On the Effects of Partial Agonists of Dopamine Receptors for the Treatment of Schizophrenia

Abstract

The aim of this paper is to describe the possible effects of antipsychotic drugs on neurotransmitter interactions in cortico-striatal circuits related to schizophrenia symptoms, with special emphasis on the action of partial agonists of dopamine and serotonin receptors.

Partial agonists are characterised by a high affinity and a low intrinsic activity. However, since the intrinsic activity of the ligand-bound receptor is still higher than after antagonist binding, partial agonists can act as agonists or as antagonists, depending on the endogenous levels of dopamine and receptor reserve. Aripiprazole is a partial agonist at dopamine D2-receptors and at serotonin 1A-receptors, and is currently the only marketed drug of this class of agents that is used for the treatment of schizophrenia.

References

• 1 Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, Dyck CH van, Charney DS, Innis RB, Laruelle M. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort.  Am J Psychiatry. 1998;  155 761-767
• 2 Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang D-R, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M. Prefrontal dopamine D₁ receptors and working memory in schizophrenia.  J Neurosci. 2002;  22 3708-3719
• 3 Aizman O, Brismar H, Uhlén P, Zettergren E, Levey AI, Forssberg H, Greengard P, Aperia A. Anatomical and physiological evidence for D₁ and D₂ dopamine receptor colocalization in neostriatal neurons.  Nat Neurosci. 2000;  3 226-230
• 4 Andrezina R, Josiassen RC, Marcus RN, Oren DA, Manos G, Stock E, Carlson WH, Iwamoto T. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol.  Psychopharmacology. 2006;  188 281-292
• 5 Bortolozzi A, Diaz-Mataix L, Toth M, Celada P, Artigas F. In vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain.  Psychopharmacology. 2007;  191 745-758
• 6 Callicott JH, Mattay VS, Verchinski BA, Egan MF, Weinberger DR. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down.  Am J Psychiatry. 2003;  160 2209-2215
• 7 Carlsson A. The neurochemical circuitry of schizophrenia.  Pharmacopsychiatry. 2006;  39 S10-S14
• 8 Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence.  Annu Rev Pharmacol Toxicol. 2001;  41 237-260
• 9 Carlsson ML, Carlsson A, Nilsson M. Schizophrenia: from dopamine to glutamate and back.  Curr Med Chem. 2004;  11 267-277
• 10 Cragg SJ, Rice ME. DAncing past the DAT at a DA synapse.  Trends Neurosci. 2004;  27 270-277
• 11 Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs.  Science. 1976;  192 481-483
• 12 Cutler AJ, Marcus RN, Hardy SA, O'Donnell A, Carson WH, MacQuade RD. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia.  CNS Spectr. 2006;  11 691-702
• 13 Davies M, Sheffler D, Roth B. Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology.  CNS Drug Rev. 2004;  10 317-336
• 14 Durstewitz D. A few important points about dopamine's role in neural network dynamics.  Pharmacopsychiatry. 2006;  39 S72-S75
• 15 Durstewitz D, Seamans JK, Sejnowski TJ. Neurocomputational models of working memory.  Nat Neurosci. 2000;  3 1184-1191
• 16 Farde L, Nordström AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.  Arch Gen Psychiatry. 1992;  49 538-544
• 17 Frankle WG, Lerma J, Laruelle M. The synaptic hypothesis of schizophrenia.  Neuron. 2003;  39 205-216
• 18 Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction.  Psychopharmacology. 2004;  174 3-16
• 19 Grace AA. Gating of information flow within the limbic system and the pathophysiology of schizophrenia.  Brain Res Rev. 2000;  31 330-341
• 20 Gründer G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications.  Arch Gen Psychiatry. 2003;  60 974-977
• 21 Gründer G, Kungel M, Ebrecht M, Göröcs T, Modell S. Aripiprazole: Pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia.  Pharmacopsychiatry. 2006;  39 S21-S25
• 22 Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management.  Drugs. 2006;  64 2291-2314
• 23 Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.  Mol Psychiatry. 2005;  10 40-68
• 24 Heinrich JN, Brennan J, Lai MH, Sullivan K, Hornby G, Popiolek M, Jiang LX, Pausch MH, Stack G, Marquis KL, Andree TH. Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist.  Eur J Pharmacol. 2006;  552 36-45
• 25 Ichikawa J, Li Z, Dai J, Meltzer HY. Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT_1A receptor agonism.  Brain Res. 2002;  956 349-357
• 26 Kane JM, Carson WH, Saha AH, MacQuade RD, Ingenito GG, Zimbroff DL, Ali MW. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder.  J Clin Psychiatry. 2002;  63 763-771
• 27 Kenakin T. Principles: Receptor theory in pharmacology.  Trends Pharmacol Sci. 2004;  25 186-192
• 28 Kern RS, Green MF, Cornblatt BA, Owen JR, MacQuade RD, Carson WH, Ali M, Marcus R. The neurocognitive effects of aripiprazole: an open-label comparison with olanzapine.  Psychopharmacology. 2006;  187 312-320
• 29 Koch M. Animal models of schizophrenia. in: Koch M (ed): Animal Models of Neuropsychiatric Diseases. London, Imperial College Press pp 337-402
• 30 Lavin A, Nogueira RL, Lapish CC, Wightman RM, Phillipps PE, Seamans JK. Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling.  J Neurosci. 2005;  25 5013-5023
• 31 Leuner K, Müller WE. The complexity of the dopaminergic synapses and their modulation by antipsychotics.  Pharmacopsychiatry. 2006;  39 S15-S20
• 32 Li Z, Ichikawa J, Dai J, Meltzer HY. Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain.  Eur J Pharmacol. 2004;  493 75-83
• 33 Lieberman JA. Dopamine partial agonists: a new class of antipsychotic.  CNS Drugs. 2004;  18 251-267
• 34 Marder SR, MacQuade RD, Stock EG, Kaplita SB, Marcus R, Safferman AZ, Saha A, Ali MW, Iwamoto T. Aripiprazole in the treatment of schizophrenia: safety and tolerabilityin short-term, placebo-controlled trials.  Schizophr Res. 2003;  61 123-136
• 35 Meller E, Bohmaker K, Namba Y, Friedhoff AJ, Goldstein M. Relationship between receptor occupancy and responses at striatal dopamine autoreceptors.  Mol Pharmacol. 1987;  31 592-598
• 36 Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs.  Mol Psychiatry. 2005;  10 79-104
• 37 Murphy BP, Chung YC, Park TW, MacGorry PD. Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review.  Schizophr Res. 2006;  88 5-25
• 38 Nicola SM, Surmeier DJ, Malenka RC. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens.  Annu Rev Neurosci. 2000;  23 185-215
• 39 Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET.  Nature. 1997;  385 634-636
• 40 Pigott TA, Carlson WH, Saha AR, Torbeyns AF, Stock EG, Ingenito GG. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study.  J Clin Psychiatry. 2003;  64 1048-1056
• 41 Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth C, Schwarcz J-C, Everitt BJ, Sokoloff P. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D₃ receptor agonist.  Nature. 1999;  400 371-375
• 42 Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder.  Arch Gen Psychiatry. 2003;  60 681-690
• 43 Pulvirenti L, Koob GF. Being partial to psychostimulant addiction therapy.  Trends Pharmacol Sci. 2002;  23 151-153
• 44 Schwabe K, Koch M. Effects of aripiprazole on operant responding for a natural reward after psychostimulant withdrawal in rats.  Psychopharmacology. 2007;  191 759-765
• 45 Sesack SR, Carr DB. Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia.  Physiol Behav. 2002;  77 513-517
• 46 Takahashi H, Higuchi M, Suhara T. The role of extrastriatal dopaine D2 receptors in schizophrenia.  Biol Psychiatry. 2006;  59 919-928
• 47 Tamminga CA. Partial dopamine agonists in the treatment of psychosis.  J Neural Transm. 2002;  109 411-420
• 48 Tamminga CA, Schaffer MH, Smith RC, Davis JM. Schizophrenic symptoms improve with apomorphine.  Science. 1978;  200 567-568
• 49 Taylor DM. Aripiprazole: a review of its pharmacology and clinical use.  Int J Clin Pract. 2003;  57 49-54
• 50 Winterer G. Cortical microcircuits in schizophrenia - the dopamine hypothesis revisited.  Pharmacopsychiatry. 2006;  39 S68-S71
• 51 Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF. Dopamine D₂ and D₃ receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597) a study using positron emission tomography and [11C] raclopride.  Neuropsychopharmacology. 2002;  27 248-259
• 52 Zocchi A, Fabbri D, Heidbreder CA. Aripiprazole increases dopamine but not noradrenaline and serotonin levels in the mouse prefrontal cortex.  Neurosci Lett. 2005;  387 157-161

Correspondence