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α1-Adrenergic receptor subtypes in the central nervous system: insights from genetically engineered mouse models

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Abstract

α1-Adrenergic receptors (α1-ARs) are important players in peripheral and central nervous system (CNS) regulation and function and in mediating various behavioral responses. The α1-AR family consists of three subtypes, α1A, α1B and α1D, which differ in their subcellular distribution, efficacy in evoking intracellular signals and transcriptional profiles. All three α1-AR subtypes are present at relatively high densities throughout the CNS, but the contributions of the individual subtypes to various central functions are currently unclear. Because of the lack of specific ligands, functionally characterizing the α1-ARs and discriminating between the three subtypes are difficult. To date, studies using genetically engineered mice have provided some information on subtype-related functions of the CNS α1-ARs. In this mini-review, we discuss several CNS processes where the α1-ARs role has been delineated with pharmacological tools and by studies using mutated mice strains that infer specific α1-AR subtype functions through evaluation of behavioral phenotypes.

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Abbreviations

AR:

adrenergic receptor

CAM:

constitutively active mutant

cAMP:

cyclic adenosine monophosphate

CMS:

chronic mild stress

CNS:

central nervous system

CRF/CRH:

corticotropin releasing factor/hormone

ECS:

electroconvulsive shock

FST:

forced swim test

GPCR:

G-protein-coupled receptor

GRK:

G-protein-coupled receptor kinase

HPA:

hypothalamic-pituitary-adrenocortical

KO:

knockout

MSA:

multiple system atrophy

PCA:

p-chloroamphetamine

PKA:

protein kinase A

PKC:

protein kinase C

PLC:

phospholipase Cβ

TCA:

tricyclic antidepressant drug

TGFβ:

transforming growth factor β3

TST:

tail suspension test

WT:

wild-type

References

  1. Berridge CW, Waterhouse BD: The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev, 2003, 42, 33–84.

    Article  PubMed  Google Scholar 

  2. Bielawski A, Kowalska M, Rafa-Zabłocka K, Papp M, Nalepa I: Involvement of cerebral α1-adrenergic receptors in responsiveness to chronic mild stress and imipramine treatment. Pharmacol Rep, 2012, 64, 487.

    Article  Google Scholar 

  3. Chalothorn D, McCune DF, Edelmann SE, García-Cazarín ML, Tsujimoto G, Piascik MT: Differences in the cellular localization and agonist-mediated internalization properties of the α1-adrenoceptor subtypes. Mol Pharmacol, 2002, 6, 1008–1016.

    Article  Google Scholar 

  4. Chen ZJ, Minneman KP: Recent progress in α1-adrenergic receptor research. Acta Pharmacol Sin, 2005, 26, 1281–1287.

    Article  CAS  PubMed  Google Scholar 

  5. Cotecchia S: The α1-adrenergic receptors: diversity of signaling networks and regulation. J Recept Signal Transduct Res, 2010, 30, 410–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Day HE, Campeau S, Watson SJ Jr, Akil H: Distribution of α1a-, α1b- and α1d-adrenergic receptor mRNA in the rat brain and spinal cord. J Chem Neuroanat, 1997, 13, 115–139.

    Article  CAS  PubMed  Google Scholar 

  7. Day HE, Campeau S, Watson SJ Jr, Akil H: Expression of α1b adrenoceptor mRNA in corticotropin-releasing hormone-containing cells of the rat its regulation by corticosterone. J Neurosci, 1999, 19, 10098–10106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Docherty JR: Subtypes of functional α1-adrenoceptor. Cell Mol Life Sci, 2010, 67, 405–417.

    Article  CAS  PubMed  Google Scholar 

  9. Doze VA, Handel EM, Jensen KA, Darsie B, Luger EJ, Haselton JR, Talbot JN, Rorabaugh BR: α1A- and α1B-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse. Brain Res, 2009, 1285, 148–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Doze VA, Papay RS, Goldenstein BL, Gupta MK, Collette KM, Nelson BW, Lyons MJ et al: Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. Mol Pharmacol, 2011, 80, 747–758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Drouin C, Blanc G, Villégier AS, Glowinski J, Tassin JP: Critical role of α1-adrenergic receptors in acute and sensitized locomotor effects of D-amphetamine, cocaine, and GBR 12783: influence of preexposure conditions and pharmacological characteristics. Synapse, 2002, 43, 51–61.

    Article  CAS  PubMed  Google Scholar 

  12. Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia S, Tassin JP: α1b-Adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates. J Neurosci, 2002, 22, 2873–2884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Deupree JD, Reed AL, Bylund DB: Differential effects of the tricyclic antidepressant desipramine on the density of adrenergic receptors in juvenile and adult rats. J Pharmacol Exp Ther, 2007, 321, 770–776.

    Article  CAS  PubMed  Google Scholar 

  14. Fürst S: Transmitters involved in antinociception in the spinal cord. Brain Res Bull, 1999, 48, 129–141.

    Article  PubMed  Google Scholar 

  15. García-Sáinz JA, Villalobos-Molina R: The elusive α1D-adrenoceptor: molecular and cellular characteristics and integrative roles. Eur J Pharmacol, 2004, 500, 113–120.

    Article  PubMed  CAS  Google Scholar 

  16. Gonzalez-Cabrera PJ, Gaivin RJ, Yun J, Ross SA, Papay RS, McCune DF, Rorabaugh BR, Perez DM: Genetic profiling of α1-adrenergic receptor subtypes by oligonucleotide microarrays: coupling to interleukin-6 secretion but differences in STAT3 phosphorylation and gp-130. Mol Pharmacol, 2003, 63, 1104–1116.

    Article  CAS  PubMed  Google Scholar 

  17. Gupta MK, Papay RS, Jurgens CW, Gaivin RJ, Shi T, Doze VA, Perez DM: α1-Adrenergic receptors regulate neurogenesis and gliogenesis. Mol Pharmacol, 2009, 76, 314–326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hague C, Uberti MA, Chen Z, Hall RA, Minneman KP: Cell surface expression of α1D-adrenergic receptors is controlled by heterodimerization with α1B-adrenergic receptors. J Biol Chem, 2004, 279, 15541–15549.

    Article  CAS  PubMed  Google Scholar 

  19. Harasawa I, Honda K, Tanoue A, Shinoura H, Ishida Y, Okamura H, Murao N et al.: Responses to noxious stimuli in mice lacking α1d-adrenergic receptors. Neuroreport, 2003, 14, 1857–1860.

    Article  CAS  PubMed  Google Scholar 

  20. Kingery WS, Agashe GS, Guo TZ, Sawamura S, Davies MF, Clark JD, Kobilka BK, Maze M: Isoflurane and nociception: spinal α2A adrenoceptors mediate antinociception while supraspinal α1 adrenoceptors mediate pronociception. Anesthesiology, 2002, 96, 367–374.

    Article  CAS  PubMed  Google Scholar 

  21. Knauber J, Müller WE: Decreased exploratory activity and impaired passive avoidance behaviour in mice deficient for the α1b-adrenoceptor. Eur Neuropsychopharmacol, 2000, 10, 423–427.

    Article  CAS  PubMed  Google Scholar 

  22. Kreiner G, Bielawski A, Zelek-Molik A, Kowalska M, Nalepa I: Chronic treatment with citalopram does not affect the expression of a1-adrenergic receptor (α1-AR) subtypes. Pol J Pharmacol, 2004, 56, 831–836.

    CAS  PubMed  Google Scholar 

  23. Kreiner G, Sanak M, Zelek-Molik A, Nalepa I: Using reverse transcription and a competitive polymerase chain reaction for quantification of α1B-adrenoceptor mRNA. Pol J Pharmacol, 2002, 54, 401–405.

    CAS  PubMed  Google Scholar 

  24. Kreiner G, Zelek–Molik A, Kowalska M, Bielawski A, Antkiewicz–Michaluk L, Nalepa I: Effects of noradrenergic neurotoxin DSP-4 on expression of α1-adrenoceptor subtypes after antidepressant treatment. Pharmacol Rep, 2011, 63, 1349–1358.

    Article  CAS  PubMed  Google Scholar 

  25. Krishnan V, Nestler EJ: The molecular neurobiology of depression. Nature, 2008, 455, 894–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Michelotti GA, Price DT, Schwinn DA: α1-Adrenergic receptor regulation: basic science and clinical implications. Pharmacol Ther, 2000, 88, 281–309.

    Article  CAS  PubMed  Google Scholar 

  27. Mishima K, Tanoue A, Tsuda M, Hasebe N, Fukue Y, Egashira N, Takano Y et al.: Characteristics of behavioral abnormalities in α1d-adrenoceptors deficient mice. Behav Brain Res, 2004, 152, 365–373.

    Article  CAS  PubMed  Google Scholar 

  28. Nalepa I: The effect of psychotropic drugs on the interaction of protein kinase C with second messenger systems in the rat cerebral cortex. Pol J Pharmacol, 1994, 46, 1–14.

    Article  CAS  PubMed  Google Scholar 

  29. Nalepa I, Kreiner G, Kowalska M, Sanak M, Zelek-Molik A, Vetulani J: Repeated imipramine and electroconvulsive shock increase α1A-adrenoceptor mRNA level in rat prefrontal cortex. Eur J Pharmacol, 2002, 444, 151–159.

    Article  CAS  PubMed  Google Scholar 

  30. Nalepa I, Sulser F: New Hypotheses to guide Future Antidepressant Drug Development. In: Antidepressants: Past, Present and Future. Handbook of Experimental Pharmacology Vol. 157. Eds. Preskorn SH, Stanga C, Feighner JP, Ross R, Springer-Verlag, London, 2004, 519–563.

    Chapter  Google Scholar 

  31. Nalepa I, Vetulani J: Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram. J Neurochem, 1993, 60, 2029–2035.

    Article  CAS  PubMed  Google Scholar 

  32. Nalepa I, Vetulani J: The responsiveness of cerebral cortical adrenergic receptors after chronic administration of atypical antidepressant mianserin. J Psychiatry Neurosci, 1994, 19, 120–128.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Nalepa I, Vetulani J, Borghi V, Kowalska M, Przewłocka B, Pavone F: Formalin hindpaw injection induces changes in the [3H]prazosin binding to α1-adrenoceptors in specific regions of the mouse brain and spinal cord. J Neural Transm, 2005, 112, 1309–1319.

    Article  CAS  PubMed  Google Scholar 

  34. Nalepa I, Witarski T, Kowalska M, Filip M, Vetulani J: The effect of cocaine sensitization on α1-adrenoceptors in brain regions of the rat: an autoradiographic study. Pharmacol Rep, 2006, 58, 827–835.

    CAS  PubMed  Google Scholar 

  35. Nowacka M, Obuchowicz E: BDNF and VEGF in the pathogenesis of stress-induced affective diseases: An insight from experimental studies. Pharmacol Rep, 2013, 65, 535–446.

    Article  CAS  PubMed  Google Scholar 

  36. Pan WH, Yang SY, Lin SK: Neurochemical interaction between dopaminergic and noradrenergic neurons in the medial prefrontal cortex. Synapse, 2004, 53, 44–52.

    Article  CAS  PubMed  Google Scholar 

  37. Papay R, Gaivin R, Jha A, McCune DF, McGrath JC, Rodrigo MC, Simpson PC et al.: Localization of the mouse α1A-adrenergic receptor (AR) in the brain: α1AAR is expressed in neurons, GABAergic interneurons, and NG2 oligodendrocyte progenitors. J Comp Neurol, 2006, 497, 209–222.

    Article  CAS  PubMed  Google Scholar 

  38. Piascik MT, Perez DM: α1-Adrenergic receptors: new insights and directions. J Pharmacol Exp Ther, 2001, 298, 403–410.

    CAS  PubMed  Google Scholar 

  39. Robinson TE, Berridge KC: Addiction. Annu Rev Psychol, 2003, 54, 25–53.

    Article  PubMed  Google Scholar 

  40. Sadalge A, Coughlin L, Fu H, Wang B, Valladares O, Valentino R, Blendy JA: α1d Adrenoceptor signaling is required for stimulus induced locomotor activity. Mol Psychiatry, 2003, 8, 664–672.

    Article  CAS  PubMed  Google Scholar 

  41. Sirviö J, MacDonald E: Central α1-adrenoceptors: Their role in the modulation of attention and memory formation. Pharmacol Ther, 1999, 83, 49–65.

    Article  PubMed  Google Scholar 

  42. Spreng M, Cotecchia S, Schenk F: A behavioral study of alpha-1b adrenergic receptor knockout mice: increased reaction to novelty and selectively reduced learning capacities. Neurobiol Learn Mem, 2001, 75, 214–229.

    Article  CAS  PubMed  Google Scholar 

  43. Stone EA, Lin Y, Quartermain D: A final common pathway for depression? Progress toward a general conceptual framework. Neurosci Biobehav Rev, 2008, 32, 508–524.

    Article  PubMed  Google Scholar 

  44. Stone EA, Quartermain D, Lin Y, Lehmann ML: Central α1-adrenergic system in behavioral activity and depression. Biochem Pharmacol, 2007, 73, 1063–1075.

    Article  CAS  PubMed  Google Scholar 

  45. Stone EA, Zhang Y, Rosengarten H, Yeretsian J, Quartermain D: Brain α1-adrenergic neurotransmission is necessary for behavioral activation to environmental change in mice. Neuroscience, 1999, 94, 1245–1252.

    Article  CAS  PubMed  Google Scholar 

  46. Tanoue A, Koshimizu T, Shibata K, Nasa Y, Takeo S, Tsujimoto G: Insights into α1 adrenoceptor function in health and disease from transgenic animal studies. Trends Endocrinol Metab, 2003, 14, 107–113.

    Article  CAS  PubMed  Google Scholar 

  47. Tassin JP: Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse. Biochem Pharmacol, 2008, 75, 85–97.

    Article  CAS  PubMed  Google Scholar 

  48. Vetulani J, Nalepa I: Antidepressants: past, present and future. Eur J Pharmacol, 2000, 405, 351–363.

    Article  CAS  PubMed  Google Scholar 

  49. Wieczerzak K, Witarski T, Kowalska M, Nawrat D, Roman A, Bielawski A, Nalepa I: Effect of cocaine on responsiveness of α1-adrenergic receptors in rat cerebral cortex: Modulation by GABA-mimetic drugs. Pharmacol Rep, 2008, 60, 980–984.

    CAS  PubMed  Google Scholar 

  50. Willner P, Muscat R, Papp M: Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev, 1992, 16, 525–534.

    Article  CAS  PubMed  Google Scholar 

  51. Yun J, Gaivin RJ, McCune DF, Boongird A, Papay RS, Ying Z, Gonzalez-Cabrera PJ et al.: Gene expression profile of neurodegeneration induced by α1B-adrenergic receptor overactivity: NMDA/GABAA dysregulation and apoptosis. Brain, 2003, 126, 2667–2681.

    Article  PubMed  Google Scholar 

  52. Zhang XY, Kosten TA: Prazosin, an a-1 adrenergic antagonist, reduces cocaine-induced reinstatement of drug-seeking. Biol Psychiatry, 2005, 57, 1202–1204.

    Article  CAS  PubMed  Google Scholar 

  53. Zuscik MJ, Sands S, Ross SA, Waugh DJ, Gaivin RJ, Morilak D, Perez DM: Overexpression of the α1B-adrenergic receptor causes apoptotic neurodegeneration: multiple system atrophy. Nat Med, 2000, 6, 1388–1394.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Smętna 12, PL 31-343, Poland

    Irena Nalepa, Grzegorz Kreiner, Adam Bielawski, Katarzyna Rafa-Zabłocka & Adam Roman

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  1. Irena Nalepa
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  2. Grzegorz Kreiner
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  3. Adam Bielawski
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  4. Katarzyna Rafa-Zabłocka
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  5. Adam Roman
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Correspondence to Irena Nalepa.

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Nalepa, I., Kreiner, G., Bielawski, A. et al. α1-Adrenergic receptor subtypes in the central nervous system: insights from genetically engineered mouse models. Pharmacol. Rep 65, 1489–1497 (2013). https://doi.org/10.1016/S1734-1140(13)71509-3

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  • DOI: https://doi.org/10.1016/S1734-1140(13)71509-3

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