Abstract
Purpose
Earlier studies have shown that positron emission tomography (PET) imaging with the radioligand [18F]MPPF allows for measuring the binding potential of serotonin 5-hydroxytryptamine1A (5-HT1A) receptors in different regions of animal and human brain, including that of 5-HT1A autoreceptors in the raphe nuclei. In the present study, we sought to determine if such data could be obtained in rat, with a microPET (R4, Concorde Microsystems).
Methods
Scans from isoflurane-anaesthetised rats (n = 18, including six test–retest) were co-registered with magnetic resonance imaging data, and binding potential, blood to plasma ratio and radiotracer efflux were estimated according to a simplified reference tissue model.
Results
Values of binding potential for hippocampus (1.2), entorhinal cortex (1.1), septum (1.1), medial prefrontal cortex (1.0), amygdala (0.8), raphe nuclei (0.6), paraventricular hypothalamic nucleus (0.5) and raphe obscurus (0.5) were comparable to those previously measured with PET in cats, non-human primates or humans. Test–retest variability was in the order of 10% in the larger brain regions (hippocampus, medial prefrontal and entorhinal cortex) and less than 20% in small nuclei such as the septum and the paraventricular hypothalamic, basolateral amygdaloid and raphe nuclei.
Conclusions
MicroPET brain imaging of 5-HT1A receptors with [18F]MPPF thus represents a promising avenue for investigating 5-HT1A receptor function in rat.
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References
Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry 1998;44:151–62.
Frazer AHJ. Serotonin. Philadelphia: Lippincott-Raven; 1999.
Dahlström A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand Suppl. 1964;232:231–55.
Ungerstedt U. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand Suppl. 1971;367:1–48.
Moore RY, Halaris AE, Jones BE. Serotonin neurons of the midbrain raphe: ascending projections. J Comp Neurol. 1978;180:417–38.
Parent A, Descarries L, Beaudet A. Organization of ascending serotonin systems in the adult rat brain. A radioautographic study after intraventricular administration of [3H]5-hydroxytryptamine. Neuroscience 1981;6:115–38.
Steinbusch HW. Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 1981;6:557–618.
Hornung JP. The human raphe nuclei and the serotonergic system. J Chem Neuroanat. 2003;26:331–43.
Roth B. The serotonin receptors: from molecular pharmacology to human therapeutics. Totowa: Humana; 2006.
Lanfumey L, Hamon M. 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord. 2004;3:1–10.
Jones BJ, Blackburn TP. The medical benefit of 5-HT research. Pharmacol Biochem Behav. 2002;71:555–68.
Hensler JG. Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration. Life Sci. 2003;72:1665–82.
Piñeyro G, Blier P. Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev. 1999;51:533–91.
Haddjeri N, Blier P, de Montigny C. Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J Neurosci. 1998;18:10150–6.
Shen C, Li H, Meller E. Repeated treatment with antidepressants differentially alters 5-HT1A agonist-stimulated [35S]GTP gamma S binding in rat brain regions. Neuropharmacology 2002;42:1031–8.
Elena Castro M, Diaz A, del Olmo E, Pazos A. Chronic fluoxetine induces opposite changes in G protein coupling at pre and postsynaptic 5-HT1A receptors in rat brain. Neuropharmacology 2003;44:93–101.
Castro E, Tordera RM, Hughes ZA, Pei Q, Sharp T. Use of Arc expression as a molecular marker of increased postsynaptic 5-HT function after SSRI/5-HT1A receptor antagonist co-administration. J Neurochem. 2003;85:1480–7.
El Mansari M, Sanchez C, Chouvet G, Renaud B, Haddjeri N. Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology 2005;30:1269–77.
Shiue CY, Shiue GG, Mozley PD, Kung MP, Zhuang ZP, Kim HJ, et al. P-[18F]-MPPF: a potential radioligand for PET studies of 5-HT1A receptors in humans. Synapse 1997;25:147–54.
Le Bars D, Lemaire C, Ginovart N, Plenevaux A, Aerts J, Brihaye C, et al. High-yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635. Nucl Med Biol. 1998;25:343–50.
Plenevaux A, Weissmann D, Aerts J, Lemaire C, Brihaye C, Degueldre C, et al. Tissue distribution, autoradiography, and metabolism of 4-(2¢-methoxyphenyl)-1-[2′ -[N-2′-pyridinyl)-p-[(18)F]fluorobenzamido]ethyl]piperazine (p-[(18)F]MPPF), a new serotonin 5-HT(1A) antagonist for positron emission tomography: an in vivo study in rats. J Neurochem. 2000;75:803–11.
Zimmer L, Pain F, Mauger G, Plenevaux A, Le Bars D, Mastrippolito R, et al. The potential of the beta-Microprobe, an intracerebral radiosensitive probe, to monitor the [(18)F]MPPF binding in the rat dorsal raphe nucleus. Eur J Nucl Med Mol Imaging. 2002;29:1237–47.
Aznavour N, Zimmer L. [18F]MPPF as a tool for the in vivo imaging of 5-HT1A receptors in animal and human brain. Neuropharmacology 2007;52:695–707.
Riad M, Zimmer L, Rbah L, Watkins KC, Hamon M, Descarries L. Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in the nucleus raphe dorsalis of rat. J Neurosci. 2004;24:5420–6.
Zimmer L, Riad M, Rbah L, et al. Toward brain imaging of serotonin 5-HT1A autoreceptor internalization. NeuroImage 2004;22:1421–6.
Aznavour N, Rbah L, Riad M, Reilhac A, Costes N, Descarries L, et al. A PET imaging study of 5-HT(1A) receptors in cat brain after acute and chronic fluoxetine treatment. NeuroImage 2006;33:834–42.
Sibon I, Benkelfat C, Gravel P, Aznavour N, Costes N, Mzengeza S, et al. Decreased [(18)F]MPPF binding potential in the dorsal raphe nucleus after a single oral dose of fluoxetine: a positron-emission tomography study in healthy volunteers. Biol Psychiatry. 2008;63:1135–40.
Knoess C, Siegel S, Smith A, Newport D, Richerzhagen N, Winkeler A, et al. Performance evaluation of the microPET R4 PET scanner for rodents. Eur J Nucl Med Mol Imaging. 2003;30:737–47.
Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW, et al. Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET. NeuroImage 1998;8:426–40.
Costes N, Merlet I, Zimmer L, Lavenne F, Cinotti L, Delforge J, et al. Modeling [18F]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection. J Cereb Blood Flow Metab. 2002;22:753–65.
Costes N, Zimmer L, Reilhac A, Lavenne F, Ryvlin P, Le Bars D. Test–retest reproducibility of 18F-MPPF PET in healthy humans: a reliability study. J Nucl Med. 2007;48:1279–88.
Millet P, Moulin M, Bartoli A, Del Guerra A, Ginovart N, Lemoucheux L, et al. In vivo quantification of 5-HT(1A)-[(18)F]MPPF interactions in rats using the YAP-(S)PET scanner and a beta-microprobe. NeuroImage 2008;41:823–34.
Pazos A, Palacios JM. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res. 1985;346:205–30.
El Mestikawy S, Riad M, Laporte AM, Vergé D, Daval G, Gozlan H, et al. Production of specific anti-rat 5-HT1A receptor antibodies in rabbits injected with a synthetic peptide. Neurosci Lett. 1990;118:189–92.
Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. NeuroImage 1997;6:279–87.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 4th ed. New York: Academic; 1998.
Aznavour N, Rbah L, Leger L, Buda C, Sastre JP, Imhof A, et al. A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain. J Chem Neuroanat. 2006;31:226–32.
Ginovart N, Hassoun W, Le Bars D, Weissmann D, Leviel V. In vivo characterization of p-[(18)F]MPPF, a fluoro analog of WAY-100635 for visualization of 5-HT(1a) receptors. Synapse 2000;35:192–200.
Shively CA, Friedman DP, Gage HD, Bounds MC, Brown-Proctor C, Blair JB, et al. Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys. Arch Gen Psychiatry. 2006;63:396–403.
Passchier J, van Waarde A. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. Eur J Nucl Med. 2001;28:113–29.
Passchier J, van Waarde A, Pieterman RM, Elsinga PH, Pruim J, Hendrikse HN, et al. In vivo delineation of 5-HT1A receptors in human brain with [18F]MPPF. J Nucl Med. 2000;41:1830–5.
Passchier J, van Waarde A, Pieterman RM, Elsinga PH, Pruim J, Hendrikse HN, et al. Quantitative imaging of 5-HT(1A) receptor binding in healthy volunteers with [(18)f]p-MPPF. Nucl Med Biol. 2000;27:473–6.
Khawaja X. Quantitative autoradiographic characterisation of the binding of [3H]WAY-100635, a selective 5-HT1A receptor antagonist. Brain Res. 1995;673:217–25.
Gozlan H, Thibault S, Laporte AM, Lima L, Hamon M. The selective 5-HT1A antagonist radioligand [3H]WAY 100635 labels both G-protein-coupled and free 5-HT1A receptors in rat brain membranes. Eur J Pharmacol. 1995;288:173–86.
Udo de Haes JI, Cremers TI, Bosker FJ, Postema F, Tiemersma-Wegman TD, den Boer JA. Effect of increased serotonin levels on [18F]MPPF binding in rat brain: fenfluramine vs the combination of citalopram and ketanserin. Neuropsychopharmacology 2005;30:1624–31.
Jagoda EM, Lang L, Tokugawa J, Simmons A, Ma Y, Contoreggi C, et al. Development of 5-HT1A receptor radioligands to determine receptor density and changes in endogenous 5-HT. Synapse 2006;59:330–41.
Casteels C, Vermaelen P, Nuyts J, Van Der Linden A, Baekelandt V, Mortelmans L, et al. Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. J Nucl Med. 2006;47:1858–66.
Parsey RV, Slifstein M, Hwang DR, Abi-Dargham A, Simpson N, Mawlawi O, et al. Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tissue input functions. J Cereb Blood Flow Metab. 2000;20:1111–33.
Seeman P, Kapur S. Anesthetics inhibit high-affinity states of dopamine D2 and other G-linked receptors. Synapse 2003;50:35–40.
Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S. [11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats. Synapse 2003;47:123–33.
Hassoun W, Le Cavorsin M, Ginovart N, Zimmer L, Gualda V, Bonnefoi F, et al. PET study of the [11C]raclopride binding in the striatum of the awake cat: effects of anaesthetics and role of cerebral blood flow. Eur J Nucl Med Mol Imaging. 2003;30:141–8.
Alexoff DL, Vaska P, Marsteller D, Gerasimov T, Li J, Logan J, Fowler JS, et al. Reproducibility of 11C-raclopride binding in the rat brain measured with the microPET R4: effects of scatter correction and tracer specific activity. J Nucl Med. 2003;44:815–22.
Costes N, Merlet I, Ostrowsky K, Faillenot I, Lavenne F, Zimmer L, et al. A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging. J Nucl Med. 2005;46:1980–9.
Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001;76:1521–31.
Díaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F. Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J Neurosci. 2005;25:10831–43.
Riad M, Watkins KC, Doucet E, Hamon M, Descarries L. Agonist-induced internalization of serotonin-1a receptors in the dorsal raphe nucleus (autoreceptors) but not hippocampus (heteroreceptors). J Neurosci. 2001;21:8378–86.
Riad M, Rbah L, Verdurand M, Aznavour N, Zimmer L, Descarries L. Unchanged density of 5-HT(1A) autoreceptors on the plasma membrane of nucleus raphe dorsalis neurons in rats chronically treated with fluoxetine. Neuroscience 2008;151:692–700.
Heusler P, Newman-Tancredi A, Loock T, Cussac D. Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells. Eur J Pharmacol. 2008;581:37–46.
Liow JS, Lu S, McCarron JA, Hong J, Musachio JL, Pike VW, et al. Effect of a P-glycoprotein inhibitor, cyclosporin A, on the disposition in rodent brain and blood of the 5-HT1A receptor radioligand, [11C](R)-(−)-RWAY. Synapse 2007;61:96–105.
Giovacchini G, Lang L, Ma Y, Herscovitch P, Eckelman WC, Carson RE. Differential effects of paroxetine on raphe and cortical 5-HT1A binding: a PET study in monkeys. NeuroImage 2005;28:238–48.
Acknowledgments
The authors are grateful to Shadreck Mzengeza for his help with the radiochemistry. The work was funded by the Canadian Institutes for Health Research (operating grants to C.B. and L.D.). N.A. held a postdoctoral fellowship, and L.D. benefitted from an infrastructure grant from the Fonds de la Recherche en Santé du Québec.
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The authors declare that they have no competing financial interests.
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Aznavour, N., Benkelfat, C., Gravel, P. et al. MicroPET imaging of 5-HT1A receptors in rat brain: a test–retest [18F]MPPF study. Eur J Nucl Med Mol Imaging 36, 53–62 (2009). https://doi.org/10.1007/s00259-008-0891-1
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DOI: https://doi.org/10.1007/s00259-008-0891-1