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Chronic therapy with citalopram decreases regional cerebral glucose utilization in OBX, and not sham-operated, rats: an autoradiographic study

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Abstract

Rationale

Chronic treatment with the selective serotonin reuptake inhibitor, citalopram, normalizes several behavioral and neurochemical abnormalities in the olfactory bulbectomized (OBX) rat model of depression.

Objective

To assess the changes in regional cerebral glucose utilization (rCGU) following chronic treatment with citalopram in OBX and sham-operated rats.

Methods

Male Sprague Dawley rats (160–190 g) were used. Two weeks following the surgeries, the rats were implanted with osmotic minipumps which delivered 10 mg/kg/day of citalopram (the sham-CTP and OBX-CTP groups) or saline (to the sham-SAL and OBX-SAL groups) for 2 weeks. Following the treatment, the rates of rCGU were determined in 43 brain regions using 2-[14C]deoxyglucose (2-[14C]DG) autoradiography.

Results

The general linear model statistical analysis revealed significantly lower rCGU in the OBX-SAL group compared to the sham-SAL group in the medial prefrontal cortex and the median forebrain bundle. The sham-CTP group had significantly lower rCGU relative to the sham-SAL group in the medial prefrontal cortex. The OBX-CTP group had significantly lower rCGU than the OBX-SAL group in the anterior olfactory nucleus, orbitofrontal cortex, frontal cortex, anterior cingulate cortex, visual cortex, and substantia nigra—pars reticulata. The rCGU in the OBX-CTP group was significantly lower than that in the sham-CTP group in the anterior olfactory nucleus, orbitofrontal cortex, visual cortex, and substantia nigra—pars reticulata.

Conclusion

The results imply that chronic citalopram treatment, shown previously to result in behavioral normalization in OBX rats, establishes a new pattern of rCGU, rather than normalizing it to the pattern of the sham-CTP rats.

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Abbreviations

2-[14C]DG:

(2-[14C]deoxyglucose)5-HT (serotonin)

ANOVA:

analysis of variance

MANCOVA:

multivariate analysis of variance

gCGU:

global cerebral glucose utilization

rCGU:

regional cerebral glucose utilization

DA:

dopamine

MAO:

monoamino oxydase

NA:

noradrenaline

OBX:

olfactory bulbectomy

OB:

olfactory bulbs

OF:

open field

PET:

positron emission tomography

SERT:

serotonin transporter

SSRI:

selective serotonin reuptake inhibitor

References

  • 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 Schmiedebergs Arch Pharmacol 352:597–606

    Article  CAS  PubMed  Google Scholar 

  • Bel N, Artigas F (1993) Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 15:243–245

    Article  CAS  PubMed  Google Scholar 

  • Buchsbaum MS, Wu J, Siegel BV, Hackett E, Trenary M, Abel L, Reynolds C (1997) Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry 41:15–22

    Article  CAS  PubMed  Google Scholar 

  • Caldecott-Hazard S, Mazziotta J, Phelps M (1988) Cerebral correlates of depressed behavior in rats, visualized using 14C-2-deoxyglucose autoradiography. J Neurosci 8(6):1951–1961

    CAS  PubMed  Google Scholar 

  • Cooper RM, Thurlow GA (1985) Depression and recovery of metabolic activity in rat visual system after eye removal. Exp Neurol 89(2):322–336

    Article  CAS  PubMed  Google Scholar 

  • Duncan GE, Johnson KB, Breese GR (1993) Topographic patterns of brain activity in response to swim stress: assessment by 2-deoxyglucose uptake and expression of Fos-like immunoreactivity. J Neurosci 13(9):3932–3943

    CAS  PubMed  Google Scholar 

  • Duncan GE, Knapp DJ, Johnson KB, Breese GR (1996) Functional classification of antidepressants based on antagonism of swim stress-induced fos-like immunoreactivity. J Pharmacol Exp Ther 277(2):1076–1089

    CAS  PubMed  Google Scholar 

  • Earley B, Glennon M, Lally M, Leonard BE, Junien JL (1994) Autoradiographic distribution of cholinergic muscarinic receptors and serotonin(2) receptors in olfactory bulbectomized (OB) rats after chronic treatment with mianserin and desipramine. Hum Psychopharmacol 9:397–407

    Article  CAS  Google Scholar 

  • Eidelberg D, Moeller JR, Dhawan V, Sidtis JJ, Ginos JZ, Strother SC, Cedarbaum J, Greene P, Fahn S, Rottenberg DA (1990) The metabolic anatomy of Parkinson's disease: complementary [18F]fluorodeoxyglucose and [18F]fluorodopa positron emission tomographic studies. Mov Disord 5(3):203–213

    Article  CAS  PubMed  Google Scholar 

  • Foster NL, Minoshima S, Johanns J, Little R, Heumann ML, Kuhl DE, Gilman S (2000) PET measures of benzodiazepine receptors in progressive supranuclear palsy. Neurology 54(9):1768–1773

    CAS  PubMed  Google Scholar 

  • Freo U (1996) Cerebral metabolic effects of serotonin drugs and neurotoxins. Life Sci 59:877–891

    Article  CAS  PubMed  Google Scholar 

  • Freo U, Ori C, Dam M, Merico A, Pizzolato G (2000) Effects of acute and chronic treatment with fluoxetine on regional glucose cerebral metabolism in rats: implications for clinical therapies. Brain Res 854:35–41

    Article  CAS  PubMed  Google Scholar 

  • Freo U, Merico A, Ermani M, Ori C (2008) Cerebral metabolic effects of fluoxetine, fluvoxamine, paroxetine and sertraline in the conscious rat. Neurosci Lett. 436(2):148–152

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa S, Watanabe A, Nguyen KQ, Debonnel G, Diksic M (2005) Chronic administration of citalopram in olfactory bulbectomy rats restores brain 5-HT synthesis rates: an autoradiographic study. Psychopharmacology (Berl) 179:781–790

    Article  CAS  Google Scholar 

  • Holthoff VA, Beuthien-Baumann B, Zundorf G, Triemer A, Ludecke S, Winiecki P, Koch R, Fuchtner F, Herholz K (2004) Changes in brain metabolism associated with remission in unipolar major depression. Acta Psychiatr Scand 110:184–194

    Article  CAS  PubMed  Google Scholar 

  • Hyttel J (1994) Pharmacological characterization of selective serotonin reuptake inhibitors (SSRIs). Int Clin Psychopharmacol 9(Suppl 1):19–26

    Article  PubMed  Google Scholar 

  • Invernizzi R, Bramante M, Samanin R (1994) Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors. Eur J Pharmacol 260:243–246

    Article  CAS  PubMed  Google Scholar 

  • Jueptner M, Weiller C (1995) Review: does measurement of regional cerebral blood flow reflect synaptic activity? Implications for PET and fMRI. Neuroimage 2:148–156

    Article  CAS  PubMed  Google Scholar 

  • Kadekaro M, Crane AM, Sokoloff L (1985) Differential effects of electrical stimulation of sciatic nerve on metabolic activity in spinal cord and dorsal root ganglion in the rat. Proc Natl Acad Sci USA 82:6010–6013

    Article  CAS  PubMed  Google Scholar 

  • Kelly JP, Wrynn AS, Leonard BE (1997) The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther 74:299–316

    Article  CAS  PubMed  Google Scholar 

  • Kennedy SH, Javanmard M, Vaccarino FJ (1997) A review of functional neuroimaging in mood disorders: positron emission tomography and depression. Can J Psychiatry 42:467–475

    CAS  PubMed  Google Scholar 

  • Kennedy SH, Konarski JZ, Segal ZV, Lau MA, Bieling PJ, McIntyre RS, Mayberg HS (2007) Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatry 164(5):778–788

    Article  PubMed  Google Scholar 

  • Kuipers SD, Trentani A, Westenbroek C, Bramham CR, Korf J, Kema IP, Ter Horst GJ, Den Boer JA (2006) Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment. Neuropharmacology 50(4):428–440

    Article  CAS  PubMed  Google Scholar 

  • Lerer B, Gelfin Y, Gorfine M, Allolio B, Lesch KP, Newman ME (1999) 5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: blunted temperature and hormone responses to ipsapirone challenge. Neuropsychopharmacology 20:628–639

    Article  CAS  PubMed  Google Scholar 

  • Lino-de-Oliveira C, Sales AJ, Del Bel EA, Silveira MC, Guimarães FS (2001) Effects of acute and chronic fluoxetine treatments on restraint stress-induced Fos expression. Brain Res Bull 55(6):747–754

    Article  CAS  PubMed  Google Scholar 

  • Liotti M, Mayberg HS, McGinnis S, Brannan SL, Jerabek P (2002) Unmasking disease-specific cerebral blood flow abnormalities: mood challenge in patients with remitted unipolar depression. Am J Psychiatry 159:1830–1840

    Article  PubMed  Google Scholar 

  • Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, Lambas-Senas L, Wiborg O, Haddjeri N, Pineyro G, Sadikot AF, Debonnel G (2007) Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55:712–725

    Article  CAS  PubMed  Google Scholar 

  • Marsteller DA, Barbarich-Marsteller NC, Patel VD, Dewey SL (2007) Brain metabolic changes following 4-week citalopram infusion: increased 18FDG uptake and gamma-amino butyric acid levels. Synapse 61:877–881

    Article  CAS  PubMed  Google Scholar 

  • Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA (2000) Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–843

    Article  CAS  PubMed  Google Scholar 

  • Moncrieff J, Cohen D (2005) Rethinking models of psychotropic drug action. Psychother Psychosom 74:145–153

    Article  PubMed  Google Scholar 

  • Moncrieff J, Cohen D (2006) Do antidepressants cure or create abnormal brain states? PLoS Med 3:e240

    Article  PubMed  CAS  Google Scholar 

  • Morgan JI, Curran T (1990) Inducible proto-oncogenes of the nervous system: their contribution to transcription factors and neuroplasticity. Prog Brain Res 86:287–294

    Article  CAS  PubMed  Google Scholar 

  • Morilak DA, Frazer A (2004) Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int J Neuropsychopharmacol 7:193–218

    Article  CAS  PubMed  Google Scholar 

  • Nagano-Saito A, Kato T, Arahata Y, Washimi Y, Nakamura A, Abe Y, Yamada T, Iwai K, Hatano K, Kawasumi Y, Kachi T, Dagher A, Ito K (2004) Cognitive- and motor-related regions in Parkinson's disease: FDOPA and FDG PET studies. Neuroimage 22(2):553–561

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, Sydney

    Google Scholar 

  • Roche M, Harkin A, Kelly JP (2007) Chronic fluoxetine treatment attenuates stressor-induced changes in temperature, heart rate, and neuronal activation in the olfactory bulbectomized rat. Neuropsychopharmacology 32:1312–1320

    Article  CAS  PubMed  Google Scholar 

  • Sato H, Skelin I, Debonnel G, Diksic M (2008) Chronic buspirone treatment normalizes open field behavior in olfactory bulbectomized rats: assessment with a quantitative autoradiographic evaluation of the 5-HT1A binding sites. Brain Res Bull. 75(5):545–555

    Article  CAS  PubMed  Google Scholar 

  • Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S (2004) Limbic-frontal circuitry in major depression: a path modeling meta-analysis. Neuroimage 22(1):409–418

    Article  CAS  PubMed  Google Scholar 

  • Skelin I, Sato H, Diksic M (2008) Olfactory bulbectomy reduces cerebral glucose utilization: 2-[14C]deoxyglucose autoradiographic study. Brain Res Bull 76:485–492

    Article  CAS  PubMed  Google Scholar 

  • Smith GS, Reynolds CF 3rd, Pollock B, Derbyshire S, Nofzinger E, Dew MA, Houck PR, Milko D, Meltzer CC, Kupfer DJ (2001) Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression. Am J Psychiatry 156(5):683–689

    Google Scholar 

  • Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916

    Article  CAS  PubMed  Google Scholar 

  • Stanic D, Finkelstein DI, Bourke DW, Drago J, Horne MK (2003) Timecourse of striatal re-innervation following lesions of dopaminergic SNpc neurons of the rat. Eur J Neurosci 18(5):1175–1188

    Article  CAS  PubMed  Google Scholar 

  • van der Hart MG, Czéh B, de Biurrun G, Michaelis T, Watanabe T, Natt O, Frahm J, Fuchs E (2002) Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume. Mol Psychiatry 7(9):933–941

    Article  PubMed  CAS  Google Scholar 

  • van Riezen H, Leonard BE (1990) Effects of psychotropic drugs on the behavior and neurochemistry of olfactory bulbectomized rats. Pharmacol Ther 47:21–34

    Article  PubMed  Google Scholar 

  • Veening JG, Coolen LM, Spooren WJ, Joosten H, van Oorschot R, Mos J, Ronken E, Olivier B (1998) Patterns of c-fos expression induced by fluvoxamine are different after acute vs. chronic oral administration. Eur Neuropsychopharmacol 8(3):213–226

    Article  CAS  PubMed  Google Scholar 

  • Videbech P (2000) PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand 101:11–20

    Article  CAS  PubMed  Google Scholar 

  • Watanabe A, Hasegawa S, Nishi K, Nguyen KQ, Diksic M (2006) Chronic buspirone treatment normalizes regional serotonin synthesis in the olfactory bulbectomized rat brain: an autoradiographic study. Brain Res Bull 69(2):101–108

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Grecksch G, Becker A, Frank C, Pilz J, Huether G (1998) Serotonergic hyperinnervation of the frontal cortex in an animal model of depression, the bulbectomized rat. J Neurosci Res 54:109–116

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The research reported here was supported in part by grants from the Croatian Ministry of Science, Education, and Sports (219-1081970-2032) and Medical Research of Canada (MT-13368). The authors wish to thank Ms. Valerie Ann Cherneski for the editorial help.

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Author notes

  1. Hiroki Sato

    Present address: Department of Neurosurgery, University of Yamanashi, 1110 Shimokato Tamaho-cho, Nakakoma-gun, Yamanashi, 409-3898, Japan

Authors and Affiliations

  1. Cone Neurological Research laboratory, Department of Neurology and Neurosurgery, McGill University, 3801 University St., Montreal, QC, H3A2B4, Canada

    Ivan Skelin, Hiroki Sato, Tomislav Kovačević & Mirko Diksic

  2. Department of Pathophysiology, University of Split School of Medicine, Split, Croatia

    Ivan Skelin

  3. School of Medicine, J.J. Strossmayer University, Osijek, Croatia

    Mirko Diksic

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  1. Ivan Skelin
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Correspondence to Mirko Diksic.

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Skelin, I., Sato, H., Kovačević, T. et al. Chronic therapy with citalopram decreases regional cerebral glucose utilization in OBX, and not sham-operated, rats: an autoradiographic study. Psychopharmacology 207, 315–323 (2009). https://doi.org/10.1007/s00213-009-1659-4

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