Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?:: A new hypothesis

被引:846
作者
Kapur, S
Seeman, P
机构
[1] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada
[2] Univ Toronto, Dept Psychiat, Toronto, ON, Canada
[3] CAMH, Clarke Div, PET Ctr, Toronto, ON M5T 1R8, Canada
[4] CAMH, Schizophrenia Program, Toronto, ON M5T 1R8, Canada
关键词
D O I
10.1176/appi.ajp.158.3.360
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
Objective: Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic "atypical" is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics. Method: Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical antipsychotics were reviewed to develop this hypothesis. Particular attention was paid to data regarding the role of the serotonin 5-HT2 and dopamine D-4 receptors in atypicality. Results: Neuroimaging data show that optimal dopamine D-2 occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D-2 occupancy, not from high 5-HT2 occupancy. If D-2 occupancy is excessive, atypicality is lost even in the presence of high 5-HT2 occupancy Animal data show that a rapid dissociation from the D-2 receptor at a molecular level produces the atypical antipsychotic effect. In vitro data show that the single most powerful predictor of atypicality for the current generation of atypical antipsychotics is fast dissociation from the D-2 receptor, not its high affinity at 5-HT2, D-4, or another receptor Conclusions: The authors propose that fast dissociation from the D-2 receptor makes an antipsychotic more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without motor side effects, prolactin elevation, or secondary negative symptoms. in contrast to the multireceptor hypotheses, the authors predict that the atypical antipsychotic effect can be produced by appropriate modulation of the D-2 receptor alone; the blockade of other receptors is neither necessary nor sufficient.
引用
收藏
页码:360 / 369
页数:10
相关论文
共 84 条
[1]   EFFECTS OF CLOZAPINE ON CEREBRAL CATECHOLAMINERGIC NEURON SYSTEMS [J].
BARTHOLINI, G ;
HAEFELY, W ;
JALFRE, M ;
KELLER, HH ;
PLETSCHER, A .
BRITISH JOURNAL OF PHARMACOLOGY, 1972, 46 (04) :736-740
[2]  
BLANCHET PJ, 1995, J PHARMACOL EXP THER, V272, P854
[3]   Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method [J].
Breier, A ;
Su, TP ;
Saunders, R ;
Carson, RE ;
Kolachana, BS ;
de Bartolomeis, A ;
Weinberger, DR ;
Weisenfeld, N ;
Malhotra, AK ;
Eckelman, WC ;
Pickar, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (06) :2569-2574
[4]  
Bristow LJ, 1997, TRENDS PHARMACOL SCI, V18, P186, DOI 10.1016/S0165-6147(97)90618-0
[5]  
Buchanan RW, 1998, AM J PSYCHIAT, V155, P751
[6]  
BURKI HR, 1986, PSYCHOPHARMACOLOGY, V89, P77
[7]   Neurotransmitter interactions in schizophrenia - Therarpeutic implications [J].
Carlsson, A ;
Waters, N ;
Carlsson, ML .
BIOLOGICAL PSYCHIATRY, 1999, 46 (10) :1388-1395
[8]   On schizophrenia and new generation drugs [J].
Carpenter, WT ;
Conley, R ;
Kirkpatrick, B .
NEUROPSYCHOPHARMACOLOGY, 2000, 22 (06) :660-661
[9]  
CARPENTER WT, 1988, AM J PSYCHIAT, V145, P578
[10]   CLOZAPINE FAILS TO PREVENT THE DEVELOPMENT OF HALOPERIDOL-INDUCED BEHAVIORAL HYPERSENSITIVITY IN A COTREATMENT PARADIGM [J].
CARVEY, PM ;
NATH, ST ;
KAO, LC ;
ZHANG, TJ ;
LIN, DH ;
SINGH, R ;
AMDUR, RL ;
KLAWANS, HL .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1990, 184 (01) :43-53