Skip to main content

Advertisement

SpringerLink
Log in

Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment

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

Abstract

Rationale

Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT1B receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial.

Objectives

The aim of this study was to evaluate the effect of venlafaxine (10 mg kg−1 day−1, p.o.) after 21 days of treatment on the density of 5-HT1B receptors and their functionality in rat brain.

Methods

Effects of chronic venlafaxine were evaluated at different levels of 5-HT1B receptor by using receptor autoradiography, [35S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT1B agonist.

Results

Our results show that venlafaxine induced an increase in sensitivity of 5-HT1B receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density.

Conclusions

These results demonstrate that adaptive changes on 5-HT1B receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.

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

Similar content being viewed by others

Abbreviations

5-HT:

5-Hydroxytryptamine serotonin

NSRI:

Serotonin and noradrenaline reuptake inhibitor

SSRI:

Selective serotonin reuptake inhibitor

HPA:

Hypothalamic–pituitary–adrenocortical

References

  • Adell A, Castro E, Celada P, Bortolozzi A, Pazos A, Artigas F (2005) Strategies for producing faster acting antidepressants. Drug Discov Today 10:578–585. doi:10.1016/S1359-6446(05)03398-2

    Article  PubMed  CAS  Google Scholar 

  • Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12. doi:10.1677/joe.0.1600001

    Article  PubMed  CAS  Google Scholar 

  • Artaiz I, Zazpe A, Innerarity A, Del Olmo E, Diaz A, Ruiz-Ortega JA, Castro E, Pena R, Labeaga L, Pazos A, Orjales A (2005) Preclinical pharmacology of F98214-TA, a novel potent serotonin and noradrenaline uptake inhibitor with antidepressant and anxiolytic properties. Psychopharmacology (Berl) 182:400–413. doi:10.1007/s00213-005-0087-3

    Article  PubMed  CAS  Google Scholar 

  • Auerbach SB, Hjorth S (1995) Effect of chronic administration of the selective serotonin (5-HT) uptake inhibitor citalopram on extracellular 5-HT and apparent autoreceptor sensitivity in rat forebrain in vivo. Naunyn Schmiedeberg´s Arch Pharmacol 352:597–606. doi:10.1007/BF00171317

    CAS  Google Scholar 

  • Barden N, Reul JM, Holsboer F (1995) Do antidepressants stabilize mood through actions on the hypothalamic–pituitary–adrenocortical system? Trends Neurosci 18:6–11. doi:10.1016/0166-2236(95)93942-Q

    Article  PubMed  CAS  Google Scholar 

  • Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N (2009) The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis. Eur Arch Psychiatry Clin Neurosci 259:172–185. doi:10.1007/s00406-008-0849-0

    Article  PubMed  Google Scholar 

  • Béïque JC, Lavoie N, de Montigny C, Debonnel G (1998) Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters. Eur J Pharmacol 349:129–132. doi:10.1016/S0014-2999(98)00241-6

    Article  PubMed  Google Scholar 

  • Béïque JC, de Montigny C, Blier P, Debonnel G (2000a) Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: I. In vivo electrophysiological studies in the rat. Neuropharmacology 39:1800–1812. doi:10.1016/S0028-3908(00)00017-4

    Article  PubMed  Google Scholar 

  • Béïque JC, de Montigny C, Blier P, Debonnel G (2000b) Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat. Neuropharmacology 39:1813–1822. doi:10.1016/S0028-3908(00)00018-6

    Article  PubMed  Google Scholar 

  • Blier P, Chaput Y, de Montigny C (1988) Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain. Naunyn Schmiedeberg´s Arch Pharmacol 337:246–254. doi:10.1007/BF00168834

    CAS  Google Scholar 

  • Bolaños-Jiménez F, Manhães de Castro R, Fillion G (1994) Effect of chronic antidepressant treatment on 5-HT1B presynaptic heteroreceptors inhibiting acetylcholine release. Neuropharmacology 33:77–81. doi:10.1016/0028-3908(94)90099-X

    Article  PubMed  Google Scholar 

  • Boschert U, Amaram DA, Segu L, Hen R (1994) The mouse 5-hydroxytryptamine1B receptor is localized predominantly on axon terminals. Neuroscience 58:167–182. doi:10.1016/0306-4522(94)90164-3

    Article  PubMed  CAS  Google Scholar 

  • Bosker FJ, van Esseveldt KE, Klompmakers AA, Westenberg HG (1995) Chronic treatment with fluvoxamine by osmotic minipumps fails to induce persistent functional changes in central 5-HT1A and 5-HT1B receptors, as measured by in vivo microdialysis in dorsal hippocampus of conscious rats. Psychopharmacology (Berl) 117:358–363. doi:10.1007/BF02246110

    Article  CAS  Google Scholar 

  • Bramley JR, Sollars PJ, Pickard GE, Dudek FE (2005) 5-HT1B receptor-mediated presynaptic inhibition of GABA release in the suprachiasmatic nucleus. J Neurophysiol 93:3157–3164. doi:10.1152/jn.00770.2004

    Article  PubMed  CAS  Google Scholar 

  • Bruinvels AT, Palacios JM, Hoyer D (1993) Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain. Naunyn Schmiedeberg´s Arch Pharmacol 347:569–582. doi:10.1007/BF00166939

    Article  CAS  Google Scholar 

  • Castro ME, Díaz A, del Olmo E, Pazos A (2003) Chronic fluoxetine induces opposite changes in G protein coupling at pre and postsynaptic 5-HT1A receptors in rat brain. Neuropharmacology 44:903–101. doi:10.1016/S0028-3908(02)00340-4

    Article  Google Scholar 

  • Castro E, Díaz A, Rodríguez-Gaztelumendi A, del Olmo E, Pazos A (2008) WAY100635 prevents the changes induced by fluoxetine upon the 5-HT1A receptor functionality. Neuropharmacology 55:1391–1396. doi:10.1016/j.neuropharm.2008. 08.038

    Article  PubMed  CAS  Google Scholar 

  • Chaput Y, de Montigny C, Blier P (1986) Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: electrophysiological studies in the rat brain. Naunyn-Schmiedeberg´s Arch Pharmacol 333:342–348. doi:10.1007/BF00500007

    Article  CAS  Google Scholar 

  • Chenu F, David DJ, Leroux-Nicollet I, Le Maitre E, Gardier AM, Bourin M (2008) Serotonin1B heteroreceptor activation induces an antidepressant-like effect in mice with an alteration of the serotonergic system. J Psychiatry Neurosci 33:541–550

    PubMed  Google Scholar 

  • Clark MS, Neumaier JF (2001) The 5-HT1B receptor: behavioral implications. Psychopharmacol Bull 35:170–185

    PubMed  CAS  Google Scholar 

  • Coppen A (1967) The biochemistry of affective disorders. Br J Psychiatry 113:1237–1264. doi:10.1192/bjp.113.504.1237

    Article  PubMed  CAS  Google Scholar 

  • Doménech T, Beleta J, Palacios JM (1997) Characterization of human serotonin 1D and 1B receptors using [3H]-GR-125743, a novel radiolabelled serotonin 5HT1D/1B receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol 356:328–334. doi:10.1007/PL00005058

    Article  PubMed  Google Scholar 

  • Edwards E, Harkins K, Wright G, Henn FA (1991) 5-HT1B receptors in an animal model of depression. Neuropharmacology 30:101–105

    Article  PubMed  CAS  Google Scholar 

  • El Mansari M, Bouchard C, Blier P (1995) Alteration of serotonin release in the guinea pig orbito-frontal cortex by selective serotonin reuptake inhibitors. Relevance to treatment of obsessive–compulsive disorder. Neuropsychopharmacology 13:117–127. doi:10.1016/0893-133×(95)00045-F

    Article  PubMed  CAS  Google Scholar 

  • Fink KB, Gothert M (2007) 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev 59:360–417. doi:10.1124/pr.59.07103

    PubMed  CAS  Google Scholar 

  • Gardier AM, Guiard BP, Guilloux JP, Repérant C, Coudoré F, David DJ (2009) Interest of using genetically manipulated mice as models of depression to evaluate antidepressant drugs activity: a review. Fundam Clin Pharmacol 23:23–42. doi:10.1111/j.1472-8206.2008.00640.x

    Article  PubMed  CAS  Google Scholar 

  • Gobbi M, Crespi D, Foddi MC, Fracasso C, Mancini L, Parotti L, Mennini T (1997) Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats. Naunyn Schmiedeberg´s Arch Pharmacol 356:22–28. doi:10.1007/PL00005024

    Article  CAS  Google Scholar 

  • Gobert A, Dekeyne A, Millan MJ (2000) The ability of WAY100,635 to potentiate the neurochemical and functional actions of fluoxetine is enhanced by co-administration of SB224,289, but not BRL15572. Neuropharmacology 39:1608–1616. doi:10.1016/S0028-3908(99)00229-4

    Article  PubMed  CAS  Google Scholar 

  • Gur E, Dremencov E, Van de Kar LD, Lerer B, Newman ME (2002) Effects of chronically administered venlafaxine on 5-HT receptor activity in rat hippocampus and hypothalamus. Eur J Pharmacol 436:57–65. doi:10.1016/S0014-2999(01)01578-3

    Article  PubMed  CAS  Google Scholar 

  • Hensler JG (2002) Differential regulation of 5-HT1A receptor-G protein interactions in brain following chronic antidepressant administration. Neuropsychopharmacology 26:565–573. doi:10.1016/S0893-133X(01)00395-5

    Article  PubMed  CAS  Google Scholar 

  • Hervas I, Queiroz CM, Adell A, Artigas F (2000) Role of uptake inhibition and autoreceptor activation in the control of 5-HT release in the frontal cortex and dorsal hippocampus of the rat. Br J Pharmacol 130:160–166. doi:10.1038/sj.bjp.0703297

    Article  PubMed  CAS  Google Scholar 

  • Inder WJ, Prickett TC, Mulder RT, Donald RA, Joyce PR (2001) Reduction in basal afternoon plasma ACTH during early treatment of depression with fluoxetine. Psychopharmacology 156:73–78. doi:10.1007/s002130100737

    Article  PubMed  CAS  Google Scholar 

  • Jolimay N, Franck L, Langlois X, Hamon M, Darmon M (2000) Dominant role of the cytosolic C-terminal domain of the rat 5-HT1B receptor in axonal–apical targeting. J Neurosci 20:9111–9118

    PubMed  CAS  Google Scholar 

  • Le Poul E, Boni C, Hanoun N, Laporte AM, Laaris N, Chauveau J, Hamon M, Lanfumey L (2000) Differential adaptation of brain 5-HT1A and 5-HT1B receptors and 5-HT transporter in rats treated chronically with fluoxetine. Neuropharmacology 39:110–122. doi:10.1016/S0028-3908(99)00088-X

    Article  PubMed  Google Scholar 

  • Macor JE, Burkhart CA, Heym JH, Ives JL, Lebel LA, Newman ME, Nielsen JA, Ryan K, Schulz DW, Torgersen LK (1990) 3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one: a potent and selective serotonin (5-HT1B) agonist and rotationally restricted phenolic analogue of 5-methoxy-3-(1,2,5,6-tetrahydropyrid-4-yl)indole. J Med Chem 33:2087–2093. doi:10.1002/chin.199104230

    Article  PubMed  CAS  Google Scholar 

  • Montero D, De Felipe MC, Del Rio J (1991) Acute or chronic antidepressants do not modify [125I]cyanopindolol binding to 5-HT1B receptors in rat brain. Eur J Pharmacol 196:327–329. doi:10.1016/0014-2999(91)90448-Y

    Article  PubMed  CAS  Google Scholar 

  • Moret C, Briley M (2000) The possible role of 5-HT(1B/D) receptors in psychiatric disorders and their potential as a target for therapy. Eur J Pharmacol 404:1–12. doi:10.1016/S0014-2999(00)00581-1

    Article  PubMed  CAS  Google Scholar 

  • Mostany R, Pazos A, Castro ME (2005) Autoradiographic characterisation of [35S]GTPgammaS binding stimulation mediated by 5-HT1B receptor in postmortem human brain. Neuropharmacology 48:25–33. doi:10.1016/j.neuropharm.2004.08.013

    Article  PubMed  CAS  Google Scholar 

  • Murrough JW, Henry S, Hu J, Gallezot JD, Planeta-Wilson B, Neumaier JF, Neumeister A (2011) Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder. Psychopharmacology (Berl) 213:547–553. doi:10.1007/s00213-010-1881-0

    Article  CAS  Google Scholar 

  • Neumaier JF, Root DC, Hamblin MW (1996) Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus. Neuropsychopharmacology 15:515–522. doi:10.1016/S0893-133×(96)00095-4

    Article  PubMed  CAS  Google Scholar 

  • Newman ME, Gur E, Dremencov E, Garcia F, Lerer B, Van de Kar LD (2000) Chronic clomipramine alters presynaptic 5-HT(1B) and postsynaptic 5-HT(1A) receptor sensitivity in rat hypothalamus and hippocampus, respectively. Neuropharmacology 39:2309–2317. doi:10.1016/S0028-3908(00)00077-0

    Article  PubMed  CAS  Google Scholar 

  • Newman ME, Shalom G, Ran A, Gur E, Van de Kar LD (2004) Chronic fluoxetine-induced desensitization of 5-HT1A and 5-HT1B autoreceptors: regional differences and effects of WAY-100635. Eur J Pharmacol 486:25–30. doi:10.1016/j.ejphar.2003. 12.008

    Article  PubMed  CAS  Google Scholar 

  • Pariante CM, Lightman S (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci 31:464–468. doi:10.1016/j.tins.2008.06.006

    Article  PubMed  CAS  Google Scholar 

  • Pilar-Cuéllar F, Vidal R, Pazos A (2012) Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, β-catenin and antidepressant-like effects. Br J Pharmacol 165:1046–1057. doi:10.1111/j.1476-5381.2011.01516.x

    Article  PubMed  Google Scholar 

  • Ruf BM, Bhagwagar Z (2009) The 5-HT1B receptor: a novel target for the pathophysiology of depression. Curr Drug Targets 10:1118–1138

    Article  PubMed  CAS  Google Scholar 

  • Sari Y (2004) Serotonin1B receptors: from protein to physiological function and behaviour. Neurosci Biobehav Rev 28:565–582. doi:10.1016/j.neubiorev.2004.08.008

    Article  PubMed  CAS  Google Scholar 

  • Schechter LE, Ring RH, Beyer CE, Hughes ZA, Khawaja X, Malberg JE (2005) Innovative approaches for the development of antidepressant drugs: current and future strategies. NeuroRx 2:590–611. doi:10.1602/neurorx.2.4.590

    Article  PubMed  Google Scholar 

  • Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122:509–522

    PubMed  CAS  Google Scholar 

  • Schoeffter P, Hoyer D (1989) 5-Hydroxytryptamine 5-HT1B and 5-HT1D receptors mediating inhibition of adenylate cyclase activity. Pharmacological comparison with special reference to the effects of yohimbine, rauwolscine and some β-adrenoceptor antagonists. Naunyn Schmiedeberg’s Arch Pharmacol 340:285–292

    CAS  Google Scholar 

  • Stenfors C, Ross SB (2002) Failure to detect in vivo inverse agonism of the 5-HT(1B) receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs. Naunyn Schmiedeberg´s Arch Pharmacol 365:462–467. doi:10.1007/s00210-002-0564-8

    Article  CAS  Google Scholar 

  • Varnas K, Hall H, Bonaventure P, Sedvall G (2001) Autoradiographic mapping of 5-HT(1B) and 5-HT(1D) receptors in the post mortem human brain using [3H]GR125743. Brain Res 915:47–57. doi:10.1016/S0006-8993(01)02823-2

    Article  PubMed  CAS  Google Scholar 

  • Vidal R, Valdizán EM, Mostany R, Pazos A, Castro E (2009) Long-term treatment with fluoxetine induces desensitization of 5-HT4 receptor-dependent signalling and functionality in rat brain. J Neurochem 110:1120–1127. doi:10.1111/j.1471-4159.2009.06210.x

    Article  PubMed  CAS  Google Scholar 

  • Vidal R, Valdizan EM, Vilaró MT, Pazos A, Castro E (2010) Reduced 5-HT4 signal transduction by long term venlafaxine treatment. Br J Pharmacol 161:695–706. doi:10.1111/j.1476-5381.2010.00903.x

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Alicia Martín, María Josefa Castillo and Lourdes Lanza for their excellent technical assistance. This research was supported by Ministry of Science, SAF04-00941, SAF07-61862, Fundación Alicia Koplowitz, Fundación de Investigación Médica Mutua Madrileña, Instituto de Salud Carlos III and University of Cantabria-FAES research contract.

Conflict of interest

The authors (RV, AD, AP and EC) declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the last 2 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Author information

Authors and Affiliations

  1. Instituto de Biomedicina y Biotecnología (IBBTEC) (UC-CSIC-SODERCAN), Santander, Cantabria, Spain

    R. Vidal, A. Diaz, A. Pazos & E. Castro

  2. Departamento de Fisiología y Farmacología, School of Medicine, Universidad de Cantabria, Cardenal Herrera Oria s/n, 39011, Santander, Spain

    R. Vidal, A. Diaz, A. Pazos & E. Castro

  3. CIBERSAM, Ciber de Salud Mental, Instituto Carlos III, Madrid, Spain

    R. Vidal, A. Diaz, A. Pazos & E. Castro

Authors
  1. R. Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Diaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Pazos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Castro.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vidal, R., Diaz, A., Pazos, A. et al. Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment. Psychopharmacology 229, 177–185 (2013). https://doi.org/10.1007/s00213-013-3104-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3104-y

Keywords

Search

Navigation