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The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice

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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 β2- or α7-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-β-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 β2- and α7-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 β2 and α7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans.

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References

  • Breslau N (1995) Psychiatric comorbidity of smoking and nicotine dependence. Behav Genet 25:95–101

    Article  PubMed  CAS  Google Scholar 

  • Caldarone BJ, Karthigeyan K, Harrist A, Hunsberger JG, Wittmack E, King SL, Jatlow P, Picciotto MR (2003) Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice. Psychopharmacology (Berl) 170:94–101

    Article  CAS  Google Scholar 

  • Caldarone BJ, Harrist A, Cleary MA, Beech RD, King SL, Picciotto MR (2004) High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation. Biol Psychiatry 56:657–664

    Article  PubMed  CAS  Google Scholar 

  • Covey LS, Glassman AH, Stetner F (1997) Major depression following smoking cessation. Am J Psychiatry 154:263–265

    PubMed  CAS  Google Scholar 

  • Covey LS, Glassman AH, Stetner F (1998) Cigarette smoking and major depression. J Addict Dis 17:35–46

    Article  PubMed  CAS  Google Scholar 

  • Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672

    Article  PubMed  CAS  Google Scholar 

  • Crawley JN, Paylor R (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 31:197–211

    Article  PubMed  CAS  Google Scholar 

  • Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245

    Article  PubMed  CAS  Google Scholar 

  • Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625

    Article  PubMed  CAS  Google Scholar 

  • Diwan A, Castine M, Pomerleau CS, Meador-Woodruff JH, Dalack GW (1998) Differential prevalence of cigarette smoking in patients with schizophrenic vs mood disorders. Schizophr Res 33:113–118

    Article  PubMed  CAS  Google Scholar 

  • Djuric VJ, Dunn E, Overstreet DH, Dragomir A, Steiner M (1999) Antidepressant effect of ingested nicotine in female rats of Flinders resistant and sensitive lines. Physiol Behav 67:533–537

    Article  PubMed  CAS  Google Scholar 

  • Ferguson SM, Brodkin JD, Lloyd GK, Menzaghi F (2000) Antidepressant-like effects of the subtype-selective nicotinic acetylcholine receptor agonist, SIB-1508Y, in the learned helplessness rat model of depression. Psychopharmacology (Berl) 152:295–303

    Article  CAS  Google Scholar 

  • Giniatullin R, Nistri A, Yakel JL (2005) Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends Neurosci 28:371–378

    Article  PubMed  CAS  Google Scholar 

  • Gosling JA, Lu TC (1969) Uptake and distribution of some quaternary ammonium compounds in the central nervous system of the rat. J Pharmacol Exp Ther 167:56–62

    PubMed  CAS  Google Scholar 

  • Hall SM, Reus VI, Munoz RF, Sees KL, Humfleet G, Hartz DT, Frederick S, Triffleman E (1998) Nortriptyline and cognitive–behavioral therapy in the treatment of cigarette smoking. Arch Gen Psychiatry 55:683–690

    Article  PubMed  CAS  Google Scholar 

  • Hayford KE, Patten CA, Rummans TA, Schroeder DR, Offord KP, Croghan IT, Glover ED, Sachs DP, Hurt RD (1999) Efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism. Br J Psychiatry 174:173–178

    Article  PubMed  CAS  Google Scholar 

  • Janowsky DS, el-Yousef MK, Davis JM, Hubbard B, Sekerke HJ (1972a) Cholinergic reversal of manic symptoms. Lancet 1:1236–1237

    Article  PubMed  CAS  Google Scholar 

  • Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ (1972b) A cholinergic–adrenergic hypothesis of mania and depression. Lancet 2:632–635

    Article  PubMed  CAS  Google Scholar 

  • Killen JD, Fortmann SP, Schatzberg A, Hayward C, Varady A (2003) Onset of major depression during treatment for nicotine dependence. Addict Behav 28:461–470

    Article  PubMed  Google Scholar 

  • King SL, Marks MJ, Grady SR, Caldarone BJ, Koren AO, Mukhin AG, Collins AC, Picciotto MR (2003) Conditional expression in corticothalamic efferents reveals a developmental role for nicotinic acetylcholine receptors in modulation of passive avoidance behavior. J Neurosci 23:3837–3843

    PubMed  CAS  Google Scholar 

  • Kos T, Legutko B, Danysz W, Samoriski G, Popik P (2006) Enhancement of antidepressant-like effects but not BDNF mRNA expression by the novel NMDA receptor antagonist neramexane in mice. J Pharmacol Exp Ther

  • Laje RP, Berman JA, Glassman AH (2001) Depression and nicotine: preclinical and clinical evidence for common mechanisms. Curr Psychiatry Rep 3:470–474

    PubMed  CAS  Google Scholar 

  • Malin DH, Lake JR, Schopen CK, Kirk JW, Sailer EE, Lawless BA, Upchurch TP, Shenoi M, Rajan N (1997) Nicotine abstinence syndrome precipitated by central but not peripheral hexamethonium. Pharmacol Biochem Behav 58:695–699

    Article  PubMed  CAS  Google Scholar 

  • Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL (1988) Intravenous nicotine in Alzheimer’s disease: a pilot study. Psychopharmacology (Berl) 95:171–175

    CAS  Google Scholar 

  • O’Neil MF, Moore NA (2003) Animal models of depression: are there any? Hum Psychopharmacol 18:239–254

    Article  PubMed  Google Scholar 

  • Orr-Urtreger A, Goldner FM, Saeki M, Lorenzo I, Goldberg L, De Biasi M, Dani JA, Patrick JW, Beaudet AL (1997) Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents. J Neurosci 17:9165–9171

    PubMed  CAS  Google Scholar 

  • Overstreet DH (1993) The Flinders sensitive line rats: a genetic animal model of depression. Neurosci Biobehav Rev 17:51–68

    Article  PubMed  CAS  Google Scholar 

  • Picciotto MR, Zoli M, Lena C, Bessis A, Lallemand Y, Le Novere N, Vincent P, Pich EM, Brulet P, Changeux JP (1995) Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374:65–67

    Article  PubMed  CAS  Google Scholar 

  • Picciotto MR, Caldarone BJ, King SL, Zachariou V (2000) Nicotinic receptors in the brain. Links between molecular biology and behavior. Neuropsychopharmacology 22:451–465

    Article  PubMed  CAS  Google Scholar 

  • Picciotto MR, Brunzell DH, Caldarone BJ (2002) Effect of nicotine and nicotinic receptors on anxiety and depression. Neuroreport 13:1097–1106

    Article  PubMed  CAS  Google Scholar 

  • Pomerleau OF, Pomerleau CS (1984) Neuroregulators and the reinforcement of smoking: towards a biobehavioral explanation. Neurosci Biobehav Rev 8:503–513

    Article  PubMed  CAS  Google Scholar 

  • Popik P, Kozela E, Krawczyk M (2003) Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram. Br J Pharmacol 139:1196–1202

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    PubMed  CAS  Google Scholar 

  • Salin-Pascual RJ, de la Fuente JR, Galicia-Polo L, Drucker-Colin R (1995) Effects of transderman nicotine on mood and sleep in nonsmoking major depressed patients. Psychopharmacology (Berl) 121:476–479

    Article  CAS  Google Scholar 

  • Semba J, Mataki C, Yamada S, Nankai M, Toru M (1998) Antidepressant-like effects of chronic nicotine on learned helplessness paradigm in rats. Biol Psychiatry 43:389–391

    Article  PubMed  CAS  Google Scholar 

  • Shytle RD, Silver AA, Lukas RJ, Newman MB, Sheehan DV, Sanberg PR (2002) Nicotinic acetylcholine receptors as targets for antidepressants. Mol Psychiatry 7:525–535

    Article  PubMed  CAS  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370

    Article  CAS  Google Scholar 

  • Thierry B, Steru L, Simon P, Porsolt RD (1986) The tail suspension test: ethical considerations. Psychopharmacology (Berl) 90:284–285

    CAS  Google Scholar 

  • Tizabi Y, Overstreet DH, Rezvani AH, Louis VA, Clark E Jr, Janowsky DS, Kling MA (1999) Antidepressant effects of nicotine in an animal model of depression. Psychopharmacology (Berl) 142:193–199

    Article  CAS  Google Scholar 

  • Wahlsten D, Metten P, Phillips TJ, Boehm SL 2nd, Burkhart-Kasch S, Dorow J, Doerksen S, Downing C, Fogarty J, Rodd-Henricks K, Hen R, McKinnon CS, Merrill CM, Nolte C, Schalomon M, Schlumbohm JP, Sibert JR, Wenger CD, Dudek BC, Crabbe JC (2003) Different data from different labs: lessons from studies of gene–environment interaction. J Neurobiol 54:283–311

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH grants DA13334/AA15632, MH77681, and DA00436 and the NARSAD Foster Bam Award.

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Authors and Affiliations

  1. Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, 06508, USA

    R. L. Rabenstein & M. R. Picciotto

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06508, USA

    R. L. Rabenstein, B. J. Caldarone & M. R. Picciotto

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  1. R. L. Rabenstein
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  2. B. J. Caldarone
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  3. M. R. Picciotto
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Correspondence to M. R. Picciotto.

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Rabenstein, R.L., Caldarone, B.J. & Picciotto, M.R. The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice. Psychopharmacology 189, 395–401 (2006). https://doi.org/10.1007/s00213-006-0568-z

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  • DOI: https://doi.org/10.1007/s00213-006-0568-z

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