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Effects of chronic treatment with citalopram on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain regions

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Abstract

Rationale

There is growing interest in investigating the mechanisms of action of selective serotonin reuptake inhibitors (SSRIs), beyond their association with the serotonergic system, due to their wide therapeutic potential for disorders including depression, pain and addiction.

Objective

The aim of this study was to investigate whether chronic treatment with the SSRI, citalopram, alters the functional coupling of Gi/o-associated cannabinoid type 1 (CB1) and μ-opioid receptors in selected areas of rat brain implicated in psychiatric disorders and pain.

Methods

Using an autoradiographic approach, the effects of the cannabinoid receptor agonist, HU210 (in the presence or absence of the CB1 receptor antagonist AM251), or the μ-opioid receptor agonist, [d-Ala2,N–Me–Phe4,Gly5-ol]-enkephalin (DAMGO; in the presence or absence of the μ-opioid receptor antagonist d-Phe–Cys–Tyr-d-Trp–Orn–Thr–Pen–Thr–NH2), on [35S]GTPγS binding in discrete brain regions of citalopram-treated (10 mg kg−1 day−1 for 14 days by subcutaneous minipump) and control rats were investigated.

Results

The HU210-induced increase in [35S]GTPγS binding observed in the hypothalamic paraventricular nucleus of control rats was abolished after chronic treatment with citalopram. Reduced response to HU210 in rats receiving chronic treatment with citalopram was also observed in the hippocampus and medial geniculate nucleus. Citalopram had no significant effect on DAMGO-induced [35S]GTPγS binding in the brain regions investigated, with the exception of the medial geniculate nucleus where a modest impairment was observed.

Conclusions

These data provide evidence for reduced cannabinoid receptor-mediated G-protein coupling in the hypothalamus, hippocampus and medial geniculate nucleus of rats chronically treated with citalopram, effects which may, in part, underlie the mechanism of action of SSRIs.

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References

  • Bezchlibnyk-Butler K, Aleksic I, Kennedy SH (2000) Citalopram—a review of pharmacological and clinical effects. J Psychiatry Neurosci 25:241–253

    PubMed  CAS  Google Scholar 

  • Burnett FE, Scott LV, Weaver MG, Medbak SH, Dinan TG (1999) The effect of naloxone on adrenocorticotrophin and cortisol release: evidence for a reduced response in depression. J Affect Disord 53:263–268

    Article  PubMed  CAS  Google Scholar 

  • Ceglia I, Acconcia S, Fracasso C, Colovic M, Caccia S, Invernizzi RW (2004) Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors. Br J Pharmacol 142:469–478

    Article  PubMed  CAS  Google Scholar 

  • Churruca I, Zumalabe JM, Macarulla MT (2005) Fluoxetine alters mu opioid receptor expression in obese Zucker rat extrahypothalamic regions. Int J Neurosci 116:289–298

    Article  CAS  Google Scholar 

  • Cornelius JR, Bukstein OG, Birmaher B, Salloum IM, Lynch K, Pollock NK, Gershon S, Clark D (2001) Fluoxetine in adolescents with major depression and an alcohol use disorder: an open label trial. Addict Behav 26:735–739

    Article  PubMed  CAS  Google Scholar 

  • Devlin MG, Christopoulos A (2002) Modulation of cannabinoid agonist binding by 5-HT in the rat cerebellum. J Neurochem 80:1095–1102

    Article  PubMed  CAS  Google Scholar 

  • Dinan T (1994) Glucocorticoids and the genesis of depressive illness. A psychobiological model. Br J Psychiatry 164:365–371

    Article  PubMed  CAS  Google Scholar 

  • Doraiswamy PM, Varia I, Hellegers C, Wagner HR, Clary GL, Beyer JL, Newby LK, O’Connor JF, Beebe KL, O’Connor C, Krishnan KR (2006) A randomized controlled trial of paroxetine for non-cardiac chest pain. Psychopharmacol Bull 39:15–24

    PubMed  Google Scholar 

  • Drew LJ, Harris J, Millns JP, Kendall DA, Chapman V (2000) Activation of spinal cannabinoid 1 receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTPγS binding in the dorsal horn of the spinal cord of noninflamed and inflamed rats. Eur J Neurosci 12:2079–2086

    Article  PubMed  CAS  Google Scholar 

  • Duman ED, Kesim M, Kadioglu M, Yaris E, Kalyoncu NI, Erciyes N (2004) Possible involvement of opioidergic and serotonergic mechanisms in antinociceptive effect of paroxetine in acute pain. J Pharmacol Sci 94:161–165

    Article  PubMed  CAS  Google Scholar 

  • Emrich HM, Leweke FM, Schneider U (1997) Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol Biochem Behav 56:803–807

    Article  PubMed  CAS  Google Scholar 

  • Finn DP, Chapman V (2004) Cannabinoids as analgesic agents: evidence from in vivo studies. Curr Neuropharmacol 2:75–89

    Article  CAS  Google Scholar 

  • Gandarias JM, Echevarria E, Acebes I, Abecia L, Casis O, Casis L (1999) Effects of fluoxetine administration on mu-opioid receptor immunostaining in the rat forebrain. Brain Res 817:236–240

    Article  PubMed  Google Scholar 

  • Gatch MB, Negus SS, Mello K (1998) Antinociceptive effects of monoamine re-inhibitor administration alone or in combination with mu opioid agonist on rhesus monkeys. Psychopharmacology 135:99–106

    Article  PubMed  CAS  Google Scholar 

  • Herkenhem M, Lynn AB, Little MD, Johnston MR, Melvin LS, De Costa BR, Rice KC (1990) Cannabinoid receptor localisation in brain. Proc Natl Acad Sci USA 87:1932–1936

    Article  Google Scholar 

  • Herman H, Lutz B (2005) Coexpression of the cannabinoid receptor type 1 with the corticotrophic-releasing hormone receptor type 1 in distinct regions of the mouse forebrain. Neurosci Lett 375:13–18

    Article  CAS  Google Scholar 

  • Hesketh S, Jessop DS, Hogg S, Harbuz MS (2005) Differential actions of acute and chronic citalopram on the rodent hypothalamic–pituitary–adrenal axis response to acute restraint stress. J Endocrinol 185:373–382

    Article  PubMed  CAS  Google Scholar 

  • Hill MN, Ho WS, Sinopoli KJ, Viau V, Hillard CJ, Gorzalka BB (2006) Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic–pituitary–adrenal axis. Neuropsychopharmacology 31:2591–2599

    Article  PubMed  CAS  Google Scholar 

  • Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB, Mann JJ, Arango V (2004) Up-regulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry 9:184–190

    Article  PubMed  CAS  Google Scholar 

  • Jensen JB, Jessop DS, Harbuz MS, Mork A, Sanchez C, Mikkelson JD (1999) Acute and long-term treatments with selective serotonin reuptake inhibitor citalopram modulates the HPA axis activity at different levels in male rats. J Neuroendocrinol 11:465–471

    Article  PubMed  CAS  Google Scholar 

  • Jensen JB, Mork A, Mikkelson JD (2001) Chronic antidepressant treatments decrease pro-opiomelanocortin mRNA expression in the pituitary gland: effects of acute stress and 5HT1A receptor activation. J Neuroendocrinol 13:887–893

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen H, Knigge U, Kjaer A, Moller M, Warburg J (2002) Serotonergic stimulation of corticotrophin-releasing hormone and pro-opiomelanocortin gene expression. J Neuroendocrinol 14:788–795

    Article  PubMed  CAS  Google Scholar 

  • Jung AC, Staiger T, Sullivan M (1997) The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med 12:384–389

    Article  PubMed  CAS  Google Scholar 

  • Kelai S, Hanoun N, Aufrere G, Beauge F, Hamon M, Lanfumey L (2006) Cannabinoid–serotonin interactions in alcohol-preferring vs. alcohol-avoiding mice. J Neurochem 99:308–320

    Article  PubMed  CAS  Google Scholar 

  • Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1988) Anatomy of CNS opioid receptors. Trends Neurosci 11:308–314

    Article  PubMed  CAS  Google Scholar 

  • Manzanares J, Uriguen L, Rubio G, Palmo T (2004) Role of endocannabinoid system in mental diseases. Neurotox Res 6:213–224

    Article  PubMed  Google Scholar 

  • Murphy DL, Andrews AM, Wichems CH, Li Q, Tohda M, Greenberg B (1998) Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter system, and consequent implications for understanding the actions of serotonergic drugs. J Clin Psychiatry 59(Suppl 15):4–12

    PubMed  CAS  Google Scholar 

  • Nemmani KV, Mogil JS (2003) Serotonin–GABA interactions in the modulation of mu- and kappa-opioid analgesia. Neuropharmacology 44:304–310

    Article  PubMed  CAS  Google Scholar 

  • Nozaki C, Kamei J (2006) Possible involvement of opioidergic systems in the anti-nociceptive effect of selective serotonin re-uptake inhibitors in sciatic nerve-injured mice. Eur J Pharmacol 552:99–104

    Article  PubMed  CAS  Google Scholar 

  • Oliva J, Uriguen L, Perez-Rial S, Manzanares J (2005) Time course of opioid and cannabinoid gene transcription alterations induced by repeated administration with fluoxetine in the rat brain. Neuropharmacology 49:618–626

    PubMed  CAS  Google Scholar 

  • Pälvimäki EP, Kuoppamäki M, Syvälahti E, Hietala J (1999) Differential effects of fluoxetine and citalopram treatments on serotonin 5-HT2C receptor occupancy in rat brain. Int J Neuropsychopharmacol 2:95–99

    Article  PubMed  Google Scholar 

  • Paterson SJ, Robson LE, Kosterlitz HW (1988) Classification of opioid receptors. Br Med Bull 39:31–36

    Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, New York

    Google Scholar 

  • Raap DK, Van der Kar LD (1999) Selective serotonin reuptake inhibitors and neuroendocrine function. Life Sci 65:1217–1235

    Article  PubMed  CAS  Google Scholar 

  • Ryberg E, Larsson N, Sjörgen S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152:1092–1101

    Article  PubMed  CAS  Google Scholar 

  • Schreiber S, Backer MM, Yanai J, Pick CG (1996) The antinociceptive effect of fluvoxamine. Eur Neuropsychopharmacol 6:281–284

    Article  PubMed  CAS  Google Scholar 

  • Sim LJ, Selley DE, Childers SR (1995) In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5′-[gamma-[35S]thio]-triphosphate binding. Proc Natl Acad Sci USA 92:7242–7246

    Article  PubMed  CAS  Google Scholar 

  • Singh UP, Jain NK, Kulkami SK (2001) The antinociceptive effect of fluoxetine: a SSRI. Brain Res 915:218–226

    Article  PubMed  CAS  Google Scholar 

  • Slattery DA, Hudson AL, Nutt DJ (2004) The evolution of antidepressant mechanisms. Fundam Clin Pharmacol 18:1–21

    Article  PubMed  CAS  Google Scholar 

  • Takamatsu Y, Yamamoto H, Ogai Y, Hagino Y, Markou A, Ikeda K (2006) Fluoxetine as a potential pharmacotherapy for methamphetamine dependence: studies in mice. Ann N Y Acad Sci 1074:295–302

    Article  PubMed  CAS  Google Scholar 

  • Tasker J (2004) Endogenous cannabinoids take the edge off neuroendocrine responses to stress. Endocrinology 145:5429–5430

    Article  PubMed  CAS  Google Scholar 

  • Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos GG (2003) The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol 138:544–553

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Science Foundation Ireland and by a Research Visit Grant to SH from the British Society for Neuroendocrinology. We are grateful to Lundbeck plc, Copenhagen, for their kind gift of citalopram.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, National Centre for Biomedical Engineering Science Neuroscience Cluster, Center for Pain Research, National University of Ireland, Galway, University Road, Galway, Ireland

    Adrian K. Brennan & David P. Finn

  2. Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK

    Shirley A. Hesketh & David S. Jessop

Authors
  1. Shirley A. Hesketh
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  2. Adrian K. Brennan
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  3. David S. Jessop
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  4. David P. Finn
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Corresponding author

Correspondence to David P. Finn.

Additional information

Hesketh and Brennan have contributed equally to this work.

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Hesketh, S.A., Brennan, A.K., Jessop, D.S. et al. Effects of chronic treatment with citalopram on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain regions. Psychopharmacology 198, 29–36 (2008). https://doi.org/10.1007/s00213-007-1033-3

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  • DOI: https://doi.org/10.1007/s00213-007-1033-3

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