Beyond the Dopamine Hypothesis

G. P. Reynolds

doi:10.1192/bjp.155.3.305

Beyond the Dopamine Hypothesis

The British Journal of Psychiatry ◽

10.1192/bjp.155.3.305 ◽

1989 ◽

Vol 155 (3) ◽

pp. 305-316 ◽

Cited By ~ 131

Author(s):

G. P. Reynolds

Keyword(s):

Amino Acid ◽

Drug Treatment ◽

Dopamine Neurons ◽

Postmortem Brain ◽

Neuroleptic Drug ◽

Neuroleptic Drugs ◽

Imaging Studies ◽

Postmortem Brain Tissue ◽

Dopamine Hypothesis

The dopamine hypothesis still provides a valuable approach to the study of schizophrenia and its treatment by drugs. Although the neuroleptic drugs appear to act via an inhibition of dopamine receptors, measurements of dopamine metabolites in vivo, or of the transmitter and its receptors in postmortem brain tissue, do not provide unequivocal evidence of a hyperactivity of dopaminergic neurotransmission in the disease. Nevertheless, increased dopamine function might be a consequence of a primary neuronal abnormality in another system. Recent imaging studies and neuropathological reports suggest that, in some patients, there may be a deficit and/or disturbance of neurons in certain temporal limbic regions, and this is supported by some neurochemical investigations, particularly of neuropeptide and amino-acid transmitter systems. A loss of such neurons could conceivably lead to a disinhibition of limbic dopamine neurons, providing the means whereby neuroleptic drug treatment might ameliorate the effects of a neuronal deficit in schizophrenia.

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Pre-clinical Pharmacology of Atypical Antipsychotic Drugs: A Selective Review

The British Journal of Psychiatry ◽

10.1192/s0007125000298280 ◽

1996 ◽

Vol 168 (S29) ◽

pp. 23-31 ◽

Cited By ~ 39

Author(s):

Herbert Y. Meltzer

Keyword(s):

Atypical Antipsychotic ◽

Antipsychotic Drugs ◽

Chronic Administration ◽

Receptor Occupancy ◽

Dopamine Neurons ◽

Neuroleptic Drug ◽

Neuroleptic Drugs ◽

Subsequent Decrease ◽

Dopamine Hypothesis ◽

Ventral Tegmental

The primary basis for the action of neuroleptic drugs has been suggested to be a blockade of D2 receptors in the mesolimbic system, with subsequent decrease in the firing rate of ventral tegmental (A10) dopamine neurons by the process of depolarisation inactivation (Matthyssee, 1974; Bunney et al, 1991). The main evidence for this hypothesis is that: the affinities for the D2 receptor of all effective antipsychotic drugs are positively correlated with their average clinical dose (Seeman & Lee, 1975; Creese et al, 1976); and chronic administration of antipsychotic drugs produces nearly complete inhibition of the firing of ventral tegmental (A10) dopamine neurons that project to the limbic forebrain (Chiodo & Bunney, 1983). Clozapine, the prototypical atypical antipsychotic drug, also satisfies both criteria (Seeman & Lee, 1975; Chiodo & Bunney, 1985). However, the demonstration that clozapine is more effective than other neuroleptics for the treatment of both schizophrenic patients who are responsive to typical neuroleptics (Meltzer, 1992) as well as those who are resistant (Kane et al, 1988) suggests that this simple dopamine hypothesis of neuroleptic drug action is insufficient. Indeed, there is evidence that clozapine at clinically effective doses produces less D2 receptor occupancy and, hence, less antagonism of D2 receptors in the striatum, and probably also in the limbic system, than typical neuroleptic drugs (Farde et al, 1992); this further challenges the adequacy of the dopamine hypothesis to explain the greater efficacy of clozapine. This leaves the need to consider what else besides a D2 receptor blockade may explain the action of clozapine and, indeed, whether limited blockade is superior to a more complete one.

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Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors

Molecules ◽

10.3390/molecules24234218 ◽

2019 ◽

Vol 24 (23) ◽

pp. 4218 ◽

Cited By ~ 3

Author(s):

Koprdova ◽

Csatlosova ◽

Durisova ◽

Bogi ◽

Majekova ◽

...

Keyword(s):

Forced Swim Test ◽

Behavioral Assessment ◽

Dopamine Neurons ◽

Neuroleptic Drug ◽

Swim Test ◽

Forced Swim ◽

Reuptake Inhibition ◽

Immobility Time ◽

Dopamine Reuptake

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.

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Molecular imaging studies of the striatal dopaminergic system in psychosis and predictions for the prodromal phase of psychosis

The British Journal of Psychiatry ◽

10.1192/bjp.191.51.s13 ◽

2007 ◽

Vol 191 (S51) ◽

pp. s13-s18 ◽

Cited By ~ 77

Author(s):

Oliver D. Howes ◽

Andrew J. Montgomery ◽

Marie-Claude Asselin ◽

Robin M. Murray ◽

Paul M. Grasby ◽

...

Keyword(s):

Molecular Imaging ◽

Dopaminergic System ◽

Dopamine Synthesis ◽

Imaging Studies ◽

Prodromal Phase ◽

Dopamine Hypothesis

SummaryThe dopamine hypothesis has been the major pathophysiological theory of psychosis in recent decades. Molecular imaging studies have provided in vivo evidence of increased dopamine synaptic availability and increased presynaptic dopamine synthesis in the striata of people with psychotic illnesses. These studies support the predictions of the dopamine hypothesis, but it remains to be determined whether dopaminergic abnormalities pre-date or are secondary to the development of psychosis. We selectively review the molecular imaging studies of the striatal dopaminergic system in psychosis and link this to models of psychosis and the functional subdivisions of the striatum to make predictions for the dopaminergic system in the prodromal phase of psychosis

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Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Pharmaceuticals ◽

10.3390/ph14090847 ◽

2021 ◽

Vol 14 (9) ◽

pp. 847 ◽

Cited By ~ 1

Author(s):

Špela Korat ◽

Natasha Shalina Rajani Bidesi ◽

Federica Bonanno ◽

Adriana Di Nanni ◽

Anh Nguyên Nhât Hoàng ◽

...

Keyword(s):

Alpha Synuclein ◽

Postmortem Brain ◽

Comprehensive Overview ◽

Pet Tracers ◽

Ligand Selectivity ◽

Affinity Ligand ◽

Pet Tracer ◽

Positron Emission ◽

Postmortem Brain Tissue

Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with α-syn pathology. The lack of a defined crystal structure of α-syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective α-syn PET tracers.

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Commentary on Dinan's Hypothesis

The British Journal of Psychiatry ◽

10.1192/bjp.151.4.459 ◽

1987 ◽

Vol 151 (4) ◽

pp. 459-460 ◽

Cited By ~ 6

Author(s):

Leslie L. Iversen

Keyword(s):

Dopamine Receptors ◽

Drug Action ◽

Common Mechanism ◽

Neuroleptic Drug ◽

Pharmacological Properties ◽

Neuroleptic Drugs ◽

Dopamine Hypothesis ◽

Potent Antagonist ◽

D2 Antagonists ◽

Rich Spectrum

Dinan's paper seeks to question the validity of the now widely accepted hypothesis that neuroleptic drugs of various different chemical categories all act by a common mechanism, namely by blockade of dopamine receptors of the D2 type in brain (for review see Creese et al, 1978, 1983; Iversen, 1985). While it is always refreshing to re-examine existing scientific dogma, his criticisms did not appear to me to be very substantial. Having quite fairly reviewed the evidence in favour of the “dopamine hypothesis” for neuroleptic drug action, Dinan summarises his reasons for questioning it. He points out that many neuroleptic drugs have potent actions on a number of other targets, apart from the dopamine receptors in brain. This is indeed so, and the archetypal compound, chlorpromazine, has a particularly rich spectrum of pharmacological activity, being a potent antagonist of serotonin (5-HT2) receptors, ?-adrenoceptors, and histamine (HI) receptors in brain and other tissues. Other neuroleptics also have potent actions on a number of other systems. Indeed, if one were to have studied only chlorpromazine, it is doubtful whether the “dopamine hypothesis” could ever have been developed. The strength of this hypothesis lies in the fact that of all the diverse pharmacological actions which different neuroleptic drugs exhibit, this is the only action that is common to all neuroleptic compounds. Furthermore, in a large group of neuroleptics, which differ widely in potency (doses in man ranging from 1 mg/day to almost 1000 mg/day), the potencies of these drugs as dopamine (D2) antagonists correlate significantly with their clinical potencies. Attempts to make such correlations with any other known pharmacological properties of these drugs fail to show significance (Creese et al, 1978, 1983).

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Cellular abnormalities in depression: evidence from postmortem brain tissue

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2004.6.2/cstockmeier ◽

2004 ◽

Vol 6 (2) ◽

pp. 185-197

Keyword(s):

Brain Tissue ◽

Basic Research ◽

Brain Regions ◽

Microscopic Level ◽

Anterior Cingulate ◽

Postmortem Brain ◽

Cell Counting ◽

The Past ◽

Postmortem Brain Tissue

During the past two decades, in vivo neuroimaging studies have permitted significant insights into the general location of dysfunctional brain regions in depression. In parallel and often intersecting ways, neuroanatomical, pharmacological, and biochemical studies of postmortem brain tissue are permitting new insights into the pathophysiology of depression. In addition to long-recognized neurochemical abnormalities in depression, novel studies at the microscopic level support the contention that mood disorders are associated with abnormalities in cell morphology and distribution. In the past 6 years, cell-counting studies have identified changes in the density and size of both neurons and glia in a number of frontolimbic brain regions, including dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortex, and the amygdala and hippocampus. Convergence of cellular changes at the microscopic level with neuroimaging changes detected in vivo provides a compelling integration of clinical and basic research for disentangling the pathophysiology of depression. The ultimate integration of these two research approaches will occur with premortem longitudinal clinical studies on well-characterized patients linked to postmortem studies of the same subjects.

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The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

10.1101/539700 ◽

2019 ◽

Cited By ~ 1

Author(s):

Maritza Oñate ◽

Alejandra Catenaccio ◽

Natalia Salvadores ◽

Cristian Saquel ◽

Alexis Martinez ◽

...

Keyword(s):

Cortical Neurons ◽

Axonal Degeneration ◽

Neuronal Loss ◽

Postmortem Brain ◽

Death Process ◽

Early Event ◽

Genetic Ablation ◽

Postmortem Brain Tissue

AbstractParkinson’s disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum. Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in vivo, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.

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In Vivo Detection of Cerebral Cortical Microinfarcts with High-Resolution 7T MRI

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.196 ◽

2012 ◽

Vol 33 (3) ◽

pp. 322-329 ◽

Cited By ~ 118

Author(s):

Susanne J van Veluw ◽

Jaco JM Zwanenburg ◽

JooYeon Engelen-Lee ◽

Wim GM Spliet ◽

Jeroen Hendrikse ◽

...

Keyword(s):

High Resolution ◽

Cognitive Decline ◽

Ex Vivo ◽

Brain Slices ◽

Postmortem Brain ◽

Vascular Pathology ◽

Elderly Subjects ◽

Postmortem Brain Tissue ◽

Fluid Attenuated Inversion Recovery

Cerebrovascular disease has an important role in cognitive decline and dementia. In this context, cerebral microinfarcts are attracting increasing attention, but these lesions could thus far not be detected in vivo. The aim of this study was to try to identify possible cortical microinfarcts on high-resolution 7T in vivo magnetic resonance imaging (MRI) and to perform a histopathologic validation study on similar appearing lesions on 7T ex vivo MRI of postmortem brain tissue. The study population consisted of 22 elderly subjects, who underwent 7T MRI. The fluid attenuated inversion recovery, T2, and T1 weighted scans of these subjects were examined for possible cortical microinfarcts. In the ex vivo MRI study, 15 formalin-fixed coronal brain slices of 6 subjects with Alzheimer and vascular pathology were examined and subjected to histopathologic verification. On the in vivo scans, 15 cortical lesions could be identified that were likely to be microinfarcts in 6 subjects. In the postmortem tissue, 6 similar appearing lesions were identified of which 5 were verified as cortical microinfarcts on histopathology. This study provides strong evidence that cortical microinfarcts can be detected in vivo, which will be of great value in further studies into the role of vascular disease in cognitive decline and dementia.

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Classification of neuroleptic drugs - lack of relationship to effect on negative symptoms in schizophrenia

Psychiatry and Psychobiology ◽

10.1017/s0767399x00000936 ◽

1987 ◽

Vol 2 (4) ◽

pp. 289-294

Author(s):

Svein G. Dahl

Keyword(s):

Drug Treatment ◽

Negative Symptoms ◽

Chemical Properties ◽

Drug Level ◽

Neuroleptic Drug ◽

Positive Symptoms ◽

Neuroleptic Drugs ◽

Dependent Relationship ◽

The Individual

SummaryThere is both pharmacological and clinical support for a classification of the schizophrenic syndrome into negative and positive subtypes. For neuroleptics that act upon both types of symptoms, it appears that lower doses are required for treatment of negative than for positive symptoms. Successful drug treatment of negative symptoms may therefore depend upon the choice of a correct dosage for the individual patient. Due to variation in pharamacokinetic parameters, similar doses of a neuroleptic drug may result in different plasma levels in individual patients, especially after oral medication. Pharmacokinetic variations, if not under proper control, may easily disguise a concentration-dependent relationship, such as the effects of a neuroleptic drug upon negative and positive symptoms. In drug treatment of negative symptoms it may therefore be an advantage to individualize the doses as a function of plasma drug level measurements, when available. No general relationship has been demonstrated between the chemical properties or pharmacodynamics of neuroleptic drugs and their potential to act upon negative symptoms. Also, the drugs which have been demonstrated to have an “energizing” effect have widely different pharmacokinetic properties. A chemical or pharmacological classification of neuroleptics therefore does not seem to give any information about their possible efficacy in treating negative symptoms in schizophrenia.

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