History of the Discovery of the Antipsychotic Dopamine D2 Receptor: A Basis for the Dopamine Hypothesis of Schizophrenia (original) (raw)
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Half a century of antipsychotics and still a central role for dopamine D2 receptors
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2003
A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D 2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D 2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D 2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a ''one-size-fits-all polypharmacy-in-a-pill'' approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology.
The British Journal of Psychiatry, 2001
Background Both traditional and atypical antipsychotics have been hypothesised to be effective in schizophrenia through limbic and cortical D2 dopamine receptor blockade. Aims To investigate this hypothesis with the D2/D3-selective positron emission tomography (PET) probe [76Br]-FLB457. Method PETscans were performed on 6 controls and 18 patients with schizophreniatreated with haloperidol or with risperidone, clozapine, amisulpride or olanzapine. Results The D2 dopamine receptor blockade was high in the temporal cortex with both haloperidol and atypical antipsychotics. The atypicals, however, induced a significantly lower D2 binding index than haloperidol in the thalamus and in the striatum. Conclusions Results suggest that cortical D2 dopamine receptors are a common target of traditional and atypical antipsychotics for therapeutic action. Higher in vivo binding to the D2 receptors in the cortex than in the basal ganglia is suggested as an indicator of favourable profile for a putat...
Psychopharmacology, 2004
To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments. Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3") after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D2 receptor occupancy was calculated by comparing V3" measured in treated patients to an age-corrected V3" value derived from a group of untreated patients with schizophrenia, previously published, according ...
Theoretical Research Proposal - Against the dopamine hypothesis of schizophrenia.
2013
1950's -Origin of Dopamine Hypothesis. First antipsychotics used to treat schizophrenia. Called "typical" antipsychotics or major tranquilizers. Inverse agonist on D 1 -D 5 . Frequently induce debilitating side-effects in the Extrapyramidal System. 1970's -Atypical antipsychotics introduced. Second generation antipsychotics, dopamine and serotonin receptor antagonists. Considered to have fewer side-effects. 1991 -Dopamine Hypothesis version II. Davis et al. Dopamine in Schizophrenia: A Review and Reconceptualization. Mid-late 2000's-Genomics revolution takes off in neuropsychiatry. Cheaper and more robust genomic technologies provide hundreds of candidate loci/molecules associated with schizophrenia. 2007 -First mouse model of schizophrenia developed. First model based on genetic manipulation. Future models would include manipulations to DISC1, NRG1, Dysbindin, Calcinuerin, and Reelin. 2009 -The Dopamine Hypothesis of Schizophrenia: Version III. The Final Common Pathway. Howes O. and Kapur S. 2012 -"Golden age" of CBT in treatment of schizophrenia. Increased success in the used of CBT for treatment of schizophrenia emphasizes the involvement of neuroplasticity in disease progression and treatment. 2013 -A serotonin hypothesis of schizophrenia. Review published by A. E. Eggers in Medical Hypotheses.
The Importance of Dopamine D4 Receptors in the Action and Development of Antipsychotic Agents
Drugs, 1996
The dopamine D4 receptor, recently identified by molecular biological techniques, is expressed in areas of the brain implicated in the pathophysiology of schizophrenia. Although it has a lower affinity than the D2 receptor for most antipsychotic drugs, the D4 receptor has a higher affinity for clozapine, which may explain the unique efficacy of clozapine in the treatment of schizophrenia. However, there is no association between genetic alterations of the D4 gene and either the development of schizophrenia or response to clozapine administration, nor is the absence of the receptor related to major neuropsychiatric deficits. The report of an increase in D4 receptor density in the striatum in schizophrenia has not been consistently confirmed. Thus, it appears that there is little to support the development of D4 antagonists as potential antipsychotic agents.
Brain Research Reviews, 2000
The D receptor may represent an important target for antipsychotic drugs which all bind with high affinity and do not induce upon 3 repeated administration either tolerance or receptor upregulation. The D receptor is localized in brain areas, namely the nucleus 3 accumbens and cerebral cortex, implicated in neural circuits believed to display defective functioning in schizophrenia. Overexpression of the D receptor, which accounts for the behavioral sensitization to levodopa in a rodent model of Parkinson's disease, might also be 3 responsible for the sensitization to dopamine agonists observed in schizophrenia. The appearance of the D receptor during brain 3 development, early in proliferating neuroepithelia and later in neurons from limbic areas, suggests further studies to assess its participation in the neurodevelopmental disorders of schizophrenia. Finally, meta-analysis of ; 30 studies comprising over 2500 patients indicate that a polymorphism in the coding sequence of the D receptor is associated with a small but significant enhancement of 3 vulnerability to the disease. q
International Journal of Molecular Sciences
Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics’ receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occ...