.

Materials And 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.

Citing Articles

Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression.

Guhathakurta D, Petruskova A, Akdas E, Perello-Amoros B, Frischknecht R, Anni D Transl Psychiatry. 2024; 14(1):47.

PMID: 38253622 PMC: 10803733. DOI: 10.1038/s41398-024-02744-y.

ACh signaling modulates activity of the GABAergic signaling network in the basolateral amygdala and behavior in stress-relevant paradigms.

Mineur Y, Mose T, Maibom K, Pittenger S, Soares A, Wu H Mol Psychiatry. 2022; 27(12):4918-4927.

PMID: 36050437 PMC: 10718266. DOI: 10.1038/s41380-022-01749-7.

Exploring the Potential Antidepressant Mechanisms of Pinellia by Using the Network Pharmacology and Molecular Docking.

Xiao Y, Wu H, Chen J, Li X, Qiu Z Metab Brain Dis. 2022; 37(4):1071-1094.

PMID: 35230627 DOI: 10.1007/s11011-022-00930-9.

Disrupting the α7nAChR-NR2A protein complex exerts antidepressant-like effects.

Jiang A, Su P, Li S, Wong A, Liu F Mol Brain. 2021; 14(1):107.

PMID: 34225758 PMC: 8256601. DOI: 10.1186/s13041-021-00817-3.

Converging evidence that short-active photoperiod increases acetylcholine signaling in the hippocampus.

Cope Z, Lavadia M, Joosen A, van de Cappelle C, Lara J, Huval A Cogn Affect Behav Neurosci. 2020; 20(6):1173-1183.

PMID: 32794101 PMC: 7718303. DOI: 10.3758/s13415-020-00824-2.

References

Kos T, Legutko B, Danysz W, Samoriski G, Popik P . Enhancement of antidepressant-like effects but not brain-derived neurotrophic factor mRNA expression by the novel N-methyl-D-aspartate receptor antagonist neramexane in mice. J Pharmacol Exp Ther. 2006; 318(3):1128-36. DOI: 10.1124/jpet.106.103697. View

Thierry B, Steru L, Simon P, Porsolt R . The tail suspension test: ethical considerations. Psychopharmacology (Berl). 1986; 90(2):284-5. DOI: 10.1007/BF00181261. View

Breslau N . Psychiatric comorbidity of smoking and nicotine dependence. Behav Genet. 1995; 25(2):95-101. DOI: 10.1007/BF02196920. View

Shytle R, Silver A, Lukas R, Newman M, Sheehan D, Sanberg P . Nicotinic acetylcholine receptors as targets for antidepressants. Mol Psychiatry. 2002; 7(6):525-35. DOI: 10.1038/sj.mp.4001035. View

King S, Marks M, Grady S, Caldarone B, Koren A, Mukhin A . Conditional expression in corticothalamic efferents reveals a developmental role for nicotinic acetylcholine receptors in modulation of passive avoidance behavior. J Neurosci. 2003; 23(9):3837-43. PMC: 6742204. View

Covey L, Glassman A, Stetner F . Cigarette smoking and major depression. J Addict Dis. 1998; 17(1):35-46. DOI: 10.1300/J069v17n01_04. View

Popik P, Kozela E, Krawczyk M . Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram. Br J Pharmacol. 2003; 139(6):1196-202. PMC: 1573951. DOI: 10.1038/sj.bjp.0705359. View

Newhouse P, Sunderland T, Tariot P, Blumhardt C, Weingartner H, Mellow A . Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology (Berl). 1988; 95(2):171-5. DOI: 10.1007/BF00174504. View

Ferguson S, Brodkin J, Lloyd G, Menzaghi F . Antidepressant-like effects of the subtype-selective nicotinic acetylcholine receptor agonist, SIB-1508Y, in the learned helplessness rat model of depression. Psychopharmacology (Berl). 2000; 152(3):295-303. DOI: 10.1007/s002130000531. View

10.

Semba J, Mataki C, Yamada S, Nankai M, Toru M . Antidepressantlike effects of chronic nicotine on learned helplessness paradigm in rats. Biol Psychiatry. 1998; 43(5):389-91. DOI: 10.1016/s0006-3223(97)00477-0. View

11.

Overstreet D . The Flinders sensitive line rats: a genetic animal model of depression. Neurosci Biobehav Rev. 1993; 17(1):51-68. DOI: 10.1016/s0149-7634(05)80230-1. View

12.

Diwan A, Castine M, Pomerleau C, Meador-Woodruff J, Dalack G . Differential prevalence of cigarette smoking in patients with schizophrenic vs mood disorders. Schizophr Res. 1998; 33(1-2):113-8. DOI: 10.1016/s0920-9964(98)00045-0. View

13.

Killen J, Fortmann S, Schatzberg A, Hayward C, Varady A . Onset of major depression during treatment for nicotine dependence. Addict Behav. 2003; 28(3):461-70. DOI: 10.1016/s0306-4603(01)00266-0. View

14.

Laje R, Berman J, Glassman A . Depression and nicotine: preclinical and clinical evidence for common mechanisms. Curr Psychiatry Rep. 2001; 3(6):470-4. DOI: 10.1007/s11920-001-0040-z. View

15.

Orr-Urtreger A, Goldner F, Saeki M, Lorenzo I, Goldberg L, De Biasi M . Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents. J Neurosci. 1997; 17(23):9165-71. PMC: 6573618. View

16.

Crawley J, Paylor R . A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav. 1997; 31(3):197-211. DOI: 10.1006/hbeh.1997.1382. View

17.

Steru L, Chermat R, Thierry B, Simon P . The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985; 85(3):367-70. DOI: 10.1007/BF00428203. View

18.

Janowsky D, Davis J, Hubbard B, Sekerke H . Cholinergic reversal of manic symptoms. Lancet. 1972; 1(7762):1236-7. DOI: 10.1016/s0140-6736(72)90956-7. View

19.

Covey L, Glassman A, Stetner F . Major depression following smoking cessation. Am J Psychiatry. 1997; 154(2):263-5. DOI: 10.1176/ajp.154.2.263. View

20.

Picciotto M, Zoli M, Lena C, BESSIS A, Lallemand Y, Le Novere N . Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature. 1995; 374(6517):65-7. DOI: 10.1038/374065a0. View