Abstract
The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including α-1, α-2, β-1, and β-2 subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the α-2 adrenergic antagonist idazoxan (0.1–2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5–2.5 mg/kg, i.p.) or centrally (1–10 μg, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the β-adrenergic antagonists propranolol and CGP-12177 or the α-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of β-adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in β-1, β-2, or both β-1 and β-2 adrenergic receptors. In addition, desipramine (3–30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both β-1 and β-2 adrenergic receptors. As antagonism of presynaptic α-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic α-2 adrenergic receptors play an important role in its antidepressant effects.
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References
Brodde OE, Daul A, Michel MC (1990). Subtype-selective modulation of human beta 1- and beta 2-adrenoceptor function by beta-adrenoceptor agonists and antagonists. Clin Physiol Biochem 8: 11–17.
Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP et al (1994). International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46: 121–136.
Callado LF, Gabilondo AM, Meana JJ (1999). Differential modulation of alpha2-adrenoceptor subtypes in rat kidney by chronic desipramine treatment. Life Sci 64: 2327–2339.
Cervo L, Grignaschi G, Samanin R (1990). Alpha 2-adrenoceptor blockade prevents the effect of desipramine in the forced swimming test. Eur J Pharmacol 175: 301–307.
Chruscinski AJ, Rohrer DK, Schauble E, Desai KH, Bernstein D, Kobilka BK (1999). Targeted disruption of the beta2 adrenergic receptor gene. J Biol Chem 274: 16694–16700.
Crissman AM, Makhay MM, O'Donnell JM (2001). Discriminative stimulus effects of centrally administered isoproterenol in rats: mediation by beta-1 adrenergic receptors. Psychopharmacology (Berl) 154: 70–75.
Crissman AM, O'Donnell JM (2002). Effects of antidepressants in rats trained to discriminate centrally administered isoproterenol. J Pharmacol Exp Ther 302: 606–611.
Cryan JF, Valentino RJ, Lucki I (2005). Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29: 547–569.
Curet O, De Montigny C, Blier P (1992). Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain. Eur J Pharmacol 221: 59–70.
Dableh LJ, Yashpal K, Rochford J, Henry JL (2005). Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat. Eur J Pharmacol 507: 99–105.
Daws LC, Lopez R, Frazer A (1998). Effects of antidepressant treatment on inhibitory avoidance behavior and amygdaloid beta-adrenoceptors in rats. Neuropsychopharmacology 19: 300–313.
Dekeyne A, Gobert A, Auclair A, Girardon S, Millan MJ (2002). Differential modulation of efficiency in a food-rewarded ‘differential reinforcement of low-rate’ 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors. Psychopharmacology (Berl) 162: 156–167.
Dennis T, L'Heureux R, Carter C, Scatton B (1987). Presynaptic alpha-2 adrenoceptors play a major role in the effects of idazoxan on cortical noradrenaline release (as measured by in vivo dialysis) in the rat. J Pharmacol Exp Ther 241: 642–649.
Duman CH, Schlesinger L, Kodama M, Russell DS, Duman RS (2007). A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol Psychiatry 61: 661–670.
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.
Finn DP, Martí O, Harbuz MS, Vallès A, Belda X, Márquez C et al (2003). Behavioral, neuroendocrine and neurochemical effects of the imidazoline I2 receptor selective ligand BU224 in naive rats and rats exposed to the stress of the forced swim test. Psychopharmacology (Berl) 167: 195–202.
Frazer A (2000). Norepinephrine involvement in antidepressant action. J Clin Psychiatry 61: 25–30.
Garcia AS, Barrera G, Burke TF, Ma S, Hensler JG, Morilak DA (2004). Autoreceptor-mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment. J Neurochem 91: 683–693.
Garcia-Sevilla JA, Escriba PV, Guimon J (1999a). Imidazoline receptors and human brain disorders. Ann NY Acad Sci 881: 392–409.
Garcia-Sevilla JA, Escriba PV, Ozaita A, La Harpe R, Walzer C, Eytan A et al (1999b). 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.
Ge ZJ, Zeng YM, Tan YF (2005). Effects of intrathecal 6-hydroxydopamine, alpha1 and alpha2 adrenergic receptor antagonists on antinociception of propofol in mice. Acta Pharmacol Sin 26: 186–191.
Gillman PK (2007). Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 151: 737–748.
González AM, Pascual J, Meana JJ, Barturen F, del Arco C, Pazos A et al (1994). Autoradiographic demonstration of increased alpha 2-adrenoceptor agonist binding sites in the hippocampus and frontal cortex of depressed suicide victims. J Neurochem 63: 256–265.
Haller J, Makara GB, Pintér I, Gyertyán I, Egyed A (1997). The mechanism of action of alpha 2 adrenoceptor blockers as revealed by effects on open field locomotion and escape reactions in the shuttle-box. Psychopharmacology (Berl) 134: 107–114.
Hieble JP (2007). Subclassification and nomenclature of alpha- and beta-adrenoceptors. Curr Top Med Chem 7: 129–134.
Invernizzi RW, Garattini S (2004). Role of presynaptic alpha2-adrenoceptors in antidepressant action: recent findings from microdialysis studies. Prog Neuropsychopharmacol Biol Psychiatry 28: 819–827.
Itoi K, Suda T, Tozawa F, Dobashi I, Ohmori N, Sakai Y et al (1994). Microinjection of norepinephrine into the paraventricular nucleus of the hypothalamus stimulates corticotropin-releasing factor gene expression in conscious rats. Endocrinology 135: 2177–2182.
Lapiz MD, Zhao Z, Bondi CO, O'Donnell JM, Morilak DA (2007). Blockade of autoreceptor-mediated inhibition of norepinephrine release by atipamezole is maintained after chronic reuptake inhibition. Int J Neuropsychopharmacol 10: 827–833.
Linner L, Arborelius L, Nomikos GG, Bertilsson L, Svensson TH (1999). Locus coeruleus neuronal activity and noradrenaline availability in the frontal cortex of rats chronically treated with imipramine: effect of alpha 2-adrenoceptor blockade. Biol Psychiatry 46: 766–774.
Lucki I, Dalvi A, Mayorga AJ (2001). Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology (Berl) 155: 315–322.
Maes M, Van Gastel A, Delmeire L, Meltzer HY (1999). Decreased platelet alpha-2 adrenoceptor density in major depression: effects of tricyclic antidepressants and fluoxetine. Biol Psychiatry 45: 278–284.
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.
McElroy JF, O'Donnell JM (1988). Discriminative stimulus properties of clenbuterol: evidence for beta adrenergic involvement. J Pharmacol Exp Ther 245: 155–163.
Menargues A, Obach R, García-Sevilla JA (1990). Modulation by antidepressant drugs of CNS postsynaptic alpha 2-adrenoceptors mediating mydriasis in the rat. Naunyn Schmiedebergs Arch Pharmacol 341: 101–107.
Miao CY, Xie HH, Yu H, Chu ZX, Su DF (2003). Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 30: 189–193.
Molinoff PB (1984). Alpha- and beta-adrenergic receptor subtypes properties, distribution and regulation. Drugs 28: 1–15.
Mongeau R, de Montigny C, 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.
Mügge A, Reupcke C, Scholz H (1985). Increased myocardial alpha 1 adrenoceptor density in rats chronically treated with propranolol. Eur J Pharmacol 112: 249–252.
Murugaiah KD, O'Donnell JM (1995). Facilitation of noradrenaline release from rat brain slices by beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 351: 483–490.
O'Donnell JM (1987). Effects of clenbuterol and prenalterol on performance during differential reinforcement of low response rate in the rat. J Pharmacol Exp Ther 241: 68–75.
O'Donnell JM (1990). Behavioral effects of beta adrenergic agonists and antidepressant drugs after down-regulation of beta-2 adrenergic receptors by clenbuterol. J Pharmacol Exp Ther 254: 147–157.
O'Donnell JM, Frith S, Wilkins J (1994). Involvement of beta-1 and beta-2 adrenergic receptors in the antidepressant-like effects of centrally administered isoproterenol. J Pharmacol Exp Ther 271: 246–254.
O'Donnell JM, Marek GJ, Seiden LS (2005). Antidepressant effects assessed using behavior maintained under a differential-reinforcement-of-low-rate (DRL) operant schedule. Neurosci Biobehav Rev 29: 785–798.
Ohkuma S, Katsura M, Shibasaki M, Tsujimura A, Hirouchi M (2006). Expression of beta-adrenergic receptor up-regulation is mediated by two different processes. Brain Res 1112: 114–125.
O'Neill MF, Osborne DJ, Woodhouse SM, Conway MW (2001). Selective imidazoline I2 ligands do not show antidepressant-like activity in the forced swim test in mice. J Psychopharmacol 15: 18–22.
Paetsch PR, Greenshaw AJ (1993). Effects of chronic antidepressant treatment on beta-adrenoceptor subtype binding in the rat cerebral cortex and cerebellum. Mol Chem Neuropathol 20: 21–31.
Pattij T, Broersen LM, van der Linde J, Groenink L, van der Gugten J, Maes RA et al (2003). Operant learning and differential-reinforcement-of-low-rate 36-s responding in 5-HT1A and 5-HT1B receptor knockout mice. Behav Brain Res 141: 137–145.
Poncelet M, Gaudel G, Danti S, Soubrié P, Simon P (1986). Acute versus repeated administration of desipramine in rats and mice: relationships between brain concentrations and reduction of immobility in the swimming test. Psychopharmacology (Berl) 90: 139–141.
Pulvirenti L, Samanin R (1986). Antagonism by dopamine, but not noradrenaline receptor blockers of the anti-immobility activity of desipramine after different treatment schedules in the rat. Pharmacol Res Commun 18: 73–80.
Reneric JP, Bouvard M, Stinus L (2001). Idazoxan and 8-OH-DPAT modify the behavioral effects induced by either NA, or 5-HT, or dual NA/5-HT reuptake inhibition in the rat forced swimming test. Neuropsychopharmacology 24: 379–390.
Rizk P, Salazar J, Raisman-Vozari R, Marien M, Ruberg M, Colpaert F et al (2006). The alpha2-adrenoceptor antagonist dexefaroxan enhances hippocampal neurogenesis by increasing the survival and differentiation of new granule cells. Neuropsychopharmacology 31: 1146–1157.
Rohrer DK, Chruscinski A, Schauble EH, Bernstein D, Kobilka BK (1999). Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors. J Biol Chem 274: 16701–16708.
Rohrer DK, Desai KH, Jasper JR, Stevens ME, Regula Jr DP, Barsh GS et al (1996). Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects. Proc Natl Acad Sci USA 93: 7375–7380.
Sallinen J, Haapalinna A, MacDonald E, Viitamaa T, Lahdesmaki J, Rybnikova E et al (1999). Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels. Mol Psychiatry 4: 443–452.
Sanacora G, Berman RM, Cappiello A, Oren DA, Kugaya A, Liu N et al (2004). Addition of the alpha2-antagonist yohimbine to fluoxetine: effects on rate of antidepressant response. Neuropsychopharmacology 29: 1166–1171.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301: 805–809.
Schramm NL, McDonald MP, Limbird LE (2001). The alpha(2a)-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J Neurosci 21: 4875–4882.
Segal M, Markram H, Richter-Levin G (1991). Actions of norepinephrine in the rat hippocampus. Prog Brain Res 88: 323–330.
Shen PJ, Gundlach AL (2000). Differential modulatory effects of alpha- and beta-adrenoceptor agonists and antagonists on cortical immediate-early gene expression following focal cerebrocortical lesion-induced spreading depression. Brain Res Mol Brain Res 83: 133–144.
Sokolowski JD, Seiden LS (1999). The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat. Psychopharmacology (Berl) 147: 153–161.
Steinkraus V, Nose M, Scholz H, Thormählen K (1989). Time course and extent of alpha 1-adrenoceptor density changes in rat heart after beta-adrenoceptor blockade. Br J Pharmacol 96: 441–449.
Stone EA, Lin Y, Quartermain D (2008). A final common pathway for depression? Progress toward a general conceptual framework. Neurosci Biobehav Rev 32: 508–524.
Subhash MN, Nagaraja MR, Sharada S, Vinod KY (2003). Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain. Neurochem Int 43: 603–609.
Thomas DN, Holman RB (1991). A microdialysis study of the regulation of endogenous noradrenaline release in the rat hippocampus. J Neurochem 56: 1741–1746.
Wallace-Boone TL, Newton AE, Wright RN, Lodge NJ, McElroy JF (2007). Behavioral and pharmacological validation of the gerbil forced-swim test: effects of neurokinin-1 receptor antagonists. Neuropsychopharmacology 33: 1919–1928.
Warner AL, Bellah KL, Raya TE, Roeske WR, Goldman S (1992). Effects of beta-adrenergic blockade on papillary muscle function and the beta-adrenergic receptor system in noninfarcted myocardium in compensated ischemic left ventricular dysfunction. Circulation 86: 1584–1595.
Wicke KM, Rex A, Jongen-Relo A, Groth I, Gross G (2007). The guinea pig forced swim test as a new behavioral despair model to characterize potential antidepressants. Psychopharmacology (Berl) 195: 95–102.
Yalcin I, Aksu F, Bodard S, Chalon S, Belzung C (2007). Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system. Behav Pharmacol 18: 623–631.
Zhang HT, Frith SA, Wilkins J, O'Donnell JM (2001). Comparison of the effects of isoproterenol administered into the hippocampus, frontal cortex, or amygdala on behavior of rats maintained by differential reinforcement of low response rate. Psychopharmacology (Berl) 159: 89–97.
Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M et al (2002). Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27: 587–595.
Zhang HT, Huang Y, Masood A, Stolinski LR, Li YF, Zhang L et al (2008). Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 33: 1611–1623.
Zhang HT, Huang Y, Mishler K, Roerig SC, O'Donnell JM (2005). Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram. Psychopharmacology (Berl) 182: 104–115.
Zhang HT, Huang Y, O'Donnell JM (2003). Antagonism of the antidepressant-like effects of clenbuterol by central administration of beta-adrenergic antagonists in rats. Psychopharmacology (Berl) 170: 102–107.
Zhang HT, Zhao Y, Huang Y, Deng C, Hopper AT, De Vivo M et al (2006). Antidepressant-like effects of PDE4 inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats. Psychopharmacology (Berl) 186: 209–217.
Zhang HT, Zhao Y, Huang Y, Dorairaj NR, Chandler LJ, O'Donnell JM (2004). Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Neuropsychopharmacology 29: 1432–1439.
Zhao Z, Baros AM, Zhang HT, Lapiz MD, Bondi CO, Morilak DA et al (2008). Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine. Neuropsychopharmacology, in press (April 16 2008, Epub ahead of print).
Acknowledgements
This work was supported by research grants (MH040694, MH051175, MH072646) from the National Institute of Mental Health. We thank Dr Brian K Kobilka of Stanford University School of Medicine for providing the β-adrenergic receptor KO mice and Mr Ajay K Venkatesan for his technical assistance.
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James M O'Donnell is on the Scientific Advisory Board of Fission Pharmaceuticals (unpaid). Han-Ting Zhang and James M O'Donnell have received financial support for their research from Memory Pharmaceuticals, Lundbeck Pharmaceuticals, and Wyeth Pharmaceuticals.
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Zhang, HT., Whisler, L., Huang, Y. et al. Postsynaptic α-2 Adrenergic Receptors are Critical for the Antidepressant-Like Effects of Desipramine on Behavior. Neuropsychopharmacol 34, 1067–1077 (2009). https://doi.org/10.1038/npp.2008.184
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