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| 2. |
- Emilsson, Lina, et al.
(author)
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Low mRNA levels of RGS4 splice variants in Alzheimer’s disease and association between a rare haplotype and decreased mRNA expression
- 2006
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In: Synapse. - 0887-4476 .- 1098-2396. ; 59:3, s. 173-176
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Journal article (peer-reviewed)abstract
- Regulator of G-protein signaling 4 (RGS4) showed decreased mRNAlevels in Alzheimer’s disease in a large collection of human brain autopsies from prefrontalcortex. The expression levels of three RGS4 splice variants were examined inthe same samples, and the association between RGS4 gene expression and/or the diseasewith single nucleotide polymorphisms located in this gene was explored. We showthat all splice variants are down-regulated in patients. We also demonstrate that onerare haplotype (ATAG) is associated with decreased mRNA levels in both cases andcontrols. Our results suggest that an altered regulation in transcription initiation maybe an important mechanism for low RGS4 protein levels in Alzeimer’s disease.
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| 10. |
- Henriksson, Richard, et al.
(author)
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Elevated synaptophysin I in the prefrontal cortex of human chronic alcoholics
- 2008
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In: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 62:11, s. 829-33
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Journal article (peer-reviewed)abstract
- Convergent lines of evidence suggest potentiation of glutamatergic synapses after chronic ethanol exposure, and indicate that the presynaptic effect hereof is on modulators of synaptic strength rather than on executors of glutamate release. To address this hypothesis in the context of ethanol dependence in humans, we used semiquantitative immunoblotting to compare the immunoreactivities of synaptophysin I, syntaxin 1A, synaptosome-associated protein 25, and vesicle-associated membrane protein in the prefrontal and motor cortices between chronic alcoholics and control subjects. We found a region-specific elevation in synaptophysin I immunoreactivity in the prefrontal cortex of alcoholics, but detected no significant differences between the groups in the immunoreactivities of the other three proteins. Our findings are consistent with an effect of repeated ethanol exposure on modulators of synaptic strength but not on executors of glutamate release, and suggest a role for synaptophysin I in the enduring neuroplasticity in the prefrontal cortical glutamate circuitry that is associated with ethanol dependence.
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| 11. |
- Jardemark, Kent E, et al.
(author)
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Differential effects of topiramate on prefrontal glutamatergic transmission when combined with raclopride or clozapine.
- 2009
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In: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 63:10
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Journal article (peer-reviewed)abstract
- Treatment with topiramate may improve negative symptoms in schizophrenia when added to typical antipsychotic drugs (APDs) but not to clozapine. Both dopaminergic and glutamatergic transmissions in the medial prefrontal cortex (mPFC) are facilitated by atypical, but not typical, APDs, which is thought to improve negative symptoms and cognitive dysfunction in schizophrenia. Our previous results show that topiramate increases prefrontal dopamine (DA) outflow when added to the D(2/3) receptorantagonist raclopride. Here, using intracellular recording in vitro, we investigated the effects of topiramate on glutamatergic neurotransmission in the rat mPFC, both when given alone and in combination with raclopride or clozapine. Neither topiramate nor raclopride alone had any effect on N-methyl-D-aspartate (NMDA)-induced currents in pyramidal cells of the mPFC. However, the combination of topiramate and raclopride facilitated the NMDA-induced currents, and this effect was blocked by the D1 receptor antagonist SCH23390. Topiramate also facilitated the effect of a submaximal, but inhibited the effect of a maximal, concentration of clozapine on these currents. The effect of combined topiramate and a submaximal concentration of clozapine could be blocked by SCH23390. In addition, combined topiramate and raclopride facilitated excitatory postsynaptic potentials. In contrast, topiramate inhibited clozapine's facilitating effect on these potentials. These data may help explain the improvement of negative symptoms when topiramate is used as adjunctive therapy in schizophrenic patients receiving typical APDs, but they may also shed light on the observed deterioration of symptoms when topiramate is added to full dose clozapine.
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| 12. |
- Konradsson, Asa, et al.
(author)
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Inhibition of the glycine transporter GlyT-1 potentiates the effect of risperidone, but not clozapine, on glutamatergic transmission in the rat medial prefrontal cortex.
- 2006
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In: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 81, s. 104-104
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Journal article (peer-reviewed)abstract
- Clinical studies suggest that the efficacy of the atypical antipsychotic drug (APD) risperidone (but not clozapine) can be augmented by adjunctive treatment with agonists at the glycine site of the N-methyl-D-aspartate (NMDA) receptor. By using intracellular recording, we have investigated the effect of the glycine transporter-1 (GlyT-1) inhibitor N [3-(4'-fluorophenyl)-3-(4'phenylphenylphenoxy) propyl] sarcosine (NFPS) on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex (mPFC), both when given alone and in combination with either risperidone or clozapine. Both risperidone and clozapine enhanced the NMDA-induced currents. The concentration-response curves were biphasic, and the maximal effect of clozapine on the NMDA-induced currents was significantly larger than the maximal effect of risperidone. NFPS also significantly potentiated the NMDA-induced currents, when given alone. Moreover, NFPS (1 microM) augmented the effect of both the maximal (20 nM), and a submaximal (10 nM), concentration of risperidone. In contrast, NFPS did not potentiate either the effect of the maximal (100 nM) or a submaximal (80 nM) concentration of clozapine on the NMDA-induced currents. These data may explain the beneficial clinical results of using glycine reuptake antagonists as adjuvant treatment to risperidone. Our findings also suggest that risperidone and clozapine may affect NMDA receptor-mediated neurotransmission differently in the mPFC.
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| 13. |
- Konradsson-Geuken, Asa, et al.
(author)
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Second-by-second analysis of alpha 7 nicotine receptor regulation of glutamate release in the prefrontal cortex of awake rats.
- 2009
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In: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 63:12
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Journal article (peer-reviewed)abstract
- These experiments utilized an enzyme-based microelectrode selective for the second-by-second detection of extracellular glutamate to reveal the alpha 7-based nicotinic modulation of glutamate release in the prefrontal cortex (PFC) of freely moving rats. Rats received intracortical infusions of the nonselective nicotinic agonist nicotine (12.0 mM, 1.0 microg/0.4 microl) or the selective alpha 7 agonist choline (2.0 mM/0.4 microl). The selectivity of drug-induced glutamate release was assessed in subgroups of animals pretreated with the alpha 7 antagonist, alpha-bungarotoxin (alpha-BGT, 10 microM), or kynurenine (10 microM) the precursor of the astrocyte-derived, negative allosteric alpha 7 modulator kynurenic acid. Local administration of nicotine increased glutamate signals (maximum amplitude = 4.3 +/- 0.6 microM) that were cleared to baseline levels in 493 +/- 80 seconds. Pretreatment with alpha-BGT or kynurenine attenuated nicotine-induced glutamate by 61% and 60%, respectively. Local administration of choline also increased glutamate signals (maximum amplitude = 6.3 +/- 0.9 microM). In contrast to nicotine-evoked glutamate release, choline-evoked signals were cleared more quickly (28 +/- 6 seconds) and pretreatment with alpha-BGT or kynurenine completely blocked the stimulated glutamate release. Using a method that reveals the temporal dynamics of in vivo glutamate release and clearance, these data indicate a nicotinic modulation of cortical glutamate release that is both alpha 7- and non-alpha 7-mediated. Furthermore, these data may also provide a mechanism underlying the recent focus on alpha 7 full and partial agonists as therapeutic agents in the treatment of cortically mediated cognitive deficits in schizophrenia.
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| 15. |
- Lundquist, Pinelopi, et al.
(author)
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Effect on [11C]DASB binding after tranylcypromine-induced increase in serotonin concentration : positron emission tomography studies in monkeys and rats
- 2007
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In: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 61:6, s. 440-449
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Journal article (peer-reviewed)abstract
- Several research groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentrations of endogenous transmitters in the vicinity of neuroreceptors. The aim of this study was to investigate whether [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([11C]DASB) binding to the plasma membrane serotonin transporter (SERT) in the rhesus monkey and rat brain decreased after a pharmacologically-induced increase in the interstitial serotonin (5HT) concentration. Three rhesus monkeys were given repeated single boluses of [11C]DASB in sequential positron emission tomography (PET) experiments. Rats were given the tracer as a bolus dose plus a constant infusion. In vivo binding in both models was studied before and after presumably having increased interstitial 5HT concentrations using tranylcypromine (TCP), which inhibits the enzyme (monoamine oxidase, MAO), that degrades 5HT. The rat brain tissue was analyzed using high-performance liquid chromatography (HPLC) to determine the proportion of the PET signal comprising unchanged [11C]DASB. The binding of [11C]DASB in the thalamus decreased in both rhesus monkeys and rats after TCP administration. The possibility of using [11C]DASB as a tool for monitoring changes in endogenous serotonin concentrations merits further investigation.
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| 16. |
- Lundquist, Pinelopi, et al.
(author)
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Validation studies on the 5-hydroxy-L-[beta-11C]-tryptophan/PET method for probing the decarboxylase step in serotonin synthesis
- 2006
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In: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 59:8, s. 521-531
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Journal article (peer-reviewed)abstract
- The two-tissue compartment model, including irreversible trapping in the second compartment (2TCM) is used to describe the kinetics of 5-Hydroxy-L-[beta-(11)C]-tryptophan ([(11)C]HTP), a radioligand used in positron emission tomography (PET) for probing the second enzymatic step in the biosynthesis of serotonin. In this study, we examined the capacity of the model to track pharmacological changes in this biological process. We also investigated the potential loss of [(11)C]HTP-derived radioactivity during a PET study, since loss should be negligible not to alter quantification. Six rhesus monkeys were investigated using bolus [(11)C]HTP/PET methodology before and after pharmacological intervention. The second enzymatic step in serotonin synthesis was inhibited using the aromatic L-amino acid decarboxylase inhibitor NSD1015 (10 mg/kg). The extent of [(11)C]-derived radioactivity loss from the brain was studied by inhibition of the enzyme responsible for formation of the tissue metabolite, monoamine oxidase A, using clorgyline (2 mg/kg). After NSD1015, the uptake of [(11)C]HTP-derived radioactivity was increased in all the investigated brain regions, while the parameter used to reflect decarboxylase activity, the net accumulation rate constant (K(acc)), was decreased by 37% in the striatum, compared with baseline. Pretreatment with clorgyline did not change the brain uptake of [(11)C]HTP-derived radioactivity or K(acc). This study demonstrates that the 2TCM for [(11)C]HTP/PET is able to detect changes occurring during alteration of the biological process (i.e., the conversion of HTP to serotonin). Elimination of the radiotracer metabolite [(11)C]HIAA from the brain may be considered negligible if the PET study is limited to 60 min.
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| 18. |
- Pålsson, Erik, 1975, et al.
(author)
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Increased cortical nitric oxide release after phencyclidine administration.
- 2009
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In: Synapse (New York, N.Y.). - : Wiley. - 1098-2396 .- 0887-4476. ; 63:12, s. 1083-1088
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Journal article (peer-reviewed)abstract
- Phencyclidine exerts psychotomimetic effects in humans and is used as a pharmacological animal model for schizophrenia. We, and others, have demonstrated that phencyclidine induces cognitive deficits in rats that are associated with schizophrenia. These cognitive deficits can be normalized by inhibition of nitric oxide synthase. The development of selective microelectrochemical nitric oxide sensors may provide direct evidence for the involvement of nitric oxide in these effects. The aim of the present study was to use LIVE (long term in vivo electrochemistry) to investigate the effect of phencyclidine, alone or in combination with the nitric oxide synthase inhibitor L-NAME, on nitric oxide levels in the medial prefrontal cortex of freely moving rats. Phencyclidine (2 mg kg(-1)) produced an increase in cortical nitric oxide levels and this increase was ameliorated by L-NAME (10 mg kg(-1)). Tentatively, the results from the present study provide a biochemical rationale for the involvement of nitric oxide in the phencyclidine model of schizophrenia. Synapse 63:1083-1088, 2009. (c) 2009 Wiley-Liss, Inc.
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| 26. |
- Shahabi, H Niazi, et al.
(author)
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Cytochrome P450 2E1 in the substantia nigra: relevance for dopaminergic neurotransmission and free radical production.
- 2008
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In: Synapse (New York, N.Y.). - : Wiley. - 0887-4476 .- 1098-2396. ; 62:5, s. 379-88
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Journal article (peer-reviewed)abstract
- Cytochrome P450 2E1 (CYP2E1) has been detected in brain regions which are of relevance for the pathophysiology of Parkinson's disease, such as the substantia nigra (SN). Furthermore, CYP2E1 is known to generate reactive oxygen species (ROS), toxic molecules which have been implicated in the pathogenesis of the disease. We have previously reported that CYP2E1 inhibition increases extracellular dopamine (DA) in the SN. The aims of the present study were by using in vivo microdialysis in rat, to elucidate the mechanisms responsible for the increase in extracellular DA induced by CYP2E1 inhibition and to explore whether ROS is produced in the SN, both with and without the presence of an exogenous CYP2E1 substrate. The effect of inhibition of CYP2E1 by phenylethyl isothiocyanate (100 mg/kg) on extracellular DA in the SN was unaltered following pretreatment with gamma-butyrolactone and GBR-12909, drugs that inhibit firing of DA neurons and DA re-uptake, respectively. Preadministration of tetrodotoxin or reserpine, however, abolished the effect of CYP2E1 inhibition. Administration of isoflurane, an anesthetic which is metabolized by CYP2E1, increased the production of *OH in the SN, as measured by the transformation of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid during local perfusion compared with animals given other anesthetics. The results support the notion that CYP2E1 is located near or in the same compartment in the SN as stored DA, tentatively the endoplasmatic reticulum, and that the enzyme activity might modulate the amount of DA that is available for release. Furthermore, our findings indicate that the production of ROS can be stimulated by CYP2E1 substrates.
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