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Differential modulation of alpha-1 adrenoceptor subtypes by antidepressants in the rat brain

  • Biological Psychiatry - Original Article
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Abstract

The aim of the present study was to examine the effect of chronic antidepressants treatment on the density of α1-adrenoceptor (AR) subtypes in rat brain. Density of total α1 and α1A- and α1Β-ARs was measured in cortex and cerebellum of rats treated with amitriptyline (AMI), desipramine (DMI) and fluoxetine (FLX), (10 mg/kg body wt), for 30 days, using [3H]prazosin in presence and absence of WB-4101. The density of cortical total α1-ARs was significantly decreased with AMI (54%) and DMI (25%) treatment, without altering the affinity of the receptor. Fluoxetine did not alter the density of cortical α1-ARs. The density of cortical α1A-ARs was also significantly decreased with AMI (85%) and DMI (50%) treatment, without affecting the affinity. The density of cerebellar total α1-ARs was significantly decreased with AMI (37%), DMI (50%) and FLX (70%) treatment, without affecting the affinity for [3H]prazosin. The density of α1A-ARs was significantly decreased with AMI (67%), DMI (59%) and FLX (92%) treatment. α1B-AR density was decreased only with FLX (47%) and DMI (47%) treatment. Correspondingly the basal IP3 and NE (10 μM) stimulated IP3 levels were significantly decreased in AMI (47%), DMI (22%) and FLX (48%) treated rat cortex. The results suggest that chronic antidepressant (AD) treatment down-regulates the cortical and cerebellar total α1-ARs in rat brain. However, α1A subtype is predominantly down-regulated by AMI and DMI, where as FLX affects cerebellar α1A-ARs. The region-specific and subtype specific down-regulation of α1-ARs density, which occurs after prolonged AD treatment, may underline the therapeutic mechanism of action.

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References

  • Ahlquist RP (1948) A study of the adrenotropic receptors. Am J Physiol 153:586–600

    CAS  PubMed  Google Scholar 

  • Arango V, Underwood MD, Mann JJ (1996) Fewer pigmented locus coeruleus neurons in suicide victims: preliminary results. Biol Psychiatry 39:112–120

    Article  CAS  PubMed  Google Scholar 

  • Arango V, Underwood MD, Mann JJ (2002) Serotonin brain circuits involved in major depression and suicide. Prog Brain Res 136:443–453

    Article  CAS  PubMed  Google Scholar 

  • Brunello N, Riva M, Volterra A, Racagni G (1987) Effect of some tricyclic and nontricyclic antidepressants on [3H]imipramine binding and serotonin uptake in rat cerebral cortex after prolonged treatment. Fundam Clin Pharmacol 1:327–333

    Article  CAS  PubMed  Google Scholar 

  • Callado LF, Meana JJ, Grijalba B, Pazos A, Sastre M, Garcia-Sevilla JA (1998) Selective increase of alpha2A-adrenoceptor agonist binding sites in brains of depressed suicide victims. J Neurochem 70:1114–1123

    Article  CAS  PubMed  Google Scholar 

  • Charney DS, Menkes DB, Heninger GR (1981) Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression. Arch Gen Psychiatry 38:1160–1180

    CAS  PubMed  Google Scholar 

  • Chen S, Lin F, Iismaa S, Lee KN, Birckbichler PJ, Graham RM (1996) Alpha1-adrenergic receptor signaling via Gh is subtype specific and independent of its transglutaminase activity. J Biol Chem 271:32385–32391

    Article  CAS  PubMed  Google Scholar 

  • Chuang DM (1989) Neurotransmitter receptors and phosphoinositide turnover. Annu Rev Pharmacol Toxicol 29:71–110

    Article  CAS  PubMed  Google Scholar 

  • Coge F, Guenin SP, Renouard-Try A, Rique H, Ouvry C, Fabry N, Beauverger P, Nicolas JP, Galizzi JP, Boutin JA, Canet E (1999) Truncated isoforms inhibit [3H]prazosin binding and cellular trafficking of native human alpha1A-adrenoceptors. Biochem J 343(Pt 1):231–239

    Article  CAS  PubMed  Google Scholar 

  • Cordi AA, Berque-Bestel I, Persigand T, Lacoste JM, Newman-Tancredi A, Audinot V, Millan MJ (2001) Potential antidepressants displayed combined alpha(2)-adrenoceptor antagonist and monoamine uptake inhibitor properties. J Med Chem 44:787–805

    Article  CAS  PubMed  Google Scholar 

  • Creese I, Snyder SH (1978) 3H-Spiroperidol labels serotonin receptors in rat cerebral cortex and hippocampus. Eur J Pharmacol 49:201–202

    Article  CAS  PubMed  Google Scholar 

  • Devaki R, Shankar RS, Nadgir SM (2006) The effect of lithium on the adrenoceptor-mediated second messenger system in the rat brain. J Psychiatry Neurosci 31:246–252

    PubMed  Google Scholar 

  • Dinan TG (1996) Noradrenergic and serotonergic abnormalities in depression: stress-induced dysfunction? J Clin Psychiatry 57(Suppl 4):14–18

    CAS  PubMed  Google Scholar 

  • Esteban S, Llado J, Sastre-Coll A, Garcia-Sevilla JA (1999) Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo. Naunyn Schmiedebergs Arch Pharmacol 360:135–143

    Article  CAS  PubMed  Google Scholar 

  • Fu CH, Reed LJ, Meyer JH, Kennedy S, Houle S, Eisfeld BS, Brown GM (2001) Noradrenergic dysfunction in the prefrontal cortex in depression: an [15O] H2O PET study of the neuromodulatory effects of clonidine. Biol Psychiatry 49:317–325

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Sevilla JA, Zubieta JK (1986) Activation and desensitization of presynaptic alpha 2-adrenoceptors after inhibition of neuronal uptake by antidepressant drugs in the rat vas deferens. Br J Pharmacol 89:673–683

    CAS  PubMed  Google Scholar 

  • Garcia-Sevilla JA, Padro D, Giralt MT, Guimon J, Areso P (1990) Alpha 2-adrenoceptor-mediated inhibition of platelet adenylate cyclase and induction of aggregation in major depression. Effect of long-term cyclic antidepressant drug treatment. Arch Gen Psychiatry 47:125–132

    CAS  PubMed  Google Scholar 

  • Garcia-Sevilla JA, Escriba PV, Ozaita A, La HR, Walzer C, Eytan A, Guimon J (1999) Up-regulation of immunolabeled alpha2A-adrenoceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides. J Neurochem 72:282–291

    Article  CAS  PubMed  Google Scholar 

  • Graham RM, Perez DM, Hwa J, Piascik MT (1996) alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling. Circ Res 78:737–749

    CAS  PubMed  Google Scholar 

  • Hauger RL, Risbrough V, Oakley RH, Olivares-Reyes JA, Dautzenberg FM (2009) Role of CRF receptor signaling in stress vulnerability, anxiety, and depression. Ann N Y Acad Sci 1179:120–143

    Article  CAS  PubMed  Google Scholar 

  • Hirasawa A, Shibata K, Horie K, Takei Y, Obika K, Tanaka T, Muramoto N, Takagaki K, Yano J, Tsujimoto G (1995) Cloning, functional expression and tissue distribution of human alpha 1c-adrenoceptor splice variants. FEBS Lett 363:256–260

    Article  CAS  PubMed  Google Scholar 

  • Hyttel J, Nielsen JB, Nowak G (1992) The acute effect of sertindole on brain 5-HT2, D2 and alpha 1 receptors (ex vivo radioreceptor binding studies). J Neural Transm Gen Sect 89:61–69

    Article  CAS  PubMed  Google Scholar 

  • Invernizzi RW, Parini S, Sacchetti G, Fracasso C, Caccia S, Annoni K, Samanin R (2001) Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize alpha(2)-adrenoceptors in the prefrontal cortex. Br J Pharmacol 132:183–188

    Article  CAS  PubMed  Google Scholar 

  • Klimek V, Stockmeier C, Overholser J, Meltzer HY, Kalka S, Dilley G, Ordway GA (1997) Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci 17:8451–8458

    CAS  PubMed  Google Scholar 

  • Klimek V, Rajkowska G, Luker SN, Dilley G, Meltzer HY, Overholser JC, Stockmeier CA, Ordway GA (1999) Brain noradrenergic receptors in major depression and schizophrenia. Neuropsychopharmacology 21:69–81

    Article  CAS  PubMed  Google Scholar 

  • Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown TG Jr (1967) Differentiation of receptor systems activated by sympathomimetic amines. Nature 214:597–598

    Article  CAS  PubMed  Google Scholar 

  • Langer SZ (1974) Presynaptic regulation of catecholamine release. Biochem Pharmacol 23:1793–1800

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Mann JJ (1999) Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior. Neuropsychopharmacology 21:99S–105S

    CAS  PubMed  Google Scholar 

  • Mateo Y, Fernandez-Pastor B, Meana JJ (2001) Acute and chronic effects of desipramine and clorgyline on alpha(2)-adrenoceptors regulating noradrenergic transmission in the rat brain: a dual-probe microdialysis study. Br J Pharmacol 133:1362–1370

    Article  CAS  PubMed  Google Scholar 

  • McPherson GA (1983) A practical computer-based approach to the analysis of radioligand binding experiments. Comput Programs Biomed 17:107–113

    Google Scholar 

  • Michelotti GA, Price DT, Schwinn DA (2000) Alpha 1-adrenergic receptor regulation: basic science and clinical implications. Pharmacol Ther 88:281–309

    Article  CAS  PubMed  Google Scholar 

  • Mongeau R, de MC, Blier P (1994) Electrophysiologic evidence for desensitization of alpha 2-adrenoceptors on serotonin terminals following long-term treatment with drugs increasing norepinephrine synaptic concentration. Neuropsychopharmacology 10:41–51

    CAS  PubMed  Google Scholar 

  • Nalepa I, Kreiner G, Kowalska M, Sanak M, Zelek-Molik A, Vetulani J (2002) Repeated imipramine and electroconvulsive shock increase alpha 1A-adrenoceptor mRNA level in rat prefrontal cortex. Eur J Pharmacol 444:151–159

    Article  CAS  PubMed  Google Scholar 

  • Nowak G, Przegalinski E (1988) Effect of repeated treatment with antidepressant drugs and electroconvulsive shock (ECS) on [3H] prazosin binding to different rat brain structures. J Neural Transm 71:57–64

    Article  CAS  PubMed  Google Scholar 

  • Ordway GA, Widdowson PS, Smith KS, Halaris A (1994) Agonist binding to alpha 2-adrenoceptors is elevated in the locus coeruleus from victims of suicide. J Neurochem 63:617–624

    Article  CAS  PubMed  Google Scholar 

  • Pacheco MA, Stockmeier C, Meltzer HY, Overholser JC, Dilley GE, Jope RS (1996) Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain. Brain Res 723:37–45

    Article  CAS  PubMed  Google Scholar 

  • Pilc A, Enna SJ (1985) Synergistic interaction between alpha- and beta-adrenergic receptors in rat brain slices: possible site for antidepressant drug action. Life Sci 37:1183–1194

    Article  CAS  PubMed  Google Scholar 

  • Rehavi M, Ramot O, Yavetz B, Sokolovsky M (1980) Amitriptyline: long-term treatment elevates alpha-adrenergic and muscarinic receptor binding in mouse brain. Brain Res 194:443–453

    Article  CAS  PubMed  Google Scholar 

  • Ressler KJ, Nemeroff CB (1999) Role of norepinephrine in the pathophysiology and treatment of mood disorders. Biol Psychiatry 46:1219–1233

    Article  CAS  PubMed  Google Scholar 

  • Sacchetti G, Bernini M, Gobbi M, Parini S, Pirona L, Mennini T, Samanin R (2001) Chronic treatment with desipramine facilitates its effect on extracellular noradrenaline in the rat hippocampus: studies on the role of presynaptic alpha2-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 363:66–72

    Article  CAS  PubMed  Google Scholar 

  • Schwinn DA, Johnston GI, Page SO, Mosley MJ, Wilson KH, Worman NP, Campbell S, Fidock MD, Furness LM, Parry-Smith DJ (1995) Cloning and pharmacological characterization of human alpha-1 adrenergic receptors: sequence corrections and direct comparison with other species homologues. J Pharmacol Exp Ther 272:134–142

    CAS  PubMed  Google Scholar 

  • Stanasila L, Perez JB, Vogel H, Cotecchia S (2003) Oligomerization of the alpha 1a- and alpha 1b-adrenergic receptor subtypes. Potential implications in receptor internalization. J Biol Chem 278:40239–40251

    Article  CAS  PubMed  Google Scholar 

  • Stockmeier CA, McLeskey SW, Blendy JA, Armstrong NR, Kellar KJ (1987) Electroconvulsive shock but not antidepressant drugs increases alpha 1-adrenoceptor binding sites in rat brain. Eur J Pharmacol 139:259–266

    Article  CAS  PubMed  Google Scholar 

  • Subhash MN, Jagadeesh S (1997) Imipramine-induced changes in 5-HT2 receptor sites and inositoltrisphosphate levels in rat brain. Neurochem Res 22:1095–1099

    Article  CAS  PubMed  Google Scholar 

  • Subhash MN, Srinivas BN, Vinod KY, Jagadeesh S (1998) Inactivation of 5-HT1A and [3H]5-HT binding sites by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) in rat brain. Neurochem Res 23:1321–1326

    Article  CAS  PubMed  Google Scholar 

  • Subhash MN, Srinivas BN, Vinod KY, Jagadeesh S (2000) Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain. J Neural Transm 107:377–387

    Article  CAS  PubMed  Google Scholar 

  • Theroux TL, Esbenshade TA, Peavy RD, Minneman KP (1996) Coupling efficiencies of human alpha 1-adrenergic receptor subtypes: titration of receptor density and responsiveness with inducible and repressible expression vectors. Mol Pharmacol 50:1376–1387

    CAS  PubMed  Google Scholar 

  • Toews ML, Prinster SC, Schulte NA (2003) Regulation of alpha-1B adrenergic receptor localization, trafficking, function, and stability. Life Sci 74:379–389

    Article  CAS  PubMed  Google Scholar 

  • VanderMaelen CP, Braselton JP (1990) Acute administration of the antidepressant trazodone increases noradrenergic locus coeruleus neuronal firing in rats. Arch Int Pharmacodyn Ther 308:13–20

    CAS  PubMed  Google Scholar 

  • Vetulani J, Antkiewicz-Michaluk L, Rokosz-Pelc A, Pilc A (1983) Chronic electroconvulsive treatment enhances the density of [3H]prazosin binding sites in the central nervous system of the rat. Brain Res 275:392–395

    Article  CAS  PubMed  Google Scholar 

  • Vila E, Salles J, Badia A (1990) Effects of chronic antidepressant treatment on alpha 1- and alpha 2-adrenoceptors in the rat anococcygeus muscle. J Neural Transm Gen Sect 82:205–212

    Article  CAS  PubMed  Google Scholar 

  • Wroblewski BA, Joseph AB, Cornblatt RR (1996) Antidepressant pharmacotherapy and the treatment of depression in patients with severe traumatic brain injury: a controlled, prospective study. J Clin Psychiatry 57:582–587

    Article  CAS  PubMed  Google Scholar 

  • Zhong H, Lee D, Robeva A, Minneman KP (2001) Signaling pathways activated by alpha1-adrenergic receptor subtypes in PC12 cells. Life Sci 68:2269–2276

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Indian Council of Medical Research, New Delhi (Project No. 9800140). We thank Kamineni Institute of Medical Sciences for constant encouragement and support to publish this work and Dr. Pragna Rao for reviewing the draft article.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Kamineni Institute of Medical Sciences, Sreepuram, Narketpally, Nalgonda, 508254, Andhra Pradesh, India

    D. Ramakrishna

  2. National Institute of Mental Health and Neurosciences, Hosur Road, P.B.No.2900, Bangalore, 560029, India

    M. N. Subhash

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Ramakrishna, D., Subhash, M.N. Differential modulation of alpha-1 adrenoceptor subtypes by antidepressants in the rat brain. J Neural Transm 117, 1423–1430 (2010). https://doi.org/10.1007/s00702-010-0522-4

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  • DOI: https://doi.org/10.1007/s00702-010-0522-4

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