Dopamine Uptake Sites and Dopamine Receptors in Parkinson’s Disease and Schizophrenia

Pearce, R. K. B.; Seeman, Philip; Jellinger, K.; Tourtellotte, W. W.

doi:10.1159/000117168

Cited by 68 publications

(27 citation statements)

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“…19 The negative results of our meta-analysis are also in line with several postmortem studies of DAT concentration, which reported no alteration in DAT density in striatal tissue of patients with schizophrenia compared with control subjects. 46,47 However it is known that the DAT density decreases as people get older, with a decline in dopaminergic neurons of 4% to 8% per decade in the general population. 48 Some authors have speculated that loss of striatal dopamine terminals can be associated with evolution of the illness from an active phase associated with positive symptoms to a more stable or phase in which negative symptoms dominate the clinical picture.…”

Section: Discussionmentioning

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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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: 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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“…This specificity could be related to the superior clinical efficacy of CLOZ over HAL, because numerous reports have implicated striatal (Pearce et al, 1990), cortical (Goldman-Rakic, 1991Shenton et al, 1992;Selemon et al, 1995), and hippocampal (Luchins, 1990) structures in the pathophysiology of schizophrenia. It is quite possible that Fig.…”

Section: Antipsychotics and Protein Kinase A 205mentioning

confidence: 99%

Differential Effects of Haloperidol and Clozapine on [3H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

Dwivedi

Rizavi²,

Pandey³

2002

The Journal of Pharmacology and Experimental Therapeutics

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The present study was undertaken to examine whether the mechanism of action of typical and atypical antipsychotics is related in their ability to regulate key phosphorylating enzyme of adenylyl cyclase-cAMP pathway, i.e., protein kinase A (PKA). For this purpose, regulatory (R) and catalytic (Cat) activities of PKA and expression of various isoforms of regulatory and catalytic subunits were examined in rat brain after single or chronic (21-day) treatment with haloperidol (HAL, 1 mg/kg) or clozapine (CLOZ, 20 mg/kg). It was observed that chronic but not acute treatment of CLOZ significantly decreased [ 3 H]cAMP binding to the regulatory subunit of PKA as well as catalytic activity of PKA in particulate and cytosol fractions of the rat cortex, hippocampus, and striatum. In these fractions, CLOZ significantly decreased protein levels of selective RII␣-, RII␤-, and Cat␤-subunit isoforms of PKA. These decreases were accompanied by decreases in their respective mRNA expression. In contrast, chronic but not acute treatment of HAL significantly increased [3 H]cAMP binding and the catalytic activity of PKA in particulate and cytosol fractions of only the striatum brain area. In addition, chronic treatment of HAL significantly increased mRNA and protein levels of RII␣-and RII␤-subunit isoforms in the striatum. None of the antipsychotics caused any change in the expression of the Cat␣-, RI␣-, or RI␤-subunit isoform. These results, thus, suggest that HAL and CLOZ differentially regulate PKA catalytic and regulatory activities and the expression of selective catalytic and regulatory subunit isoforms of PKA, which may be associated with their mechanisms of action.

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“…For instance, schizophrenic patients may have greater dopaminergic innervation in the striatum. Regulation of transmitter release, and uptake, could be normal, while greater terminal density could lead to more release of dopamine after re-uptake blockade and vesicular release by amphetamine.Although post-mortem studies have found normal density of presynaptic dopamine markers, such as the dopamine transporter (Hirai et al 1988;Joyce et al 1988;Pearce et al 1990) and expressed mRNA for tyrosine hydroxylase (Ichinose et al 1994), excessive innervation could be obscured by normal aging and more rapid degeneration of terminals in schizophrenia. Dopamine receptors Volkow et al 1996b), transporters (Volkow et al 1996a), and vesicles (Frey et al 1998 all decline with aging, with rates estimated at 2-8% per decade.…”

mentioning

confidence: 99%

In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia

Taylor

Koeppe

Tandon

et al. 2000

Neuropsychopharmacology

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Given evidence for excessive striatal dopamine activity in schizophrenia, we sought to test the hypothesis that dopaminergic innervation in the striatum is abnormally elevated, and a secondary hypothesis that age-related loss is accelerated. Twelve schizophrenic subjects on stable doses of medications, along with 12 age and sex-matched healthy control subjects, underwent positron emission tomography (PET) studies with [ 11 C]dihydrotetrabenazine (DTBZ), which binds to the vesicular monoamine transporter, type 2 (VMAT2).Since the 1960's, indirect evidence has implicated dopamine systems in schizophrenia and psychosis (Angrist et al. 1974;Creese et al. 1976;Seeman 1987;Snyder 1972). In the last 10 years, neuroimaging studies targeting dopamine systems have begun to characterize the role of dopamine in schizophrenia, although many questions remain. In vivo studies using radioligands which bind to post-synaptic dopamine receptors have provided equivocal evidence for abnormalities of striatal receptors. Some investigators have reported greater receptor density (Gjedde et al. 1996;Wong et al. 1986), whereas many groups have failed to replicate these findings (Farde et al. 1990;Hietala et al. 1994;Nordstrom et al. 1995;Pilowsky et al. 1994).A more successful approach has been to measure the change in radioligand binding after the manipulation of synaptic dopamine concentration. Two groups have demonstrated that in response to amphetamine, patients with schizophrenia displace more dopamine D 2 -ligand than healthy subjects (Abi-Dargham et al. 1998;Breier et al. 1997;Laruelle et al. 1996). Additional evidence in support of increased dopamine activity comes from demonstrations of increased metabolism of [ 18 F]fluorodopa (Dao-Castellana et al. 1997;Hietala et al. 1995;Reith et al. 1994) and [ 11 C]L-DOPA (Lindstrom et al. 1999). The prevailing interpretation of these findings is that schizophrenic patients episodically release more dopamine (Breier et al. 1997;Laruelle et al. 1996), possibly in connection with up-regulated enzyme activity of dopa-decarboxylase induced by low tonic activity of dopaminergic neurons (Reith et al. 1994). Given the importance of this data to the pathophysiology of NO . 6 schizophrenia, alternative explanations need to be ruled out. For instance, schizophrenic patients may have greater dopaminergic innervation in the striatum. Regulation of transmitter release, and uptake, could be normal, while greater terminal density could lead to more release of dopamine after re-uptake blockade and vesicular release by amphetamine.Although post-mortem studies have found normal density of presynaptic dopamine markers, such as the dopamine transporter (Hirai et al. 1988;Joyce et al. 1988;Pearce et al. 1990) and expressed mRNA for tyrosine hydroxylase (Ichinose et al. 1994), excessive innervation could be obscured by normal aging and more rapid degeneration of terminals in schizophrenia. Dopamine receptors Volkow et al. 1996b), transporters (Volkow et al. 1996a), and vesicles (Frey et al. 1998 all declin...

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Dopamine Uptake Sites and Dopamine Receptors in Parkinson’s Disease and Schizophrenia

Cited by 68 publications

References 0 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

Differential Effects of Haloperidol and Clozapine on [3H]cAMP Binding, Protein Kinase A (PKA) Activity, and mRNA and Protein Expression of Selective Regulatory and Catalytic Subunit Isoforms of PKA in Rat Brain

In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia

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