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Pharmacological Interventions That Have the Potential to Alter Neurotransmitter Levels in the Human Brain

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PET and SPECT in Psychiatry

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Abstract

Monitoring of neuronal activity in vivo is one of the greatest challenges in neuropsychiatry. Theoretically, levels of intra and extra synaptic neurotransmitters can be estimated through competition with suitable PET ligands at their receptors. When validating candidate receptor PET ligands for competition studies it is essential to manipulate neurotransmitter levels in vivo using interventions with drugs that have negligible affinity for the receptors aimed at and are allowed to be used in humans. Neurochemical evidence for pharmacological interventions mostly originates from microdialysis studies in animals. First we will give a brief historical and methodological overview of the microdialysis technique. We will focus on serotonin and present microdialysis data of various pharmacological interventions in rats that have the potential to alter serotonin levels in humans. Our primary aim is to broaden the arsenal of pharmacological tools for PET competition studies, in particular because the type of neuronal manipulation might be a critical factor. Microdialysis of glutamate is briefly discussed, merely to illustrate some of the shortcomings of the technique.

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References

  • Adham N, Romanienko P, Hartig P, Weinshank RL, Branchek T (1992) The rat 5-hydroxytryptamine1B receptor is the species homologue of the human 5-hydroxytryptamine1D beta receptor. Mol Pharmacol 41:1–7

    CAS  PubMed  Google Scholar 

  • Andersen ML, Kessler E, Murnane KS, McClung JC, Tufik S, Howell LL (2010) Dopamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology (Berl) 210:439–448

    Article  CAS  Google Scholar 

  • Artigas F, Celada P, Laruelle M, Adell A (2001) How does pindolol improve antidepressant action? Trends Pharmacol Sci 22:224–228, Review

    Article  CAS  PubMed  Google Scholar 

  • Banks ML, Andersen ML, Murnane KS, Meyer RC, Howell LL (2009) Behavioral and neurochemical effects of cocaine and diphenhydramine combinations in rhesus monkeys. Psychopharmacology (Berl) 205:467–474

    Article  CAS  Google Scholar 

  • Bauzo RM, Kimmel HL, Howell LL (2009) Interactions between the mGluR2/3 agonist, LY379268, and cocaine on in vivo neurochemistry and behavior in squirrel monkeys. Pharmacol Biochem Behav 94:204–210

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bauzo RM, Kimmel HL, Howell LL (2012) The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys. Pharmacol Biochem Behav 101:288–296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Benveniste H, Diemer NH (1987) Cellular reactions to implantation of a microdialysis tube in the rat hippocampus. Acta Neuropathol 74:234–238

    Article  CAS  PubMed  Google Scholar 

  • Bosker F, Vrinten D, Klompmakers A, Westenberg H (1997) The effects of a 5-HT1A receptor agonist and antagonist on the 5-hydroxytryptamine release in the central nucleus of the amygdala: a microdialysis study with flesinoxan and WAY 100635. Naunyn Schmiedebergs Arch Pharmacol 355:347–353

    Article  CAS  PubMed  Google Scholar 

  • Bosker FJ, Westerink BH, Cremers TI, Gerrits M, van der Hart MG, Kuipers SD, van der Pompe G, ter Horst GJ, den Boer JA, Korf J (2004) Future antidepressants: what is in the pipeline and what is missing? CNS Drugs 18:705–732, Review

    Article  CAS  PubMed  Google Scholar 

  • Bosker FJ, Tanke MA, Jongsma ME, Cremers TI, Jagtman E, Pietersen CY, van der Hart MG, Gladkevich AV, Kema IP, Westerink BH, Korf J, den Boer JA (2010) Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis. Neurochem Int 57:948–957

    Article  CAS  PubMed  Google Scholar 

  • Bradberry CW (2000) Applications of microdialysis methodology in nonhuman primates: practice and rationale. Crit Rev Neurobiol 14:143–163, Review

    Article  CAS  PubMed  Google Scholar 

  • Bradberry CW (2002) Dose-dependent effect of ethanol on extracellular dopamine in mesolimbic striatum of awake rhesus monkeys: comparison with cocaine across individuals. Psychopharmacology (Berl) 165:67–76

    Article  CAS  Google Scholar 

  • Cremers TI, de Boer P, Liao Y, Bosker FJ, den Boer JA, Westerink BH, Wikström HV (2000a) Augmentation with a 5-HT(1A), but not a 5-HT(1B) receptor antagonist critically depends on the dose of citalopram. Eur J Pharmacol 397:63–74

    Article  CAS  PubMed  Google Scholar 

  • Cremers TI, Spoelstra EN, de Boer P, Bosker FJ, Mørk A, den Boer JA, Westerink BH, Wikström HV (2000b) Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram. Eur J Pharmacol 397:351–357

    Article  CAS  PubMed  Google Scholar 

  • Cremers TI, Wiersma LJ, Bosker FJ, den Boer JA, Westerink BH, Wikström HV (2001) Is the beneficial antidepressant effect of coadministration of pindolol really due to somatodendritic autoreceptor antagonism? Biol Psychiatry 50:13–21

    Article  CAS  PubMed  Google Scholar 

  • Cremers TI, Giorgetti M, Bosker FJ, Hogg S, Arnt J, Mørk A, Honig G, Bøgesø KP, Westerink BH, den Boer H, Wikstrom HV, Tecott LH (2004) Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29:1782–1789

    Article  CAS  PubMed  Google Scholar 

  • Cremers TI, Rea K, Bosker FJ, Wikström HV, Hogg S, Mørk A, Westerink BH (2007) Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology 32:1550–1557

    Article  CAS  PubMed  Google Scholar 

  • Cremers TI, Dremencov E, Bosker FJ, Westerink BH (2010) Oxazepam and temazepam attenuate paroxetine-induced elevation of serotonin levels in guinea-pig hippocampus. Int J Neuropsychopharmacol 13:807–811

    Article  CAS  PubMed  Google Scholar 

  • Czoty PW, Ginsburg BC, Howell LL (2002) Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 300:831–837

    Article  CAS  PubMed  Google Scholar 

  • Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 47:411–418

    Article  CAS  PubMed  Google Scholar 

  • Evering – van der Zeyden M (2011) Monitoring extracellular glutamate in the rat brain by microdialysis and microsensors: pharmacological applications. Thesis, University of Groningen

    Google Scholar 

  • Finnema SJ, Varrone A, Hwang TJ, Gulyás B, Pierson ME, Halldin C, Farde L (2010) Fenfluramine-induced serotonin release decreases [11C]AZ10419369 binding to 5-HT1B-receptors in the primate brain. Synapse 64:573–577

    Article  CAS  PubMed  Google Scholar 

  • Finnema SJ, Varrone A, Hwang TJ, Halldin C, Farde L (2012) Confirmation of fenfluramine effect on 5-HT(1B) receptor binding of [(11)C]AZ10419369 using an equilibrium approach. J Cereb Blood Flow Metab 32:685–695

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Howell LL, Wilcox KM, Lindsey KP, Kimmel HL (2006) Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys. Neuropsychopharmacology 31:585–593

    Article  CAS  PubMed  Google Scholar 

  • Hoyer D, Waeber C, Pazos A, Probst A, Palacios JM (1988) Identification of a 5-HT1 recognition site in human brain membranes different from 5-HT1A, 5-HT1B and 5-HT1C sites. Neurosci Lett 85:357–362

    Article  CAS  PubMed  Google Scholar 

  • Laruelle M (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20:423–451, Review

    Article  CAS  PubMed  Google Scholar 

  • Manvich DF, Kimmel HL, Howell LL (2012) Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 341:424–434

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Milak MS, Severance AJ, Prabhakaran J, Kumar JS, Majo VJ, Ogden RT, Mann JJ, Parsey RV (2011) In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer. J Cereb Blood Flow Metab 31:243–249

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murnane KS, Fantegrossi WE, Godfrey JR, Banks ML, Howell LL (2010) Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys. J Pharmacol Exp Ther 334:642–650

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nutt DJ, Cowen PJ (1987) Diazepam alters brain 5-HT function in man: implications for the acute and chronic effects of benzodiazepines. Psychol Med 17:601–607

    Article  CAS  PubMed  Google Scholar 

  • Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM (2010) Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab 30:1682–1706, Review

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Rea K, Cremers TI, Westerink BH (2005) HPLC conditions are critical for the detection of GABA by microdialysis. J Neurochem 94:672–679

    Article  CAS  PubMed  Google Scholar 

  • Rea K, Folgering J, Westerink BH, Cremers TI (2010) Alpha1-adrenoceptors modulate citalopram-induced serotonin release. Neuropharmacology 58:962–971

    Article  CAS  PubMed  Google Scholar 

  • Saunders RC, Kolachana BS, Weinberger DR (2001) Microdialysis in nonhuman primates. Curr Protoc Neurosci Chapter 7: Unit7.3

    Google Scholar 

  • Stockmeier CA (1997) Neurobiology of serotonin in depression and suicide. Ann N Y Acad Sci 836:220–232, Review

    Article  CAS  PubMed  Google Scholar 

  • Syvälahti EK (1994) Biological aspects of depression. Acta Psychiatr Scand Suppl 377:11–15, Review

    Article  PubMed  Google Scholar 

  • Timmerman W, Westerink BH (1997) Brain microdialysis of GABA and glutamate: what does it signify? Synapse 27:242–261

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Nishiyama S, Kakiuchi T, Ohba H, Sato K, Harada N (1999) Is synaptic dopamine concentration the exclusive factor which alters the in vivo binding of [11C]raclopride? PET studies combined with microdialysis in conscious monkeys. Brain Res 841:160–169

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Harada N, Nishiyama S, Ohba H, Sato K, Fukumoto D, Kakiuchi T (2000) Ketamine decreased striatal [(11)C]raclopride binding with no alterations in static dopamine concentrations in the striatal extracellular fluid in the monkey brain: multiparametric PET studies combined with microdialysis analysis. Synapse 37:95–103

    Article  CAS  PubMed  Google Scholar 

  • Udo de Haes JI, Bosker FJ, Van Waarde A, Pruim J, Willemsen AT, Vaalburg W, Den Boer JA (2002) 5-HT(1A) receptor imaging in the human brain: effect of tryptophan depletion and infusion on [(18)F]MPPF binding. Synapse 46:108–115

    Article  CAS  PubMed  Google Scholar 

  • Udo de Haes JI, Kortekaas R, Van Waarde A, Maguire RP, Pruim J, den Boer JA (2005a) Assessment of methylphenidate-induced changes in binding of continuously infused [(11)C]-raclopride in healthy human subjects: correlation with subjective effects. Psychopharmacology (Berl) 183:322–330

    Article  CAS  Google Scholar 

  • Udo de Haes JI, Cremers TI, Bosker FJ, Postema F, Tiemersma-Wegman TD, den Boer JA (2005b) Effect of increased serotonin levels on [18F]MPPF binding in rat brain: fenfluramine vs. the combination of citalopram and ketanserin. Neuropsychopharmacology 30:1624–1631

    Article  CAS  PubMed  Google Scholar 

  • Udo de Haes JI, Harada N, Elsinga PH, Maguire RP, Tsukada H (2006) Effect of fenfluramine-induced increases in serotonin release on [18F]MPPF binding: a continuous infusion PET study in conscious monkeys. Synapse 59:18–26

    Article  CAS  PubMed  Google Scholar 

  • van der Zeyden M, Oldenziel WH, Rea K, Cremers TI, Westerink BH (2008) Microdialysis of GABA and glutamate: analysis, interpretation and comparison with microsensors. Pharmacol Biochem Behav 90:135–147

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Fowler JS, Logan J, Schlyer D, Hitzemann R, Lieberman J, Angrist B, Pappas N, MacGregor R et al (1994) Imaging endogenous dopamine competition with [11C]raclopride in the human brain. Synapse 16:255–262

    Article  CAS  PubMed  Google Scholar 

  • Wilcox KM, Kimmel HL, Lindsey KP, Votaw JR, Goodman MM, Howell LL (2005) In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys. Synapse 58:220–228

    Article  CAS  PubMed  Google Scholar 

  • Zald DH, Boileau I, El-Dearedy W, Gunn R, McGlone F, Dichter GS, Dagher A (2004) Dopamine transmission in the human striatum during monetary reward tasks. J Neurosci 24:4105–4112

    Article  CAS  PubMed  Google Scholar 

  • Zetterström T, Vernet L, Ungerstedt U, Tossman U, Jonzon B, Fredholm BB (1982) Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci Lett 29:111–115

    Article  PubMed  Google Scholar 

  • Zimmer L, Mauger G, Le Bars D, Bonmarchand G, Luxen A, Pujol JF (2002) Effect of endogenous serotonin on the binding of the 5-hT1A PET ligand 18F-MPPF in the rat hippocampus: kinetic beta measurements combined with microdialysis. J Neurochem 80:278–286

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University Center for Psychiatry, University Medical Center Groningen (UMCG), Hanzeplein 1, Groningen, 9713 GZ, The Netherlands

    Fokko J. Bosker PhD

  2. Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands

    Janine Doorduin PhD & Anniek K. D. Visser MSc

  3. Department of Biomonitoring and Sensoring, University of Groningen, University Center for Pharmacy, Antonius Deusinglaan 1, Groningen, 9713 AV, The Netherlands

    Minke E. Jongsma PhD, Thomas I. F. H. Cremers PhD & Ben H. C. Westerink PhD

  4. Clinical Pharmacology, Merck Sharp and Dohme, Molenstraat 110, Oss, 5342 CC, The Netherlands

    Joanna Udo de Haes PhD

  5. Pharmacology Department, National University of Ireland, University Road, Galway, Ireland

    Kieran Rea PhD

  6. Neuropsychopharmacology Unit, Imperial College London, South Kensington Campus, London, W12 0NN, UK

    Robin Tyacke PhD & David J. Nutt MD, PhD

  7. PRA International, Zuidlaren, The Netherlands

    Johan A. den Boer MD, PhD

  8. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen (UMCG), Hanzeplein 1, Groningen, 9713 GZ, The Netherlands

    Johan A. den Boer MD, PhD

Authors
  1. Fokko J. Bosker PhD
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  2. Janine Doorduin PhD
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  3. Minke E. Jongsma PhD
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  4. Anniek K. D. Visser MSc
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  5. Joanna Udo de Haes PhD
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  6. Thomas I. F. H. Cremers PhD
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  8. Robin Tyacke PhD
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  9. David J. Nutt MD, PhD
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  10. Johan A. den Boer MD, PhD
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  11. Ben H. C. Westerink PhD
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Corresponding author

Correspondence to Fokko J. Bosker PhD .

Editor information

Editors and Affiliations

  1. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Rudi A.J.O. Dierckx

  2. Faculty of Electrical Engineering and Information Technology, University of Applied Sciences Offenburg, Offenburg, Germany

    Andreas Otte

  3. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Erik F. J. de Vries

  4. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Aren van Waarde

  5. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen (UMCG), Groningen, The Netherlands

    Johan A. den Boer

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Bosker, F.J. et al. (2014). Pharmacological Interventions That Have the Potential to Alter Neurotransmitter Levels in the Human Brain. In: Dierckx, R., Otte, A., de Vries, E., van Waarde, A., den Boer, J. (eds) PET and SPECT in Psychiatry. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40384-2_3

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  • DOI: https://doi.org/10.1007/978-3-642-40384-2_3

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