Schizophrenia: From Dopamine to Glutamate and Back

Carlsson, Maria; Carlsson, Arvid; Nilsson, Mikael

doi:10.2174/0929867043456034

Cited by 146 publications

(101 citation statements)

References 41 publications

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“…It has been suggested that the dysregulation of dopamine transmission in schizophrenia might be secondary to alterations in glutamatergic NMDA receptor-mediated transmission (Olney and Farber, 1995;Carlsson et al, 2004). A direct linkage between the two hypotheses has recently been shown in an experiment performed in healthy volunteers.…”

Section: Introductionmentioning

confidence: 96%

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-13 C]glucose and [1,2-13 C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by 13 C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-13 C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-13 C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.

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Section: Introductionmentioning

confidence: 96%

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Kondziella

Brenner

Eyjolfsson

et al. 2005

Neuropsychopharmacol

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“…The catecholamine dopamine (DA) modulates both excitatory and inhibitory synaptic signaling (Dani and Zhou, 2004;Seamans and Yang, 2004) and in man plays a critical role in forebrain circuits implicated in motor and cognitive disorders (Reimherr et al, 1984;Crossman et al, 1987;Hernandez and Hoebel, 1988;Fiorino et al, 1993;Carlsson et al, 2004). An important mechanism of DA inactivation involves reuptake of DA by the presynaptic DA transporter (DAT) (Gainetdinov et al, 1998;BenoitMarand et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Vigorous Motor Activity inCaenorhabditis elegansRequires Efficient Clearance of Dopamine Mediated by Synaptic Localization of the Dopamine Transporter DAT-1

McDonald¹,

Hardie²,

Jessen³

et al. 2007

J. Neurosci.

117

172

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The catecholamine dopamine (DA) functions as a powerful modulatory neurotransmitter in both invertebrates and vertebrates. As in man, DA neurons in the nematode Caenorhabditis elegans express a cocaine-sensitive transporter (DAT-1), presumably to regulate synaptic DA signaling and limit DA spillover to extrasynaptic sites, although evidence supporting this is currently lacking. In this report, we describe and validate a novel and readily quantifiable phenotype, swimming-induced paralysis (SWIP) that emerges in DAT-1-deficient nematodes when animals exert maximal physical activity in water. We verify the dependence of SWIP on DA biosynthesis, vesicular packaging, synaptic release, and on the DA receptor DOP-3. Using DAT-1 specific antibodies and GFP::DAT-1 fusions, we demonstrate a synaptic enrichment of DAT-1 that is achieved independently of synaptic targeting of the vesicular monoamine transporter (VMAT). Importantly, dat-1 deletions and point mutations that disrupt DA uptake in cultured C. elegans neurons and/or impact DAT-1 synaptic localization in vivo generate SWIP. SWIP assays, along with in vivo imaging of wild-type and mutant GFP::DAT-1 fusions identify a distal COOH terminal segment of the transporter as essential for efficient somatic export, synaptic localization and in vivo DA clearance. Our studies provide the first description of behavioral perturbations arising from altered trafficking of DATs in vivo in any organism and support a model whereby endogenous DA actions in C. elegans are tightly regulated by synaptic DAT-1.

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“…6 The disability of schizophrenic patients is a composite of persistent positive symptoms, cognitive decline and mostly increasing negative symptoms over time, together with numerous features of general psychopathology. [1][2][3]7,8 The therapeutic application of dopamine antagonists, that is, antipsychotic drugs, 9 mainly addresses the 'tip of the iceberg', leading to a level of outside normality in these patients, which enables them and their environment to cope with the disease. With the newer generation of antipsychotics and their fewer side effects regarding extrapyramidal motor signs, patients' compliance, an essential factor for long-term prognosis, seemed to improve.…”

Section: Introductionmentioning

confidence: 99%

Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin

et al. 2006

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Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a doubleblind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N = 39) with defined cognitive deficit (X1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40 000 IU rhEPO (N = 20) or placebo (N = 19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) -perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

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Schizophrenia: From Dopamine to Glutamate and Back

Cited by 146 publications

References 41 publications

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Vigorous Motor Activity inCaenorhabditis elegansRequires Efficient Clearance of Dopamine Mediated by Synaptic Localization of the Dopamine Transporter DAT-1

Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin

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