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Organic cation transporter 3 (OCT3) is localized to intracellular and surface membranes in select glial and neuronal cells within the basolateral amygdaloid complex of both rats and mice

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Abstract

Organic cation transporter 3 (OCT3) is a high-capacity, low-affinity transporter that mediates corticosterone-sensitive uptake of monoamines including norepinephrine, epinephrine, dopamine, histamine and serotonin. OCT3 is expressed widely throughout the amygdaloid complex and other brain regions where monoamines are key regulators of emotional behaviors affected by stress. However, assessing the contribution of OCT3 to the regulation of monoaminergic neurotransmission and monoamine-dependent regulation of behavior requires fundamental information about the subcellular distribution of OCT3 expression. We used immunofluorescence and immuno-electron microscopy to examine the cellular and subcellular distribution of the transporter in the basolateral amygdaloid complex of the rat and mouse brain. OCT3-immunoreactivity was observed in both glial and neuronal perikarya in both rat and mouse amygdala. Electron microscopic immunolabeling revealed plasma membrane-associated OCT3 immunoreactivity on axonal, dendritic, and astrocytic processes adjacent to a variety of synapses, as well as on neuronal somata. In addition to plasma membrane sites, OCT3 immunolabeling was also observed associated with neuronal and glial endomembranes, including Golgi, mitochondrial and nuclear membranes. Particularly prominent labeling of the outer nuclear membrane was observed in neuronal, astrocytic, microglial and endothelial perikarya. The localization of OCT3 to neuronal and glial plasma membranes adjacent to synaptic sites is consistent with an important role for this transporter in regulating the amplitude, duration, and physical spread of released monoamines, while its localization to mitochondrial and outer nuclear membranes suggests previously undescribed roles for the transporter in the intracellular disposition of monoamines.

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References

  • Amphoux A, Vialou V, Drescher E, Bruss M, La Cour CM, Rochat C, Millan MJ, Giros B, Bonisch H, Gautron S (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50:941–952

    Article  CAS  PubMed  Google Scholar 

  • Aoki C, Zemcik BA, Strader CD, Pickel VM (1989) Cytoplasmic loop of beta-adrenergic receptors: synaptic and intracellular localization and relation to catecholaminergic neurons in the nuclei of the solitary tracts. Brain Res 493:331–347

    Article  CAS  PubMed  Google Scholar 

  • Asan E (1998) The catecholaminergic innervation of the rat amygdala. Adv Anat Embryol Cell Biol 142:1–118

    Article  CAS  PubMed  Google Scholar 

  • Asan E, Yilmazer-Hanke DM, Eliava M, Hantsch M, Lesch KP, Schmitt A (2005) The corticotropin-releasing factor (CRF)-system and monoaminergic afferents in the central amygdala: investigations in different mouse strains and comparison with the rat. Neuroscience 131:953–967

    Article  CAS  PubMed  Google Scholar 

  • Buu NT, Hui R, Falardeau P (1993) Norepinephrine in neonatal rat ventricular myocytes: association with the cell nucleus and binding to nuclear alpha 1- and beta-adrenergic receptors. J Mol Cell Cardiol 25:1037–1046

    Article  CAS  PubMed  Google Scholar 

  • Chu HY, Ito W, Li J, Morozov A (2012) Target-specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine. J Neurosci 32:14815–14820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Csaba G, Kovacs P (2006) Perinuclear localization of biogenic amines (serotonin and histamine) in rat immune cells. Cell Biol Int 30:861–865

    Article  CAS  PubMed  Google Scholar 

  • Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, Jackson-Lewis V, Javitch JA, Ballatori N, Przedborski S, Tieu K (2009) The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci U S A 106:8043–8048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dahl EF, Wright CD, O’Connell TD (2015) Quantification of catecholamine uptake in adult cardiac myocytes. Methods Mol Biol 1234:43–52

    Article  PubMed  Google Scholar 

  • Duvarci S, Pare D (2014) Amygdala microcircuits controlling learned fear. Neuron 82(5):966–980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferry B, Magistretti PJ, Pralong E (1997) Noradrenaline modulates glutamate-mediated neurotransmission in the rat basolateral amygdala in vitro. Eur J Neurosci 9:1356–1364

    Article  CAS  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (1997) The Mouse Brain in Stereotaxic Coordinates. Academic Press, San Diego

    Google Scholar 

  • Gan JO, Bowline E, Lourenco FS, Pickel VM (2014) Adolescent social isolation enhances the plasmalemmal density of NMDA NR1 subunits in dendritic spines of principal neurons in the basolateral amygdala of adult mice. Neuroscience 258:174–183

    Article  CAS  PubMed  Google Scholar 

  • Garzon M, Pickel VM (2006) Subcellular distribution of M2 muscarinic receptors in relation to dopaminergic neurons of the rat ventral tegmental area. J Comp Neurol 498:821–839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gasser PJ, Lowry CA, Orchinik M (2006) Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci 26:8758–8766

    Article  CAS  PubMed  Google Scholar 

  • Gasser PJ, Orchinik M, Raju I, Lowry CA (2009) Distribution of organic cation transporter 3, a corticosterone-sensitive monoamine transporter, in the rat brain. J Comp Neurol 512:529–555

    Article  CAS  PubMed  Google Scholar 

  • Graf EN, Wheeler RA, Baker DA, Ebben AL, Hill JE, McReynolds JR, Robble MA, Vranjkovic O, Wheeler DS, Mantsch JR, Gasser PJ (2013) Corticosterone acts in the nucleus accumbens to enhance dopamine signaling and potentiate reinstatement of cocaine seeking. J Neurosci 33:11800–11810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grundemann D, Schechinger B, Rappold GA, Schomig E (1998) Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci 1:349–351

    Article  CAS  PubMed  Google Scholar 

  • Grundemann D, Liebich G, Kiefer N, Koster S, Schomig E (1999) Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol 56:1–10

    CAS  PubMed  Google Scholar 

  • Haenisch B, Bonisch H (2010) Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics. Naunyn Schmiedebergs Arch Pharmacol 381:33–39

    Article  CAS  PubMed  Google Scholar 

  • Hara Y, Yakovleva T, Bakalkin G, Pickel VM (2006) Dopamine D1 receptors have subcellular distributions conducive to interactions with prodynorphin in the rat nucleus accumbens shell. Synapse 60:1–19

    Article  CAS  PubMed  Google Scholar 

  • Hill JE, Gasser PJ (2013) Organic cation transporter 3 is densely expressed in the intercalated cell groups of the amygdala: anatomical evidence for a stress hormone-sensitive dopamine clearance system. J Chem Neuroanat 52:36–43

    Article  CAS  PubMed  Google Scholar 

  • Hill JE, Makky K, Shrestha L, Hillard CJ, Gasser PJ (2011) Natural and synthetic corticosteroids inhibit uptake 2-mediated transport in CNS neurons. Physiol Behav 104:306–311

    Article  CAS  PubMed  Google Scholar 

  • Horvath G, Wanner A (2003) Molecular targets for steroids in airway vascular smooth muscle. Arch Physiol Biochem 111:341–344

    Article  CAS  PubMed  Google Scholar 

  • Horvath G, Sutto Z, Torbati A, Conner GE, Salathe M, Wanner A (2003) norepinephrine transport by the extraneuronal monoamine transporter in human bronchial arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:829–837

    Article  Google Scholar 

  • Inazu M, Takeda H, Ikoshi H, Sugisawa M, Uchida Y, Matsumiya T (2001) Pharmacological characterization and visualization of the glial serotonin transporter. Neurochem Int 39:39–49

    Article  CAS  PubMed  Google Scholar 

  • Inazu M, Takeda H, Matsumiya T (2003a) Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J Neurochem 84:43–52

    Article  CAS  PubMed  Google Scholar 

  • Inazu M, Takeda H, Matsumiya T (2003b) Functional expression of the norepinephrine transporter in cultured rat astrocytes. J Neurochem 84:136–144

    Article  CAS  PubMed  Google Scholar 

  • Jayanthi LD, Ramamoorthy S (2005) Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. AAPS J 7:E728–E738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang X, Chen A, Li H (2005) Histaminergic modulation of excitatory synaptic transmission in the rat basolateral amygdala. Neuroscience 131:691–703

    Article  CAS  PubMed  Google Scholar 

  • Jiang X, Xing G, Yang C, Verma A, Zhang L, Li H (2009) Stress impairs 5-HT2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala. Neuropsychopharmacology 34:410–423

    Article  CAS  PubMed  Google Scholar 

  • Karhunen T, Tilgmann C, Ulmanen I, Panula P (1995) Catechol-O-methyltransferase (COMT) in rat brain: immunoelectron microscopic study with an antiserum against rat recombinant COMT protein. Neurosci Lett 187:57–60

    Article  CAS  PubMed  Google Scholar 

  • Konstandi M, Johnson E, Lang MA, Malamas M, Marselos M (2000) Noradrenaline, dopamine, serotonin: different effects of psychological stress on brain biogenic amines in mice and rats. Pharmacol Res 41:341–346

    Article  CAS  PubMed  Google Scholar 

  • Li R, Nishijo H, Ono T, Ohtani Y, Ohtani O (2002) Synapses on GABAergic neurons in the basolateral nucleus of the rat amygdala: double-labeling immunoelectron microscopy. Synapse 43:42–50

    Article  CAS  PubMed  Google Scholar 

  • Lips KS, Volk C, Schmitt BM, Pfeil U, Arndt P, Miska D, Ermert L, Kummer W, Koepsell H (2005) Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am J Respir Cell Mol Biol 33:79–88

    Article  CAS  PubMed  Google Scholar 

  • McDonald AJ, Mascagni F (2007) Neuronal localization of 5-HT type 2A receptor immunoreactivity in the rat basolateral amygdala. Neuroscience 146(1):306–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McReynolds JR, Donowho K, Abdi A, McGaugh JL, Roozendaal B, McIntyre CK (2010) Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions. Neurobiol Learn Mem 93(3):312–321

    Article  CAS  PubMed  Google Scholar 

  • Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 22:389–395

    CAS  PubMed  Google Scholar 

  • Muller J, Da LC (1977) Ultracytochemical demonstration of monoamine oxidase activity in nervous and non-nervous tissue of the rat. J Histochem Cytochem 25:337–348

    Article  CAS  PubMed  Google Scholar 

  • Muller JF, Mascagni F, McDonald AJ (2006) Pyramidal cells of the rat basolateral amygdala: synaptology and innervation by parvalbumin-immunoreactive interneurons. J Comp Neurol 494:635–650

    Article  PubMed  PubMed Central  Google Scholar 

  • Muller JF, Mascagni F, McDonald AJ (2009) Dopaminergic innervation of pyramidal cells in the rat basolateral amygdala. Brain Struct Funct 213:275–288

    Article  PubMed  Google Scholar 

  • Myohanen TT, Schendzielorz N, Mannisto PT (2010) Distribution of catechol-O-methyltransferase (COMT) proteins and enzymatic activities in wild-type and soluble COMT deficient mice. J Neurochem 113:1632–1643

    CAS  PubMed  Google Scholar 

  • Nemeroff CB, Owens MJ (2004) Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis. CNS Spectr 9:23–31

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press, San Diego

    Google Scholar 

  • Peters A, Palay SL, Webster H (1991) The Fine Structure of the Nervous System. Oxford University Press, New York

    Google Scholar 

  • Pinard CR, Muller JF, Mascagni F, McDonald AJ (2008) Dopaminergic innervation of interneurons in the rat basolateral amygdala. Neuroscience 157:850–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pinard CR, Mascagni F, Muller JF, McDonald AJ (2010) Limited convergence of rhinal cortical and dopaminergic inputs in the rat basolateral amygdala: an ultrastructural analysis. Brain Res 1332:48–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pinto A, Sesack SR (2008) Ultrastructural analysis of prefrontal cortical inputs to the rat amygdala: spatial relationships to presumed dopamine axons and D1 and D2 receptors. Brain Struct Funct 213(1–2):159–175

    Article  CAS  PubMed  Google Scholar 

  • Rice ME, Cragg SJ (2008) Dopamine spillover after quantal release: rethinking dopamine transmission in the nigrostriatal pathway. Brain Res Rev 58:303–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roozendaal B, Hahn EL, Nathan SV, de Quervain DJ, McGaugh JL (2004) Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala. J Neurosci 24:8161–8169

    Article  CAS  PubMed  Google Scholar 

  • Roozendaal B, Hui GK, Hui IR, Berlau DJ, McGaugh JL, Weinberger NM (2006a) Basolateral amygdala noradrenergic activity mediates corticosterone-induced enhancement of auditory fear conditioning. Neurobiol Learn Mem 86:249–255

    Article  CAS  PubMed  Google Scholar 

  • Roozendaal B, Okuda S, Van der Zee EA, McGaugh JL (2006b) Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala. Proc Natl Acad Sci USA 103:6741–6746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenkranz JA, Grace AA (2002) Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J Neurosci 22:324–337

    CAS  PubMed  Google Scholar 

  • Schomig E, Lazar A, Grundemann D (2006) Extraneuronal monoamine transporter and organic cation transporters 1 and 2: a review of transport efficiency. Handb Exp Pharmacol 175:151–180

    Article  Google Scholar 

  • Streich S, Bruss M, Bonisch H (1996) Expression of the extraneuronal monoamine transporter (uptake2) in human glioma cells. Naunyn Schmiedebergs Arch Pharmacol 353:328–333

    Article  CAS  PubMed  Google Scholar 

  • Stutzmann GE, McEwen BS, Ledoux JE (1998) Serotonin modulation of sensory inputs to the lateral amygdala: dependency on corticosterone. J Neurosci 18:9529–9538

    CAS  PubMed  Google Scholar 

  • Takeda H, Inazu M, Matsumiya T (2002) Astroglial dopamine transport is mediated by norepinephrine transporter. Naunyn Schmiedebergs Arch Pharmacol 366:620–623

    Article  CAS  PubMed  Google Scholar 

  • Trendelenburg U (1990) The interaction of transport mechanisms and intracellular enzymes in metabolizing systems. J Neural Transm Suppl 32:3–18

    CAS  PubMed  Google Scholar 

  • Ulmanen I, Peranen J, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Bernasconi L, Aubry JP, Lundstrom K (1997) Expression and intracellular localization of catechol O-methyltransferase in transfected mammalian cells. Eur J Biochem 243:452–459

    Article  CAS  PubMed  Google Scholar 

  • Verhaagh S, Barlow DP, Zwart R (2001) The extraneuronal monoamine transporter Slc22a3/Orct3 co-localizes with the Maoa metabolizing enzyme in mouse placenta. Mech Dev 100:127–130

    Article  CAS  PubMed  Google Scholar 

  • Vialou V, Amphoux A, Zwart R, Giros B, Gautron S (2004) Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J Neurosci 24:2846–2851

    Article  CAS  PubMed  Google Scholar 

  • Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S (2008) Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem 106(3):1471–1482

    CAS  PubMed  Google Scholar 

  • Wang H, Cuzon VC, Pickel VM (2003) Ultrastructural localization of delta-opioid receptors in the rat caudate-putamen nucleus during postnatal development: relation to synaptogenesis. J Comp Neurol 467:343–353

    Article  CAS  PubMed  Google Scholar 

  • Wu SC, O’Connell TD (2015) Nuclear compartmentalization of alpha1-adrenergic receptor signaling in adult cardiac myocytes. J Cardiovasc Pharmacol 65:91–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu SC, Dahl EF, Wright CD, Cypher AL, Healy CL, O’Connell TD (2014) Nuclear localization of a1A-adrenergic receptors is required for signaling in cardiac myocytes: an “inside-out” a1-AR signaling pathway. J Am Heart Assoc 3:e000145

    Article  PubMed  PubMed Central  Google Scholar 

  • Wultsch T, Grimberg G, Schmitt A, Painsipp E, Wetzstein H, Breitenkamp AF, Grundemann D, Schomig E, Lesch KP, Gerlach M, Reif A (2009) Decreased anxiety in mice lacking the organic cation transporter 3. J Neural Transm 116(6):689–697

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa T, Naganuma F, Iida T, Nakamura T, Harada R, Mohsen AS, Kasajima A, Sasano H, Yanai K (2013) Molecular mechanism of histamine clearance by primary human astrocytes. Glia 61:905–916

    Article  PubMed  Google Scholar 

  • Zhang J, Muller JF, McDonald AJ (2013) Noradrenergic innervation of pyramidal cells in the rat basolateral amygdala. Neuroscience 228:395–408

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by Grants: National Institute on Drug Abuse (DA032895) to PJG; National Institute of Mental Health (MH40342), National Institutes of Health (HL09657) and National Institute on Drug Abuse (DA04600 and DA005130) to VMP.

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Correspondence to Paul J. Gasser.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Gasser, P.J., Hurley, M.M., Chan, J. et al. Organic cation transporter 3 (OCT3) is localized to intracellular and surface membranes in select glial and neuronal cells within the basolateral amygdaloid complex of both rats and mice. Brain Struct Funct 222, 1913–1928 (2017). https://doi.org/10.1007/s00429-016-1315-9

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