, Volume 231, Issue 5, pp 801–812 | Cite as

α2-Adrenoceptors are targets for antipsychotic drugs

  • Jan Brosda
  • Florian Jantschak
  • Heinz H. PertzEmail author



Almost all antipsychotic drugs (APDs), irrespective of whether they belong to the first-generation (e.g. haloperidol) or second-generation (e.g. clozapine), are dopamine D2 receptor antagonists. Second-generation APDs, which differ from first-generation APDs in possessing a lower propensity to induce extrapyramidal side effects, target a variety of monoamine receptors such as serotonin (5-hydroxytryptamine) receptors (e.g. 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7) and α1- and α2-adrenoceptors in addition to their antagonist effects at D2 receptors.


This short review is focussed on the potential role of α2-adrenoceptors in the antipsychotic therapy.


Schizophrenia is characterised by three categories of symptoms: positive symptoms, negative symptoms and cognitive deficits. α2-Adrenoceptors are classified into three distinct subtypes in mammals, α2A, α2B and α2C. Whereas the α2B-adrenoceptor seems to play only a minor role in the brain, activation of postsynaptic α2A-adrenoceptors in the prefrontal cortex improves cognitive functions. Preclinical models such as D-amphetamine-induced locomotion, the conditioned avoidance response and the pharmacological N-methyl-d-aspartate receptor hypofunction model have shown that α2C-adrenoceptor blockade or the combination of D2 receptor antagonists with idazoxan (α2A/2C-adrenoceptor antagonist) could be useful in schizophrenia. A potential benefit of a treatment combination of first-generation APDs with the α2A/2C-adrenoceptor antagonists idazoxan or mirtazapine was also demonstrated in patients with schizophrenia.


It is concluded that α2-adrenoceptors may be promising targets in the antipsychotic therapy.


Nucleus accumbens Prefrontal cortex Schizophrenia D2 receptor antagonists α2-Adrenoceptor agonists α2-Adrenoceptor antagonists 


Conflict of interest

The authors declare none.


  1. Abbasi SH, Behpournia H, Ghoreshi A, Salehi B, Raznahan M, Rezazadeh SA, Rezaei F, Akhondzadeh S (2010) The effect of mirtazapine add on therapy to risperidone in the treatment of schizophrenia: a double-blind randomized placebo-controlled trial. Schizophr Res 116:101–106PubMedGoogle Scholar
  2. Abi-Dargham A (2004) Do we still believe in the dopamine hypothesis? New data bring new evidence. Int J Neuropsychopharmacol 7(Suppl 1):S1–S5PubMedGoogle Scholar
  3. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 97:8104–8109PubMedCentralPubMedGoogle Scholar
  4. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22:3708–3719PubMedGoogle Scholar
  5. Adell A, Jiménez-Sánchez L, López-Gil X, Romón T (2012) Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr Bull 38:9–14PubMedGoogle Scholar
  6. Ahlenius S (1999) Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs. Pharmacol Toxicol 84:193–196PubMedGoogle Scholar
  7. Aoki C, Go CG, Venkatesan C, Kurose H (1994) Perikaryal and synaptic localization of α2A-adrenergic receptor-like immunoreactivity. Brain Res 650:181–204PubMedGoogle Scholar
  8. Aoki C, Venkatesan C, Go CG, Forman R, Kurose H (1998) Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons. Cereb Cortex 8:269–277PubMedGoogle Scholar
  9. Arnsten AF (2004) Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology (Berlin) 174:25–31Google Scholar
  10. Arnsten AF, Goldman-Rakic PS (1985) α2-Adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276PubMedGoogle Scholar
  11. Arnsten AF, Cai JX (1993) Postsynaptic α2-receptor stimulation improves memory in aged monkeys: indirect effects of yohimbine versus direct effects of clonidine. Neurobiol Aging 14:597–603PubMedGoogle Scholar
  12. Arnsten AF, Jin LE (2012) Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med 85:45–58PubMedCentralPubMedGoogle Scholar
  13. Arnsten AF, Cai JX, Goldman-Rakic PS (1988) The α2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8:4287–4298PubMedGoogle Scholar
  14. Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64:238–258PubMedGoogle Scholar
  15. Baldessarini RJ, Tarazi FJ (2006) Pharmacotherapy of psychosis and mania. In: Brunton LL, Lazo JS, Parker KL (eds) Goodman & Gilman’s the pharmacological basis of therapeutics, 11th edn. McGraw-Hill, New York, pp 461–500Google Scholar
  16. Berk M, Ichim C, Brook S (2001) Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Int Clin Psychopharmacol 16:87–92PubMedGoogle Scholar
  17. Berk M, Gama CS, Sundram S, Hustig H, Koopowitz L, D’Souza R, Malloy H, Rowland C, Monkhouse A, Monkhouse A, Bole F, Sathiyamoorthy S, Piskulic D, Dodd S (2009) Mirtazapine add-on therapy in the treatment of schizophrenia with atypical antipsychotics: a double-blind, randomised, placebo-controlled clinical trial. Hum Psychopharmacol 24:233–238PubMedGoogle Scholar
  18. Blanc G, Trovero F, Vezina P, Hervé D, Godeheu AM, Glowinski J, Tassin JP (1994) Blockade of prefronto-cortical α1-adrenergic receptors prevents locomotor hyperactivity induced by subcortical D-amphetamine injection. Eur J Neurosci 63:293–298Google Scholar
  19. Bolonna AA, Arranz MJ, Munro J, Osborne S, Petouni M, Martinez M, Kerwin RW (2000) No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response. Neurosci Lett 280:65–68PubMedGoogle Scholar
  20. Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156:234–528Google Scholar
  21. Bücheler MM, Hadamek K, Hein L (2002) Two α2-adrenergic receptor subtypes, α2A and α2C, inhibit transmitter release in the brain of gene-targeted mice. Neuroscience 109:819–826PubMedGoogle Scholar
  22. Caforio G, Di Giorgio A, Rampino A, Rizzo M, Romano R, Taurisano P, Fazio L, De Simeis G, Ursini G, Blasi G, Nardini M, Mancini M, Bertolino A (2013) Mirtazapine add-on improves olanzapine effect on negative symptoms of schizophrenia. J Clin Psychopharmacol 33:810–812PubMedGoogle Scholar
  23. Carboni E, Tanda GL, Frau R, Di Chiara G (1990) Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem 55:1067–1070PubMedGoogle Scholar
  24. Carlsson A (1978) Antipsychotic drugs, neurotransmitters, and schizophrenia. Am J Psychiatry 135:165–173PubMedGoogle Scholar
  25. Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41:237–260PubMedGoogle Scholar
  26. Carr DB, Andrews GD, Glen WB, Lavin A (2007) α2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol 584:437–450PubMedGoogle Scholar
  27. Cho SJ, Yook K, Kim B, Choi TK, Lee KS, Kim YW, Lee JE, Suh S, Yook KH, Lee SH (2011) Mirtazapine augmentation enhances cognitive and reduces negative symptoms in schizophrenia patients treated with risperidone: a randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 35:208–211PubMedGoogle Scholar
  28. Chou YH, Halldin C, Farde L (2006) Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study. Psychopharmacology (Berlin) 185:29–35Google Scholar
  29. Christie MJ, Bridge S, James LB, Beart PM (1985) Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area. Brain Res 333:169–172PubMedGoogle Scholar
  30. Clark DA, Mata I, Kerwin RW, Munro J, Arranz MJ (2007) No association between ADRA2A polymorphisms and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 144B:341–343PubMedGoogle Scholar
  31. Devoto P, Flore G (2006) On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons? Curr Neuropharmacol 4:115–125PubMedGoogle Scholar
  32. Devoto P, Flore G, Pira L, Longu G, Gessa GL (2004) Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex. Eur J Pharmacol 487:105–111PubMedGoogle Scholar
  33. Engberg G, Eriksson E (1991) Effects of α2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Naunyn Schmiedeberg‘s Arch Pharmacol 343:472–477Google Scholar
  34. Fagerholm V, Rokka J, Nyman L, Sallinen J, Tiihonen J, Tupala E, Haaparanta M, Hietala J (2008) Autoradiographic characterization of α2C-adrenoceptors in the human striatum. Synapse 62:508–515PubMedGoogle Scholar
  35. Farde L, Wiesel FA, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76PubMedGoogle Scholar
  36. Felder CC, McKinzie DL, Thompson RC, Liu B (2012) Muscarinic acetylcholine receptors as novel targets for the development of therapeutics for schizophrenia. In: Albert JS, Wood MW (eds) Targets and emerging therapies for schizophrenia, 1st edn. Wiley, New York, pp 355–379Google Scholar
  37. Fernández J, Alonso JM, Andrés JI, Cid JM, Díaz A, Iturrino L, Gil P, Megens A, Sipido VK, Trabanco AA (2005) Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents. J Med Chem 48:1709–1712PubMedGoogle Scholar
  38. Fields RB, Van Kammen DP, Peters JL, Rosen J, Van Kammen WB, Nugent A, Stipetic M, Linnoila M (1988) Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res 1:417–423PubMedGoogle Scholar
  39. Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF (2002) Mutation of the α2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci 22:8771–8777PubMedGoogle Scholar
  40. Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165:1040–1047PubMedCentralPubMedGoogle Scholar
  41. Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, White L, Parrella M, Davis KL (2001) Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology 25:402–409PubMedGoogle Scholar
  42. Ginovart N, Kapur S (2012) Role of dopamine D2 receptors for antipsychotic activity. Handb Exp Pharmacol 212:27–52PubMedGoogle Scholar
  43. Goldman-Rakic PS, Brown RM (1981) Regional changes of monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys. Neuroscience 6:177–187PubMedGoogle Scholar
  44. Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV (2004) Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berlin) 174:3–16Google Scholar
  45. Grace AA, Floresco SB, Goto Y, Lodge DJ (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 30:220–227PubMedGoogle Scholar
  46. Hall H, Sedvall G, Magnusson O, Kopp J, Halldin C, Farde L (1994) Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain. Neuropsychopharmacology 11:245–256PubMedGoogle Scholar
  47. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ, The WFSBP Task Force on Treatment Guidelines for Schizophrenia (2012) World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13:318–378PubMedGoogle Scholar
  48. Hecht EM, Landy DC (2012) Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis. Schizophr Res 134:202–206PubMedGoogle Scholar
  49. Hertel P, Nomikos GG, Svensson TH (1999a) Idazoxan preferentially increases dopamine output in the rat medial prefrontal cortex at the nerve terminal level. Eur J Pharmacol 371:153–158PubMedGoogle Scholar
  50. Hertel P, Fagerquist MV, Svensson TH (1999b) Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by α2 adrenoceptor blockade. Science 286:105–107PubMedGoogle Scholar
  51. Holmberg M, Fagerholm V, Scheinin M (2003) Regional distribution of α2C-adrenoceptors in brain and spinal cord of control mice and transgenic mice overexpressing the α2C-subtype: an autoradiographic study with [3H]RX821002 and [3H]rauwolscine. Neuroscience 117:875–898PubMedGoogle Scholar
  52. Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500PubMedCentralPubMedGoogle Scholar
  53. Horn AS (1973) Structure-activity relations for the inhibition of catecholamine uptake into synaptosomes from noradrenaline and dopaminergic neurones in rat brain homogenates. Br J Pharmacol 47:332–338PubMedGoogle Scholar
  54. Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562PubMedGoogle Scholar
  55. Hurley KM, Herbert H, Moga MM, Saper CB (1991) Efferent projections of the infralimbic cortex of the rat. J Comp Neurol 308:249–276PubMedGoogle Scholar
  56. Imaki J, Mae Y, Shimizu S, Ohno Y (2009) Therapeutic potential of α2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders. Neurosci Lett 454:143–147PubMedGoogle Scholar
  57. Inyushin MU, Arencibia-Albite F, Vázquez-Torres R, Vélez-Hernández ME, Jiménez-Rivera CA (2010) Alpha-2 noradrenergic receptor activation inhibits the hyperpolarization-activated cation current (Ih) in neurons of the ventral tegmental area. Neuroscience 167:287–297PubMedCentralPubMedGoogle Scholar
  58. Jacobson SM, Prus AJ (2010) Evaluation of the effects of α2 adrenoceptor antagonism with the D2 receptor antagonist raclopride on conditioned avoidance responding in rats. Behav Pharmacol 21:654–659PubMedGoogle Scholar
  59. Jantschak F, Brosda J, Franke RT, Fink H, Möller D, Hubner H, Gmeiner P, Pertz HH (2013) Pharmacological profile of 2-bromoterguride at human dopamine D2, porcine serotonin 5-hydroxytryptamine 2A, and α2C-adrenergic receptors, and its antipsychotic-like effects in rats. J Pharmacol Exp Ther 347:57–68PubMedGoogle Scholar
  60. Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL (2008) N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine’s antidepressant activity. Neuropsychopharmacology 33:2303–2312PubMedGoogle Scholar
  61. Joffe G, Terevnikov V, Joffe M, Stenberg JH, Burkin M, Tiihonen J (2009) Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: a double-blind, randomized, placebo-controlled trial. Schizophr Res 108:245–251PubMedGoogle Scholar
  62. Jones BE, Halaris AE, McIlhany M, Moore RY (1977) Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenaline neurons. Brain Res 127:1–21PubMedGoogle Scholar
  63. Juhila J, Honkanen A, Sallinen J, Haapalinna A, Korpi ER, Scheinin M (2005) α2A-Adrenoceptors regulate d-amphetamine-induced hyperactivity and behavioural sensitization in mice. Eur J Pharmacol 517:74–83PubMedGoogle Scholar
  64. Kalkman HO, Loetscher E (2003) α2C-Adrenoceptor blockade by clozapine and other antipsychotic drugs. Eur J Pharmacol 462:33–40PubMedGoogle Scholar
  65. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796PubMedGoogle Scholar
  66. Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 27:1081–1090PubMedGoogle Scholar
  67. Kapur S, Remington G (2001) Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 50:873–883PubMedGoogle Scholar
  68. Keefe RS, Young CA, Rock SL, Purdon SE, Gold JM, Breier A (2006) One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia. Schizophr Res 81:1–15PubMedGoogle Scholar
  69. Kegeles LS, Slifstein M, Xu X, Urban N, Thompson JL, Moadel T, Harkavy-Friedman JM, Gil R, Laruelle M, Abi-Dargham A (2010a) Striatal and extrastriatal dopamine D2/D3 receptors in schizophrenia evaluated with [18F]fallypride positron emission tomography. Biol Psychiatry 68:634–641PubMedCentralPubMedGoogle Scholar
  70. Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M, Hwang DR, Huang Y, Haber SN, Laruelle M (2010b) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67:231–239PubMedGoogle Scholar
  71. Koch M (2007) On the effects of partial agonists of dopamine receptors for the treatment of schizophrenia. Pharmacopsychiatry 40:1–6Google Scholar
  72. Krystal JH, McDougle CJ, Woods SW, Price LH, Heninger GR, Charney DS (1992) Dose–response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine. Psychopharmacology (Berl) 108:313–319Google Scholar
  73. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28:519–526PubMedGoogle Scholar
  74. Lähdesmäki J, Sallinen J, MacDonald E, Kobilka BK, Fagerholm V, Scheinin M (2002) Behavioral and neurochemical characterization of α2A-adrenergic receptor knockout mice. Neuroscience 113:289–299PubMedGoogle Scholar
  75. Lähdesmäki J, Sallinen J, MacDonald E, Scheinin M (2004) Alpha2A-adrenoceptors are important modulators of the effects of D-amphetamine on startle reactivity and brain monoamines. Neuropsychopharmacology 29:1282–1293PubMedGoogle Scholar
  76. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009) Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373:31–41PubMedGoogle Scholar
  77. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382:951–962PubMedGoogle Scholar
  78. Levey AI, Hersch SM, Rye DB, Sunahara RK, Niznik HB, Kitt CA, Price DL, Maggio R, Brann MR, Ciliax BJ (1993) Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci U S A 90:8861–8865PubMedCentralPubMedGoogle Scholar
  79. Lewis DA, Lieberman JA (2000) Catching up on schizophrenia: natural history and neurobiology. Neuron 28:325–334PubMedGoogle Scholar
  80. Li BM, Mei ZT (1994) Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol 62:134–139PubMedGoogle Scholar
  81. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedGoogle Scholar
  82. Litman RE, Su TP, Potter WZ, Hong WW, Pickar D (1996) Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. Br J Psychiatry 168:571–579PubMedGoogle Scholar
  83. Lu XY, Churchill L, Kalivas PW (1997) Expression of D1 receptor mRNA in projections from the forebrain to the ventral tegmental area. Synapse 25:205–214PubMedGoogle Scholar
  84. Ma CL, Qi XL, Peng JY, Li BM (2003) Selective deficit in no-go performance induced by blockade of prefrontal cortical α2-adrenoceptors in monkeys. Neuroreport 14:1013–1016PubMedGoogle Scholar
  85. Maas JW, Miller AL, Tekell JL, Funderburg L, Silva JA, True J, Velligan D, Berman N, Bowden CL (1995) Clonidine plus haloperidol in the treatment of schizophrenia/psychosis. J Clin Psychopharmacol 15:361–364PubMedGoogle Scholar
  86. Mao ZM, Arnsten AF, Li BM (1999) Local infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol Psychiatry 46:1259–1265PubMedGoogle Scholar
  87. Marcus MM, Jardemark KE, Wadenberg ML, Langlois X, Hertel P, Svensson TH (2005) Combined α2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat. Int J Neuropsychopharmacol 8:315–327PubMedGoogle Scholar
  88. Marcus MM, Wiker C, Frånberg O, Konradsson-Geuken A, Langlois X, Jardemark K, Svensson TH (2010) Adjunctive α2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission. Int J Neuropsychopharmacol 13:891–903PubMedGoogle Scholar
  89. Masana M, Bortolozzi A, Artigas F (2011) Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia. Int J Neuropsychopharmacol 14:53–68PubMedGoogle Scholar
  90. McCreary AC, Jones CA (2010) Antipsychotic medication: the potential role of 5-HT1A receptor agonism. Curr Pharm Des 16:516–521PubMedGoogle Scholar
  91. Meador-Woodruff JH, Damask SP, Wang J, Haroutunian V, Davis KL, Watson SJ (1996) Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology 15:17–29PubMedGoogle Scholar
  92. Meltzer HY (2012) Serotonergic mechanisms as targets for existing and novel antipsychotics. Handb Exp Pharmacol 212:87–124PubMedGoogle Scholar
  93. Meltzer HY (2013) Update on typical and atypical antipsychotic drugs. Annu Rev Med 64:393–406PubMedGoogle Scholar
  94. Meltzer HY, Huang M (2008) In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog Brain Res 172:177–197PubMedGoogle Scholar
  95. Meltzer HY, Massey BW (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 11:59–67PubMedGoogle Scholar
  96. Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255PubMedGoogle Scholar
  97. Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, Friedman JH (2010) Pimavanserin, a serotonin2A receptor inverse agonist, for the treatment of Parkinson’s disease psychosis. Neuropsychopharmacology 35:881–892PubMedGoogle Scholar
  98. Meltzer HY, Massey BW, Horiguchi M (2012a) Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in Schizophrenia. Curr Pharm Biotechnol 13:1572–1586PubMedGoogle Scholar
  99. Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (2012b) Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol, 2 mg/day: comparison with reference dose risperidone, 6 mg/day. Schizophr Res 141:144–152PubMedGoogle Scholar
  100. Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F (2000) Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci 12:1079–1095PubMedGoogle Scholar
  101. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303:791–804PubMedGoogle Scholar
  102. Morrison JH, Molliver ME, Grzanna R, Coyle JT (1981) The intra-cortical trajectory of the coeruleo-cortical projection in the rat: a tangentially organized cortical afferent. Neuroscience 6:139–158PubMedGoogle Scholar
  103. Murase S, Grenhoff J, Chouvet G, Gonon FG, Svensson TH (1993) Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo. Neurosci Lett 157:53–56PubMedGoogle Scholar
  104. Natesan S, Reckless GE, Barlow KB, Nobrega JN, Kapur S (2011) Partial agonists in schizophrenia—why some work and others do not: insights from preclinical animal models. Int J Neuropsychopharmacol 14:1165–1178PubMedGoogle Scholar
  105. Newman-Tancredi A (2010) The importance of 5-HT1A receptor agonism in antipsychotic drug action: rationale and perspectives. Curr Opin Investig Drugs 11:802–812PubMedGoogle Scholar
  106. Nicholas AP, Pieribone V, Hökfelt T (1993) Distributions of mRNAs for alpha-2 adrenergic receptor subtypes in rat brain: an in situ hybridization study. J Comp Neurol 328:575–594PubMedGoogle Scholar
  107. Nicholas AP, Hökfelt T, Pieribone VA (1996) The distribution and significance of CNS adrenoceptors examined with in situ hybridization. Trends Pharmacol Sci 17:245–255PubMedGoogle Scholar
  108. Nordström AL, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G (1995) D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 152:1444–1449PubMedGoogle Scholar
  109. Olbrich R, Schanz H (1988) The effect of the partial dopamine agonist terguride on negative symptoms in schizophrenics. Pharmacopsychiatry 21:389–390PubMedGoogle Scholar
  110. Olbrich R, Schanz H (1991) An evaluation of the partial dopamine agonist terguride regarding positive symptoms reduction in schizophrenics. J Neural Transm Gen Sect 84:233–236PubMedGoogle Scholar
  111. Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007PubMedGoogle Scholar
  112. Oranje B, Glenthøj BY (2013) Clonidine normalizes sensorimotor gating deficits in patients with schizophrenia on stable medication. Schizophr Bull 39:684–691PubMedGoogle Scholar
  113. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102–1107Google Scholar
  114. Porsolt RD, Moser PC, Castagné V (2010) Behavioral indices in antipsychotic drug discovery. J Pharmacol Exp Ther 333:632–638PubMedGoogle Scholar
  115. Raiteri M, Del Carmine R, Bertollini A, Levi G (1977) Effect of sympathomimetic amines on the synaptosomal transport of noradrenaline, dopamine and 5-hydroxytryptamine. Eur J Pharmacol 41:133–143PubMedGoogle Scholar
  116. Ramos BP, Arnsten AF (2007) Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther 113:523–536PubMedCentralPubMedGoogle Scholar
  117. Ramos BP, Stark D, Verduzco L, van Dyck CH, Arnsten AF (2006) α2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem 13:770–776PubMedGoogle Scholar
  118. Remington G, Agid O, Foussias G (2011) Schizophrenia as a disorder of too little dopamine: implications for symptoms and treatment. Expert Rev Neurother 11:589–607PubMedGoogle Scholar
  119. Ritsner MS (2013) A multi-target drug treatment in schizophrenia and schizoaffective disorder using adjunctive agents with non-D2 mechanisms of action. In: Ritsner MS (ed) Polypharmacy in psychiatry practice, vol I: multiple medication use strategies. Springer, Berlin, pp 157–210Google Scholar
  120. Roth BL, Sheffler DJ, Kroeze WK (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3:353–359PubMedGoogle Scholar
  121. Rung JP, Carlsson A, Rydén Markinhuhta K, Carlsson ML (2005) (+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 29:827–832PubMedGoogle Scholar
  122. Sallinen J, Haapalinna A, Viitamaa T, Kobilka BK, Scheinin M (1998) Adrenergic α2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice. J Neurosci 18:3035–3042PubMedGoogle Scholar
  123. Sallinen J, Höglund I, Engström M, Lehtimäki J, Virtanen R, Sirviö J, Wurster S, Savola JM, Haapalinna (2007) A pharmacological characterization and CNS effects of a novel highly selective α2C-adrenoceptor antagonist JP-1302. Br J Pharmacol 150:391–402PubMedGoogle Scholar
  124. Sallinen J, Holappa J, Koivisto A, Kuokkanen K, Chapman H, Lehtimäki J, Piepponen P, Mijatovic J, Tanila H, Virtanen R, Sirviö J, Haapalinna A (2013) Pharmacological characterisation of a structurally novel α2C-adrenoceptor antagonist ORM-10921 and its effects in neuropsychiatric models. Basic Clin Pharmacol Toxicol 113:239–249PubMedGoogle Scholar
  125. Sanacora G, Zarate CA, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7:426–437PubMedCentralPubMedGoogle Scholar
  126. Saunders C, Limbird LE (1999) Localization and trafficking of α2-adrenergic receptor subtypes in cells and tissues. Pharmacol Ther 84:193–205PubMedGoogle Scholar
  127. Scheinin M, Lomasney JW, Hayden-Hixson DM, Schambra UB, Caron MG, Lefkowitz RJ, Fremeau RT Jr (1994) Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Res Mol Brain Res 21:133–149PubMedGoogle Scholar
  128. Schmidt ME, Risinger RC, Hauger RL, Schouten JL, Henry M, Potter WZ (1997) Responses to α2-adrenoceptor blockade by idazoxan in healthy male and female volunteers. Psychoneuroendocrinology 22:177–188PubMedGoogle Scholar
  129. Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 280:83–97PubMedGoogle Scholar
  130. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berlin) 124:57–73Google Scholar
  131. Schutz G, Berk M (2001) Reboxetine add on therapy to haloperidol in the treatment of schizophrenia: a preliminary double-blind randomized placebo-controlled study. Int Clin Psychopharmacol 16:275–278PubMedGoogle Scholar
  132. Seeman P (2006) Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets 10:515–531PubMedGoogle Scholar
  133. Seeman P (2013) Schizophrenia and dopamine receptors. Eur Neuropsychopharmacol 23:999–1009PubMedGoogle Scholar
  134. Sesack SR, Pickel VM (1992) Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol 320:145–160PubMedGoogle Scholar
  135. Simpson EH, Kellendonk C, Kandel E (2010) A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65:585–596PubMedGoogle Scholar
  136. Sommer IE, Begemann MJ, Temmerman A, Leucht S (2012) Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull 38:1003–1011PubMedGoogle Scholar
  137. Stahl SM (2009) Multifunctional drugs: a novel concept for psychopharmacology. CNS Spectr 14:71–73PubMedGoogle Scholar
  138. Stargardt T, Edel MA, Ebert A, Busse R, Juckel G, Gericke CA (2012) Effectiveness and cost of atypical versus typical antipsychotic treatment in a nationwide cohort of patients with schizophrenia in Germany. J Clin Psychopharmacol 32:602–607PubMedGoogle Scholar
  139. Stenberg JH, Terevnikov V, Joffe M, Tiihonen J, Tchoukhine E, Burkin M, Joffe G (2010) Effects of add-on mirtazapine on neurocognition in schizophrenia: a double-blind, randomized, placebo-controlled study. Int J Neuropsychopharmacol 13:433–441PubMedGoogle Scholar
  140. Stenberg JH, Terevnikov V, Joffe M, Tiihonen J, Tchoukhine E, Burkin M, Joffe G (2011) More evidence on proneurocognitive effects of add-on mirtazapine in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35:1080–1086PubMedGoogle Scholar
  141. Svensson TH (2003) α-adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 27:1145–1158PubMedGoogle Scholar
  142. Swanson LW, Hartman BK (1975) The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol 163:467–505PubMedGoogle Scholar
  143. Terevnikov V, Stenberg JH, Joffe M, Tiihonen J, Burkin M, Tchoukhine E, Joffe G (2010) More evidence on additive antipsychotic effect of adjunctive mirtazapine in schizophrenia: an extension phase of a randomized controlled trial. Hum Psychopharmacol 25:431–438PubMedGoogle Scholar
  144. Terwisscha van Scheltinga AF, Bakker SC, Kahn RS, Kas MJ (2013) Fibroblast growth factors in neurodevelopment and psychopathology. Neuroscientist 19:479–494PubMedGoogle Scholar
  145. Trendelenburg AU, Klebroff W, Hein L, Starke K (2001) A study of presynaptic alpha2-autoreceptors in α2A/D-, α2B- and α2C-adrenoceptor-deficient mice. Naunyn Schmiedeberg‘s Arch Pharmacol 364:117–130Google Scholar
  146. Tsai SJ, Wang YC, Yu Younger WY, Lin CH, Yang KH, Hong CJ (2001) Association analysis of polymorphism in the promoter region of the α2a-adrenoceptor gene with schizophrenia and clozapine response. Schizophr Res 49:53–58PubMedGoogle Scholar
  147. Uhlén S, Lindblom J, Johnson A, Wikberg JE (1997) Autoradiographic studies of central α2A- and α2C-adrenoceptors in the rat using [3H]MK912 and subtype-selective drugs. Brain Res 770:261–266PubMedGoogle Scholar
  148. van den Buuse M, Garner B, Gogos A, Kusljic S (2005) Importance of animal models in schizophrenia research. Aust N Z J Psychiatry 39:550–557PubMedGoogle Scholar
  149. Van der Schyf CJ, Youdim MB (2009) Multifunctional drugs as neurotherapeutics. Neurotherapeutics 6:1–3PubMedGoogle Scholar
  150. Vidal C, Reese C, Fischer BA, Chiapelli J, Himelhoch S (2013) Meta-analysis of efficacy of mirtazapine as an adjunctive treatment of negative symptoms in schizophrenia. Clin Schizophr Relat Psychoses 4:1–24Google Scholar
  151. Villégier AS, Drouin C, Bizot JC, Marien M, Glowinski J, Colpaërt F, Tassin JP (2003) Stimulation of postsynaptic α1b- and α2-adrenergic receptors amplifies dopamine-mediated locomotor activity in both rats and mice. Synapse 50:277–284PubMedGoogle Scholar
  152. Wadenberg ML, Ericson E, Magnusson O, Ahlenius S (1990) Suppression of conditioned avoidance behavior by the local application of (−)sulpiride into the ventral, but not the dorsal, striatum of the rat. Biol Psychiatry 28:297–307PubMedGoogle Scholar
  153. Wadenberg ML, Wiker C, Svensson TH (2007) Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive α2 adrenoceptor blockade: experimental evidence. Int J Neuropsychopharmacol 10:191–202PubMedGoogle Scholar
  154. Wang M, Tang ZX, Li BM (2004) Enhanced visuomotor associative learning following stimulation of α2A-adrenoceptors in the ventral prefrontal cortex in monkeys. Brain Res 1024:176–182PubMedGoogle Scholar
  155. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF (2007) α2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410PubMedGoogle Scholar
  156. Weinberger DR, Berman KF, Chase TN (1988) Mesocortical dopaminergic function and human cognition. Ann N Y Acad Sci 537:330–338PubMedGoogle Scholar
  157. Weiner DM, Levey AI, Sunahara RK, Niznik HB, O’Dowd BF, Seeman P, Brann MR (1991) D1 and D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci U S A 88:1859–1863PubMedCentralPubMedGoogle Scholar
  158. Weinshenker D, Schroeder JP (2007) There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology 32:1433–1451PubMedGoogle Scholar
  159. Wikström HV, Mensonides-Harsema MM, Cremers TI, Moltzen EK, Arnt J (2002) Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c, f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine. J Med Chem 45:3280–3285PubMedGoogle Scholar
  160. Wong EH, Tarazi FI, Shahid M (2010) The effectiveness of multi-target agents in schizophrenia and mood disorders: Relevance of receptor signature to clinical action. Pharmacol Ther 126:173–185PubMedGoogle Scholar
  161. Zhang W, Klimek V, Farley JT, Zhu MY, Ordway GA (1999) α2C adrenoceptors inhibit adenylyl cyclase in mouse striatum: potential activation by dopamine. J Pharmacol Exp Ther 289:1286–1292PubMedGoogle Scholar
  162. Zink M, Englisch S, Meyer-Lindenberg A (2010) Polypharmacy in schizophrenia. Curr Opin Psychiatry 23:103–111PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jan Brosda
    • 1
  • Florian Jantschak
    • 2
    • 3
  • Heinz H. Pertz
    • 2
    Email author
  1. 1.Institute of Pharmacology and Toxicology, School of Veterinary MedicineFreie Universität BerlinBerlinGermany
  2. 2.Institute of PharmacyFreie Universität BerlinBerlinGermany
  3. 3.Federal Joint Committee (Healthcare)BerlinGermany

Personalised recommendations