Presynaptic Dopamine in Schizophrenia

Miyake, Nobumi; Thompson, Judy; Skinbjerg, Mette; Abi‐Dargham, Anissa

doi:10.1111/j.1755-5949.2010.00230.x

Cited by 48 publications

(40 citation statements)

References 66 publications

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“…44 Similarly, genetic studies addressing the potential association between schizophrenia and the 40-bp VNTR polymorphism in the 3#-UTR (untranslated region) of the DAT gene (SLC6A3) showed negative results (for a meta-analysis see 45 ). Our finding suggests that the increased presynaptic striatal DA activity in schizophrenia indicated by other imaging parameters (for systematic reviews see [12][13][14] ) is not secondary to dysfunctional DAT or an alteration in the density of dopaminergic terminals. In the companion paper published in the present issue, we present the first quantitative meta-analysis addressing the functional integrity of striatal presynaptic dopamine neurotransmission.…”

Section: Discussionmentioning

confidence: 72%

“…1,10 Over the past years, neurochemical imaging techniques have enabled the striatal presynaptic dopaminergic system to be independently characterized in vivo. 11 In particular, the development of new radiotracers combined with single photon emission computed tomography (SPECT) or positron emission tomography (PET) techniques has allowed accurate investigations of striatal presynaptic dopaminergic alterations in schizophrenia (for reviews see [12][13][14]. Different indexes of presynaptic dopamine neurotransmission such as dopamine synthesis capacity studies 15 and dopamine release 16 /depletion 17 studies have generally shown significant alterations in the striatal presynaptic dopaminergic function in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Striatal Presynaptic Dopamine in Schizophrenia, Part I: Meta-Analysis of Dopamine Active Transporter (DAT) Density

Fusar‐Poli

Meyer‐Lindenberg

2012

Schizophrenia Bulletin

107

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Background: Striatal dopaminergic neurotransmission has been postulated to be fundamental to the emergence of key symptoms of schizophrenia, such as psychotic symptoms, and is targeted by currently available dopaminergic drugs. A specific marker of the integrity of presynaptic dopamine neurons in the striatum, the density of striatal dopamine terminals, can be quantified through molecular neuroimaging of the dopamine active transporter (DAT). However, the currently available results using this approach in schizophrenia are inconsistent. Methods: Thirteen Single Photon Emission Tomography or Positron Emission Tomography (PET) studies investigating DAT density in the striatum of schizophrenic patients and matched controls were included in a quantitative meta-analysis. Binding potentials in the striatum, caudate, and putamen, as well as demographic, clinical, and methodological variables, were extracted from each publication. Hedges' g was used as a measure of effect size. Results: The overall database contained 202 subjects with schizophrenia and 147 controls, well matched with respect to sociodemographic variables. Striatal DAT density was not significantly different between patients and controls. Similar negative findings were regionally confirmed in the putamen and caudate. There was no moderating effect for external factors. Conclusions: Our meta-analysis uncovered no evidence indicating altered density of striatal dopamine terminals in schizophrenia. Moreover, striatal DAT density did not seem to be influenced by antipsychotic medication or illness duration. Our data suggest that altered integrity of striatal dopaminergic synapses is not critical for the emergence of schizophrenia or its treatment. These findings should be useful in further refining dopaminergic hypotheses of schizophrenia.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Striatal Presynaptic Dopamine in Schizophrenia, Part I: Meta-Analysis of Dopamine Active Transporter (DAT) Density

Fusar‐Poli

Meyer‐Lindenberg

2012

Schizophrenia Bulletin

107

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“…Electron micrographs of immunostained rat neostriatal D 2 receptors indeed revealed their location in synaptic structures as well as in extrasynaptical regions Hersch et al 1995). Yet, no information about their relative abundance in both locations could be provided, and present opinions about which population is physiologically active in the striatum are sometimes even diametrically opposite (Rice and Cragg 2008;Miyake et al 2010). In this respect, issues like release, uptake, and diffusion will greatly affect the free dopamine concentration and time-wise changes thereof in those distinct locations (Kawagoe et al 1992;Garris et al 1994;Cragg and Rice 2004;Schultz 2007).…”

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 97%

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Vauquelin

Bostoen

Vanderheyden

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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Drug-receptor interactions are traditionally quantified in terms of affinity and efficacy, but there is increasing awareness that the drug-on-receptor residence time also affects clinical performance. While most interest has hitherto been focused on slow-dissociating drugs, D(2) dopamine receptor antagonists show less extrapyramidal side effects but still have excellent antipsychotic activity when they dissociate swiftly. Fast dissociation of clozapine, the prototype of the "atypical antipsychotics", has been evidenced by distinct radioligand binding approaches both on cell membranes and intact cells. The surmountable nature of clozapine in functional assays with fast-emerging responses like calcium transients is confirmatory. Potential advantages and pitfalls of the hitherto used techniques are discussed, and recommendations are given to obtain more precise dissociation rates for such drugs. Surmountable antagonism is necessary to allow sufficient D(2) receptor stimulation by endogenous dopamine in the striatum. Simulations are presented to find out whether this can be achieved during sub-second bursts in dopamine concentration or rather during much slower, activity-related increases thereof. While the antagonist's dissociation rate is important to distinguish between both mechanisms, this becomes much less so when contemplating time intervals between successive drug intakes, i.e., when pharmacokinetic considerations prevail. Attention is also drawn to the divergent residence times of hydrophobic antagonists like haloperidol when comparing radioligand binding data on cell membranes with those on intact cells and clinical data.

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“…Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder. 4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.…”

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confidence: 99%

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

McCollum

Walker

Roche

et al. 2015

SCHBUL

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The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.Key words: electron microscopy/anatomy/striatum/ synapseThe exact pathophysiology for the origin of schizophrenia (SZ) is unknown, however evidence from decades of research implies that interactions between multiple brain regions and multiple neurotransmitter systems are likely at play. One region that is implicated in SZ pathology is the nucleus accumbens (NAcc). The NAcc integrates signaling from multiple regions of the brain, receiving input from areas including the prefrontal cortex, hippocampus, amygdala, thalamus, and midbrain.1 Importantly, all of these areas have been associated with SZ, making the NAcc a prime region for integrating multiple disrupted areas to provide a comprehensive understanding of SZ pathology.2 Reciprocal connections between the NAcc and substantia nigra/ventral tegmental area (SN/VTA) indicate further importance of this region. Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder.4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.The purpose of this study was to provide the first ultrastructural analysis in postmortem human NAcc, and examine the neurocircuitry in the NAcc in SZ to establish the role this region may play in the disorder. We used stereological analysis of electron micrographs in postmortem SZ to analyze the organization an...

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Presynaptic Dopamine in Schizophrenia

Cited by 48 publications

References 66 publications

Striatal Presynaptic Dopamine in Schizophrenia, Part I: Meta-Analysis of Dopamine Active Transporter (DAT) Density

Striatal Presynaptic Dopamine in Schizophrenia, Part I: Meta-Analysis of Dopamine Active Transporter (DAT) Density

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

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