Skip to main content
SpringerLink
Log in

Chronic oral nicotine increases brain [3H]epibatidine binding and responsiveness to antidepressant drugs, but not nicotine, in the mouse forced swim test

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Introduction

Smoking rates among depressed individuals is higher than among healthy subjects, and nicotine alleviates depressive symptoms. Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. In mice, acute nicotine administration enhances the activity of antidepressants in the mouse forced swim (mFST) and tail suspension tests. Here, we investigated if this action of nicotine is also reflected in a chronic treatment regimen.

Materials and methods

After chronic treatment with nicotine in the drinking water, mice were challenged with nicotine, duloxetine, citalopram, and reboxetine in the mFST. Additionally, 8-OH-DPAT- and clonidine-induced hypothermia was tested in vehicle- and nicotine-pretreated mice, as a measure of 5-HT1A and α2-adrenoceptor function, respectively. Finally, the effects on the brain expression levels of high- and low-affinity nicotinic acetylcholine receptors (nAChRs) and the transporters for serotonin (SERT) and noradrenaline (NET) were assessed using [3H]epibatidine, [3H]α-bungarotoxin, [3H]citalopram, and [3H]nisoxetine binding, respectively.

Results

In the mFST, nicotine-pretreated mice did not show altered response to the nicotine challenge, but increased responses to all three antidepressants tested were observed when compared to mice that had been administered drinking water without nicotine. There was no change in hypothermic responses to 8-OH-DPAT or clonidine. [3H]epibatidine binding was significantly increased in all brain regions investigated; whereas, [3H]α-bungarotoxin, [3H]citalopram, and [3H]nisoxetine binding were not altered, indicating that chronic oral nicotine increases the expression and/or affinity of high-affinity nAChRs, but not low-affinity nAChRs, SERT, or NET.

Discussion

It is suggested that the increased sensitivity to antidepressants after chronic nicotine exposure involves increased high-affinity nAChR-mediated neurotransmission.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Andreasen JT, Redrobe JP (2009) Nicotine, but not mecamylamine, enhances antidepressant-like effects of citalopram and reboxetine in the mouse forced swim and tail suspension tests. Behav Brain Res 197:150–156

    Article  PubMed  CAS  Google Scholar 

  • Andreasen JT, Andersen KK, Nielsen EO, Mathiasen L, Mirza NR (2006) Nicotine and clozapine selectively reverse a PCP-induced deficit of PPI in BALB/cByJ but not NMRI mice: comparison with risperidone. Behav Brain Res 167:118–127

    Article  PubMed  CAS  Google Scholar 

  • Andreasen JT, Olsen GM, Wiborg O, Redrobe JP (2008) Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests. J Psychopharmacol doi:10.1177/0269881108091587

  • Bauer ME, Tejani-Butt SM (1992) Effects of repeated administration of desipramine or electroconvulsive shock on norepinephrine uptake sites measured by [3H]nisoxetine autoradiography. Brain Res 582:208–214

    Article  PubMed  CAS  Google Scholar 

  • Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A (1999) Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J Neurosci 19:10494–10501

    PubMed  CAS  Google Scholar 

  • Benmansour S, Altamirano AV, Jones DJ, Sanchez TA, Gould GG, Pardon MC, Morilak DA, Frazer A (2004) Regulation of the norepinephrine transporter by chronic administration of antidepressants. Biol Psychiatry 55:313–316

    Article  PubMed  CAS  Google Scholar 

  • Bill DJ, Hughes IE, Stephens RJ (1989) The thermogenic actions of alpha 2-adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic alpha 2-adrenoceptor mechanism. Br J Pharmacol 96:133–143

    PubMed  CAS  Google Scholar 

  • Blier P (2003) The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol 13:57–66

    Article  PubMed  CAS  Google Scholar 

  • Bourin M, Colombel MC, Redrobe JP, Nizard J, Hascoet M, Baker GB (1998) Evaluation of efficacies of different classes of antidepressants in the forced swimming test in mice at different ages. Prog Neuropsychopharmacol Biol Psychiatry 22:343–351

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Brown C, Madden PA, Palenchar DR, Cooper-Patrick L (2000) The association between depressive symptoms and cigarette smoking in an urban primary care sample. Int J Psychiatry Med 30:15–26

    Article  PubMed  CAS  Google Scholar 

  • Burn JH (1951) Antidiuretic effect of nicotine and its implications. Br Med J 2:199–201

    Article  PubMed  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 

  • Cryan JF, McGrath C, Leonard BE, Norman TR (1998) Combining pindolol and paroxetine in an animal model of chronic antidepressant action—can early onset of action be detected? Eur J Pharmacol 352:23–28

    Article  PubMed  CAS  Google Scholar 

  • Cryan JF, Page ME, Lucki I (2005) Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology (Berl) 182:335–344

    Article  CAS  Google Scholar 

  • Danysz W, Minor BG, Mohammed A, Pucilowski O, Plaznik A, Kostowski W, Post C, Archer T (1987) Chronic treatment with antidepressant drugs and ECT differentially modifies the hypothermic action of clonidine and guanfacine. Pharmacol Toxicol 60:305–311

    Article  PubMed  CAS  Google Scholar 

  • David DJ, Bourin M, Hascoet M, Colombel MC, Baker GB, Jolliet P (2001) Comparison of antidepressant activity in 4- and 40-week-old male mice in the forced swimming test: involvement of 5-HT1A and 5-HT1B receptors in old mice. Psychopharmacology (Berl) 153:443–449

    Article  CAS  Google Scholar 

  • De Biasi M, Salas R (2008) Influence of neuronal nicotinic receptors over nicotine addiction and withdrawal. Exp Biol Med (Maywood) 233:917–929

    Article  Google Scholar 

  • Detke MJ, Johnson J, Lucki I (1997) Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol 5:107–112

    Article  PubMed  CAS  Google Scholar 

  • Gäddnäs H, Pietila K, Ahtee L (2000) Effects of chronic oral nicotine treatment and its withdrawal on locomotor activity and brain monoamines in mice. Behav Brain Res 113:65–72

    Article  PubMed  Google Scholar 

  • Gentry CL, Lukas RJ (2002) Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure. Curr Drug Targets CNS Neurol Disord 1:359–385

    Article  PubMed  CAS  Google Scholar 

  • Glassman AH, Helzer JE, Covey LS, Cottler LB, Stetner F, Tipp JE, Johnson J (1990) Smoking, smoking cessation, and major depression. JAMA 264:1546–1549

    Article  PubMed  CAS  Google Scholar 

  • Gopalakrishnan M, Buisson B, Touma E, Giordano T, Campbell JE, Hu IC, Donnelly-Roberts D, Arneric SP, Bertrand D, Sullivan JP (1995) Stable expression and pharmacological properties of the human alpha 7 nicotinic acetylcholine receptor. Eur J Pharmacol 290:237–246

    Article  PubMed  CAS  Google Scholar 

  • Grabus SD, Martin BR, Batman AM, Tyndale RF, Sellers E, Damaj MI (2005) Nicotine physical dependence and tolerance in the mouse following chronic oral administration. Psychopharmacology (Berl) 178:183–192

    Article  CAS  Google Scholar 

  • Grilli M, Parodi M, Raiteri M, Marchi M (2005) Chronic nicotine differentially affects the function of nicotinic receptor subtypes regulating neurotransmitter release. J Neurochem 93:1353–1360

    Article  PubMed  CAS  Google Scholar 

  • Hensler JG, Kovachich GB, Frazer A (1991) A quantitative autoradiographic study of serotonin1A receptor regulation. Effect of 5, 7-dihydroxytryptamine and antidepressant treatments. Neuropsychopharmacology 4:131–144

    PubMed  CAS  Google Scholar 

  • Houghtling RA, vila-Garcia MI, Kellar KJ (1995) Characterization of (+/−)(-)[3H]epibatidine binding to nicotinic cholinergic receptors in rat and human brain. Mol Pharmacol 48:280–287

    PubMed  CAS  Google Scholar 

  • Hukkanen J, Jacob P III, Benowitz NL (2006) Effect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearance. Clin Pharmacol Ther 80:522–530

    Article  PubMed  CAS  Google Scholar 

  • Kendler KS, Neale MC, MacLean CJ, Heath AC, Eaves LJ, Kessler RC (1993) Smoking and major depression. A causal analysis. Arch Gen Psychiatry 50:36–43

    PubMed  CAS  Google Scholar 

  • Kenny PJ, File SE, Neal MJ (2000) Evidence for a complex influence of nicotinic acetylcholine receptors on hippocampal serotonin release. J Neurochem 75:2409–2414

    Article  PubMed  CAS  Google Scholar 

  • Kent JM (2000) SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 355:911–918

    Article  PubMed  CAS  Google Scholar 

  • Koyama S (2004) Primer effects by conspecific odors in house mice: a new perspective in the study of primer effects on reproductive activities. Horm Behav 46:303–310

    Article  PubMed  Google Scholar 

  • Laplante F, Stevenson CW, Gratton A, Srivastava LK, Quirion R (2004) Effects of neonatal ventral hippocampal lesion in rats on stress-induced acetylcholine release in the prefrontal cortex. J Neurochem 91:1473–1482

    Article  PubMed  CAS  Google Scholar 

  • Ma W, Miao Z, Novotny MV (1999) Induction of estrus in grouped female mice (Mus domesticus) by synthetic analogues of preputial gland constituents. Chem Senses 24:289–293

    Article  PubMed  CAS  Google Scholar 

  • Ma Z, Strecker RE, McKenna JT, Thakkar MM, McCarley RW, Tao R (2005) Effects on serotonin of (-) nicotine and dimethylphenylpiperazinium in the dorsal raphe and nucleus accumbens of freely behaving rats. Neuroscience 135:949–958

    Article  PubMed  CAS  Google Scholar 

  • Mark GP, Rada PV, Shors TJ (1996) Inescapable stress enhances extracellular acetylcholine in the rat hippocampus and prefrontal cortex but not the nucleus accumbens or amygdala. Neuroscience 74:767–774

    Article  PubMed  CAS  Google Scholar 

  • Matta SG, Balfour DJ, Benowitz NL et al (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl) 190:269–319

    Article  CAS  Google Scholar 

  • McClernon FJ, Hiott FB, Westman EC, Rose JE, Levin ED (2006) Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial. Psychopharmacology (Berl) 189:125–133

    Article  CAS  Google Scholar 

  • Mirza NR, Nielsen EO, Troelsen KB (2007) Serotonin transporter density and anxiolytic-like effects of antidepressants in mice. Prog Neuropsychopharmacol Biol Psychiatry 31:858–866

    Article  PubMed  CAS  Google Scholar 

  • Mitchell SN (1993) Role of the locus coeruleus in the noradrenergic response to a systemic administration of nicotine. Neuropharmacology 32:937–949

    Article  PubMed  CAS  Google Scholar 

  • Nguyen HN, Rasmussen BA, Perry DC (2004) Binding and functional activity of nicotinic cholinergic receptors in selected rat brain regions are increased following long-term but not short-term nicotine treatment. J Neurochem 90:40–49

    Article  PubMed  CAS  Google Scholar 

  • Nowakowska E, Kus K, Florek E, Czubak A, Jodynis-Liebert J (2006) The influence of tobacco smoke and nicotine on antidepressant and memory-improving effects of venlafaxine. Hum Exp Toxicol 25:199–209

    Article  PubMed  CAS  Google Scholar 

  • Nuutinen S, Ahtee L, Tuominen RK (2005) Time and brain region specific up-regulation of low affinity neuronal nicotinic receptors during chronic nicotine administration in mice. Eur J Pharmacol 515:83–89

    Article  PubMed  CAS  Google Scholar 

  • Pekonen K, Karlsson C, Laakso I, Ahtee L (1993) Plasma nicotine and cotinine concentrations in mice after chronic oral nicotine administration and challenge doses. Eur J Pharm Sci 1:13–18

    Article  Google Scholar 

  • Perry DC, vila-Garcia MI, Stockmeier CA, Kellar KJ (1999) Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther 289:1545–1552

    PubMed  CAS  Google Scholar 

  • Petersen DR, Norris KJ, Thompson JA (1984) A comparative study of the disposition of nicotine and its metabolites in three inbred strains of mice. Drug Metab Dispos 12:725–731

    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 

  • Popik P, Krawczyk M, Kos T, Nalepa I, Kowalska M, Witarski T, ntkiewicz-Michaluk L, Vetulani J (2005) Nicotine produces antidepressant-like actions: behavioral and neurochemical evidence. Eur J Pharmacol 515:128–133

    Article  PubMed  CAS  Google Scholar 

  • Quattrocki E, Baird A, Yurgelun-Todd D (2000) Biological aspects of the link between smoking and depression. Harv Rev Psychiatry 8:99–110

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen K, Czachura JF (1997) Nicotine withdrawal leads to increased sensitivity of serotonergic neurons to the 5-HT1A agonist 8-OH-DPAT. Psychopharmacology (Berl) 133:343–346

    Article  CAS  Google Scholar 

  • Ribeiro EB, Bettiker RL, Bogdanov M, Wurtman RJ (1993) Effects of systemic nicotine on serotonin release in rat brain. Brain Res 621:311–318

    Article  PubMed  CAS  Google Scholar 

  • Rosenzweig-Lipson S, Beyer CE, Hughes ZA, Khawaja X, Rajarao SJ, Malberg JE, Rahman Z, Ring RH, Schechter LE (2007) Differentiating antidepressants of the future: efficacy and safety. Pharmacol Ther 113:134–153

    Article  PubMed  CAS  Google Scholar 

  • Segovia G, Del Arco A, Garrido P, de Blas M, Mora F (2008) Environmental enrichment reduces the response to stress of the cholinergic system in the prefrontal cortex during aging. Neurochem Int 52:1198–1203

    Article  PubMed  CAS  Google Scholar 

  • Semba J, Wakuta M (2008) Chronic effect of nicotine on serotonin transporter mRNA in the raphe nucleus of rats: reversal by co-administration of bupropion. Psychiatry Clin Neurosci 62:435–441

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sparks JA, Pauly JR (1999) Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice. Psychopharmacology (Berl) 141:145–153

    Article  CAS  Google Scholar 

  • Suemaru K, Yasuda K, Cui R, Li B, Umeda K, Amano M, Mitsuhashi H, Takeuchi N, Inoue T, Gomita Y, Araki H (2006) Antidepressant-like action of nicotine in forced swimming test and brain serotonin in mice. Physiol Behav 88:545–549

    Article  PubMed  CAS  Google Scholar 

  • Sugimoto Y, Kajiwara Y, Hirano K, Yamada S, Tagawa N, Kobayashi Y, Hotta Y, Yamada J (2008) Mouse strain differences in immobility and sensitivity to fluvoxamine and desipramine in the forced swimming test: analysis of serotonin and noradrenaline transporter binding. Eur J Pharmacol 592:116–122

    Article  PubMed  CAS  Google Scholar 

  • Takahashi H, Takada Y, Nagai N, Urano T, Takada A (1998) Nicotine increases stress-induced serotonin release by stimulating nicotinic acetylcholine receptor in rat striatum. Synapse 28:212–219

    Article  PubMed  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 

  • Tizabi Y, Rezvani AH, Russell LT, Tyler KY, Overstreet DH (2000) Depressive characteristics of FSL rats: involvement of central nicotinic receptors. Pharmacol Biochem Behav 66:73–77

    Article  PubMed  CAS  Google Scholar 

  • Tizabi Y, Getachew B, Rezvani AH, Hauser SR, Overstreet DH (2008) Antidepressant-like effects of nicotine and reduced nicotinic receptor binding in the fawn-hooded rat, an animal model of co-morbid depression and alcoholism. Prog Neuropsychopharmacol Biol Psychiatry. doi:10.1016/j.pnpbp.2008.09.010

    Google Scholar 

  • Toth E, Sershen H, Hashim A, Vizi ES, Lajtha A (1992) Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid. Neurochem Res 17:265–271

    Article  PubMed  CAS  Google Scholar 

  • Troelsen KB, Nielsen EO, Mirza NR (2005) Chronic treatment with duloxetine is necessary for an anxiolytic-like response in the mouse zero maze: the role of the serotonin transporter. Psychopharmacology (Berl) 181:741–750

    Article  CAS  Google Scholar 

  • University of California Breeding Information (2008) http://www.research.uci.edu/tmf/husbandry.htm#pheromone

  • Vazquez-Palacios G, Bonilla-Jaime H, Velazquez-Moctezuma J (2004) Antidepressant-like effects of the acute and chronic administration of nicotine in the rat forced swimming test and its interaction with fluoxetine [correction of flouxetine]. Pharmacol Biochem Behav 78:165–169

    Article  PubMed  CAS  Google Scholar 

  • Vazquez-Palacios G, Bonilla-Jaime H, Velazquez-Moctezuma J (2005) Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine. Prog Neuropsychopharmacol Biol Psychiatry 29:39–46

    Article  PubMed  CAS  Google Scholar 

  • Vieyra-Reyes P, Mineur YS, Picciotto MR, Tunez I, Vidaltamayo R, Drucker-Colin R (2008) Antidepressant-like effects of nicotine and transcranial magnetic stimulation in the olfactory bulbectomy rat model of depression. Brain Res Bull 77:13–18

    Article  PubMed  CAS  Google Scholar 

  • Xu Z, Seidler FJ, Ali SF, Slikker W Jr, Slotkin TA (2001) Fetal and adolescent nicotine administration: effects on CNS serotonergic systems. Brain Res 914:166–178

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Many thanks Mrs. Kathrine S. Hansen and Mrs. Ulla Borberg in the Department of Pharmacodynamics for skilful technical assistance.

Author information

Authors and Affiliations

  1. Department of Affective Disorders, NeuroSearch A/S, 93 Pederstrupvej, 2750, Ballerup, Denmark

    Jesper T. Andreasen & John P. Redrobe

  2. Department of Pharmacodynamics, NeuroSearch A/S, 93 Pederstrupvej, 2750, Ballerup, Denmark

    Elsebet Ø. Nielsen

Authors
  1. Jesper T. Andreasen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elsebet Ø. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John P. Redrobe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jesper T. Andreasen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Andreasen, J.T., Nielsen, E.Ø. & Redrobe, J.P. Chronic oral nicotine increases brain [3H]epibatidine binding and responsiveness to antidepressant drugs, but not nicotine, in the mouse forced swim test. Psychopharmacology 205, 517–528 (2009). https://doi.org/10.1007/s00213-009-1560-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1560-1

Keywords

Search

Navigation