| 1. |
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| 2. |
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| 3. |
- Schweizer, Nadine, et al.
(författare)
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Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption
- 2016
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Ingår i: eNeuro. - 2373-2822. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.
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| 4. |
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| 5. |
- Viereckel, Thomas, et al.
(författare)
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Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.
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| 6. |
- Viereckel, Thomas, 1987-
(författare)
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United in Diversity : A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this doctoral thesis aimed at characterizing restricted subpopulations of neurons in the Basal Ganglia circuitry and their importance in the wider function of the network. To this end, we identified subpopulations of neurons in the subthalamic nucleus (STN), substantia nigra (SN) and ventral tegmental area (VTA), characterized their molecular profile and investigated their physiological role in the circuitry.Within the mouse STN, reduction of glutamatergic neurotransmission in a subpopulation expressing Paired-like homeodomain transcription factor 2 (Pitx2) led to structural alterations in the nucleus as well as biochemical alterations of the dopaminergic system in the Nucleus accumbens (NAc) and changes in reward-related behavior. In the ventral midbrain, we identified and characterized novel marker genes selective to the VTA or SN. Of these, transient receptor potential cation channel subfamily V member 1 (TrpV1) marks a population of mainly glutamatergic neurons in the VTA which project to the NAc, while gastrin releasing peptide (Grp) is expressed in a population of dopaminergic neurons neuroprotected in Parkinson's disease. Furthermore, we discovered that disruption of glutamatergic co-release of dopaminergic neurons expressing dopamine transporter (DAT), diminishes fast EPSCs and glutamate release but does not affect the acquisition of reward-related behavioral tasks. To selectively quantify glutamate release from specific subpopulations, we devised a technique combining glutamate-amperometry and optogenetics. This was used to measure glutamate released from Pitx2-expressing synaptic terminals in the Globus pallidus as well as DAT- or TrpV1-expressing terminals in the NAc.In summary, this doctoral thesis has furthered understanding of the function and importance of specific subpopulations within the Basal Ganglia circuitry and provides a novel means to investigate glutamate in the intact rodent brain within clearly defined, restricted cell populations.
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| 7. |
- Viereckel, Thomas, et al.
(författare)
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Validated multi‐step approach for in vivo recording and analysis of optogenetically evoked glutamate in the mouse globus pallidus
- 2018
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 145:2, s. 125-138
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Tidskriftsartikel (refereegranskat)abstract
- Precise quantification of extracellular glutamate concentrations upon neuronal activation is crucial for the understanding of brain function and neurological disorders. While optogenetics is an outstanding method for the correlation between distinct neurons and their role in circuitry and behavior, the electrochemically inactive nature of glutamate has proven challenging for recording upon optogenetic stimulations. This difficulty is due to the necessity for using enzyme-coated microelectrodes and the risk for light-induced artifacts. In this study, we establish a method for the combination of invivo optogenetic stimulation with selective measurement of glutamate concentrations using enzyme-coated multielectrode arrays and amperometry. The glutamatergic subthalamic nucleus (STN), which is the main electrode target site in deep brain stimulation treatment of advanced Parkinsons disease, has recently proven opotogenetically targetable in Pitx2-Cre-transgenic mice and was here used as model system. Upon stereotactic injection of viral Channelrhodopsin2-eYFP constructs into the STN, amperometric recordings were performed at a range of optogenetic stimulation frequencies in the globus pallidus, the main STN target area, in anesthetized mice. Accurate quantification was enabled through a multi-step analysis approach based on self-referencing microelectrodes and repetition of the experimental protocol at two holding potentials, which allowed for the identification, isolation and removal of photoelectric and photoelectrochemical artifacts. This study advances the field of invivo glutamate detection with combined optogenetics and amperometric recordings by providing a validated analysis framework for application in a wide variety of glutamate-based approaches in neuroscience.
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| 8. |
- Wang, Dong V., et al.
(författare)
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Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 18:11, s. 2584-2591
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Tidskriftsartikel (refereegranskat)abstract
- Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.
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| 9. |
- Adem, Abdu, et al.
(författare)
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Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice
- 2019
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 29:5, s. 616-628
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR) transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA) task in mice and the ability of typical and atypical antipsychotic drugs (APDs) to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg) dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.
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| 10. |
- Bikovski, Lior, et al.
(författare)
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Lessons, insights and newly developed tools emerging from behavioral phenotyping core facilities
- 2020
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270 .- 1872-678X. ; 334
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Forskningsöversikt (refereegranskat)abstract
- Scientific investigations, in general, and research in neuroscience, in particular, are becoming ever more complex and require the integration of different techniques. Behavioral assays, which are among the most frequently used methodologies in neuroscience, nowadays rely on advanced, sophisticated technologies that require proficient application. Therefore, behavioral core facilities are becoming essential support units, as they provide the specialized expert research services needed to conduct advanced neuroscience. We here review the lessons learned and insights gathered from managing behavioral core facilities in different academic research institutes. This review addresses several issues, including: the advantages of behavioral core facilities, considerations for establishing a behavioral core facility, and the methodological advances made through calibration and standardization of assay protocols and the development of new assays. Collectively, the review highlights the benefits of both working within and collaborating with behavioral core facility units and emphasizes the potential progress in neuro-phenotyping that such facilities provide.
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| 11. |
- Björkholm, Carl, et al.
(författare)
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Adjunctive treatment with asenapine augments the escitalopram-induced effects on monoaminergic outflow and glutamatergic neurotransmission in the medial prefrontal cortex of the rat.
- 2015
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Ingår i: International Journal of Neuropsychopharmacology. - : Oxford University Press (OUP). - 1461-1457 .- 1469-5111. ; 18:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Substantial clinical data support the addition of low doses of atypical antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) to rapidly enhance the antidepressant effect in treatment-resistant depression. Preclinical studies suggest that this effect is at least partly explained by an increased catecholamine outflow in the medial prefrontal cortex (mPFC).METHODS: In the present study we used in vivo microdialysis in freely moving rats and in vitro intracellular recordings of pyramidal cells of the rat mPFC to investigate the effects of adding the novel atypical antipsychotic drug asenapine to the SSRI escitalopram with regards to monoamine outflow in the mPFC and dopamine outflow in nucleus accumbens as well as glutamatergic transmission in the mPFC.RESULTS: The present study shows that addition of low doses (0.05 and 0.1 mg/kg) of asenapine to escitalopram (5 mg/kg) markedly enhances dopamine, noradrenaline, and serotonin release in the rat mPFC as well as dopamine release in the nucleus accumbens. Moreover, this drug combination facilitated both N-methyl-d-Aspartate (NMDA)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced currents as well as electrically evoked excitatory postsynaptic potentials in pyramidal cells of the rat mPFC.CONCLUSIONS: Our results support the notion that the augmentation of SSRIs by atypical antipsychotic drugs in treatment-resistant depression may, at least in part, be related to enhanced catecholamine output in the prefrontal cortex and that asenapine may be clinically used to achieve this end. In particular, the subsequent activation of the D1 receptor may be of importance for the augmented antidepressant effect, as this mechanism facilitated both NMDA and AMPA receptor-mediated transmission in the mPFC. Our novel observation that the drug combination, like ketamine, facilitates glutamatergic transmission in the mPFC may contribute to explain the rapid and potent antidepressant effect obtained when atypical antipsychotic drugs are added to SSRIs.
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| 12. |
- Björkholm, Carl, et al.
(författare)
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The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism.
- 2017
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Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 27, s. 411-417
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Tidskriftsartikel (refereegranskat)abstract
- Brexpiprazole (Rexulti(®)), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression.
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| 13. |
- Campos-Beltran, Diana, et al.
(författare)
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Amperometric Self-Referencing Ceramic Based Microelectrode Arrays for D-Serine Detection
- 2018
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Ingår i: Biosensors. - : MDPI. - 2079-6374. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- D-serine is the major D-amino acid in the mammalian central nervous system. As the dominant co-agonist of the endogenous synaptic NMDA receptor, D-serine plays a role in synaptic plasticity, learning, and memory. Alterations in D-serine are linked to neuropsychiatric disorders including schizophrenia. Thus, it is of increasing interest to monitor the concentration of D-serine in vivo as a relevant player in dynamic neuron-glia network activity. Here we present a procedure for amperometric detection of D-serine with self-referencing ceramic-based microelectrode arrays (MEAs) coated with D-amino acid oxidase from the yeast Rhodotorula gracilis (RgDAAO). We demonstrate in vitro D-serine recordings with a mean sensitivity of 8.61 +/- 0.83 pA/mu M to D-serine, a limit of detection (LOD) of 0.17 +/- 0.01 mu M, and a selectivity ratio of 80:1 or greater for D-serine over ascorbic acid (mean +/- SEM; n = 12) that can be used for freely moving studies.
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| 14. |
- Feltmann, Kristin, et al.
(författare)
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Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats.
- 2015
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Ingår i: Behavioral Neuroscience. - : American Psychological Association (APA). - 0735-7044 .- 1939-0084. ; 129:6
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Tidskriftsartikel (refereegranskat)abstract
- Patients suffering from major depression often experience memory deficits even after the remission of mood symptoms, and many antidepressant drugs do not affect, or impair, memory in animals and humans. However, some antidepressant drugs, after a single dose, enhance cognition in humans (Harmer et al., 2009). To compare different classes of antidepressant drugs for their potential as memory enhancers, we used a version of the novel object recognition task in which rats spontaneously forget objects 24 hr after their presentation. Antidepressant drugs were injected systemically 30 min before or directly after the training phase (Session 1 [S1]). Post-S1 injections were used to test for specific memory-consolidation effects. The noradrenaline reuptake inhibitors reboxetine and atomoxetine, as well as the serotonin noradrenaline reuptake inhibitor duloxetine, injected prior to S1 significantly enhanced recognition memory. In contrast, the serotonin reuptake inhibitors citalopram and paroxetine and the cyclic antidepressant drugs desipramine and mianserin did not enhance recognition memory. Post-S1 injection of either reboxetine or citalopram significantly enhanced recognition memory, indicating an effect on memory consolidation. The fact that citalopram had an effect only when injected after S1 suggests that it may counteract its own consolidation-enhancing effect by interfering with memory acquisition. However, pretreatment with citalopram did not attenuate reboxetine's memory-enhancing effect. The D1/5-receptor antagonist SCH23390 blunted reboxetine's memory-enhancing effect, indicating a role of dopaminergic transmission in reboxetine-induced recognition memory enhancement. Our results suggest that antidepressant drugs specifically inhibiting noradrenaline reuptake enhance cognition and may be beneficial in the treatment of cognitive symptoms of depression.
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| 15. |
- Malmlöf, Torun, et al.
(författare)
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Deuterium-substituted L-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease : comparison with the effects produced by L-DOPA and an MAO-B inhibitor.
- 2015
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Ingår i: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 122:2
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Tidskriftsartikel (refereegranskat)abstract
- The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-L-DOPA and L-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-L-DOPA and L-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-L-DOPA, as compared to that of L-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/L-DOPA. The extracellular levels of dopamine were also increased following both D3-L-DOPA and selegiline/L-DOPA administration compared with L-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-L-DOPA and the combination of selegiline/L-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-L-DOPA and selegiline/L-DOPA, respectively, is of considerable clinical interest since D3-L-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.
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| 16. |
- Marcus, Monica M, et al.
(författare)
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Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.
- 2016
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 26:9, s. 1401-11
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Tidskriftsartikel (refereegranskat)abstract
- Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.
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| 17. |
- Molinero-Fernandez, Águeda, et al.
(författare)
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Demonstrating the Analytical Potential of a Wearable Microneedle-Based Device for Intradermal CO2 Detection
- 2024
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Ingår i: ACS Sensors. - : American Chemical Society (ACS). - 2379-3694. ; 9:1, s. 361-370
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Tidskriftsartikel (refereegranskat)abstract
- Monitoring of carbon dioxide (CO2) body levels is crucial under several clinical conditions (e.g., human intensive care and acid–base disorders). To date, painful and risky arterial blood punctures have been performed to obtain discrete CO2 measurements needed in clinical setups. Although noninvasive alternatives have been proposed to assess CO2, these are currently limited to benchtop devices, requiring trained personnel, being tedious, and providing punctual information, among other disadvantages. To the best of our knowledge, the literature and market lack a wearable device for real-time, on-body monitoring of CO2. Accordingly, we have developed a microneedle (MN)-based sensor array, labeled as CO2–MN, comprising a combination of potentiometric pH- and carbonate (CO32–)-selective electrodes together with the reference electrode. The CO2–MN is built on an epidermal patch that allows it to reach the stratum corneum of the skin, measuring pH and CO32– concentrations directly into the interstitial fluid (ISF). The levels for the pH–CO32– tandem are then used to estimate the PCO2 in the ISF. Assessing the response of each individual MN, we found adequate response time (t95 < 5s), sensitivity (50.4 and −24.6 mV dec–1 for pH and CO32–, respectively), and stability (1.6 mV h–1 for pH and 2.1 mV h–1 for CO32–). We validated the intradermal measurements of CO2 at the ex vivo level, using pieces of rat skin, and then, with in vivo assays in anesthetized rats, showing the suitability of the CO2–MN wearable device for on-body measurements. A good correlation between ISF and blood CO2 concentrations was observed, demonstrating the high potential of the developed MN sensing technology as an alternative to blood-based analysis in the near future. Moreover, these results open new horizons in the noninvasive, real-time monitoring of CO2 as well as other clinically relevant gases.
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| 18. |
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| 19. |
- Stiedl, Oliver, et al.
(författare)
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The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory.
- 2015
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT1AR and 5-HT7R are associated with the development of anxiety, depression and cognitive function linked to mechanisms of emotional learning and memory. In rodents fear conditioning and passive avoidance (PA) are associative learning paradigms to study emotional memory. This review assesses the role of 5-HT1AR and 5-HT7R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT1ARs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT1AR facilitates memory retention possibly via 5-HT7R activation and evidence is provided that 5HT7R can facilitate emotional memory upon reduced 5-HT1AR transmission. These findings highlight the differential role of these 5-HTRs in cognitive/emotional domains of behavior. Moreover, the results indicate that tonic and phasic 5-HT release can exert different and potentially opposing effects on emotional memory, depending on the states of 5-HT1ARs and 5-HT7Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role for the responsiveness to drug treatment, e.g., by SSRIs which increase intrasynaptic 5-HT levels thereby activating multiple pre- and postsynaptic 5-HTR subtypes.
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| 20. |
- Titulaer, Joep
(författare)
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Finding improved drug strategies for schizophrenia : Preclinical studies on lumateperone and sodium nitroprusside
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Schizophrenia is a severe psychiatric disorder affecting approximately 20 million people worldwide. The disease consists of positive symptoms e.g. hallucinations, negative symptoms such as anhedonia, and cognitive deficits, e.g. impaired episodic memory. Most of the currently available treatment options for schizophrenia only target the positive symptoms, possess severe side effects and do not work for a large group of patients. In this thesis, the unique antipsychotic drug lumateperone and adjunctive treatment of sodium nitroprusside (SNP) to sub-maximal doses of conventional antipsychotic drugs are investigated in preclinical tests as novel treatment options for schizophrenia In paper I we showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test in rats. Moreover, by using microdialysis we showed that SNP significantly enhances risperidone-induced dopamine release in the rat medial prefrontal cortex (mPFC) but not in the nucleus accumbens, indicating that adjunct SNP could be used to improve the efficacy of antipsychotic drugs, while reducing their dose and subsequently lower the risk of side effects.In paper II we used microdialysis combined to the behavioral novel object recognition test in rats to show that the release of both dopamine and norepinephrine is increased in the ventral hippocampus in response to a novel object, suggesting that dopamine and norepinephrine may play a crucial role in recognition memory. In paper III we showed that SNP significantly enhanced the antipsychotic-like effect of sub-effective doses of olanzapine in the CAR test, but not of clozapine, this could be explained by the developed tolerance towards clozapine after repeated administrations.In paper IV we used enzyme-coated microelectrode arrays to show that lumateperone significantly increased cortical glutamate release in the mPFC of anaesthetized rats. By using electrophysiology, we also show that lumateperone facilitates NMDA and AMPA-mediated currents in a dopamine D1 dependent manner in layer V/VI pyramidal neurons in the mPFC of rats. Moreover, lumateperone increases dopamine release in the mPFC of freely moving rats as shown by using microdialysis. These mechanisms may improve cognitive deficits and contribute to the clinically demonstrated antidepressant effects of lumateperone. Taken together, these results show that lumateperone is a promising novel treatment option for schizophrenia, and that adjunct SNP treatment may allow for improved efficacy at maintained or even reduced dosage of conventional antipsychotic medication.
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| 21. |
- Titulaer, Joep, et al.
(författare)
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Sex-specific differences and similarities of olanzapine and risperidone on avoidance suppression in rats in the conditioned avoidance response test
- 2023
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1818
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that antipsychotic drugs (APDs) are more effective in reducing symptoms in women than in men, and that women are more sensitive to the side effects of APDs. Therefore, it is of great importance that sex differences in drug responses are considered already in the early stages of drug development. In this study, we investigated whether sex-specific differences could be observed in response to the commonly prescribed APDs olanzapine and risperidone using the conditioned avoidance response (CAR) test. To this end we tested the effect of 1.25 and 2.5 mg/kg olanzapine and 0.25 and 0.4 mg/kg risperidone using female and male Wistar rats in the CAR test. Whereas there were no significant differences between the female and male rats in response to either dose of olanzapine administration, an injection of 0.4 mg/kg risperidone significantly suppressed avoidance more in female rats than in male rats. In addition, we found that the estrous cycle of the female rats did not have a significant effect on the avoidance response. In conclusion, we show that there are sex-specific differences as well as similarities between female and male rats in the CAR test and novel APDs should be tested on female and male rats in the future.
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| 22. |
- Titulaer, Joep, et al.
(författare)
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Sodium nitroprusside enhances the antipsychotic-like effect of olanzapine but not clozapine in the conditioned avoidance response test in rats
- 2022
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Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 60, s. 48-54
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Tidskriftsartikel (refereegranskat)abstract
- The nitric oxide (NO)-donor, sodium nitroprusside (SNP) has been proposed as an adjunct treatment to enhance the effect of antipsychotic drugs (APDs). As NO constitutes an important downstream signaling molecule of N-methyl-D-aspartate receptors, SNP may alleviate symptoms of schizophrenia by modulating glutamatergic signaling. We previously showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test, indicating that adjunct SNP may be used to lower the dose of risperidone and in this way reduce the risk of side effects. By using the CAR test, we here investigated if SNP also enhances the antipsychotic-like effect of olanzapine or clozapine. Importantly, SNP (1.5 mg/kg) significantly enhanced the antipsychotic-like effect of olanzapine (1.25 and 2.5mg/kg) to a clinically relevant level, supporting the potential clinical use of SNP as an adjunct treatment to improve the effect of APDs. However, SNP (1.5 mg/kg) did not increase the antipsychotic-like effect of clozapine (5 and 6 mg/kg). Moreover, we found that the rats developed tolerance towards clozapine after repeated administrations. Thus, our study motivates further investigation using different preclinical models to assess the effect of adjunct treatment of SNP to APDs, also targeting the negative symptoms and cognitive deficits seen in schizophrenia.
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| 23. |
- Titulaer, Joep, et al.
(författare)
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The Importance of Ventral Hippocampal Dopamine and Norepinephrine in Recognition Memory
- 2021
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media S.A.. - 1662-5153. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Dopaminergic neurons originating from the ventral tegmental area (VTA) and the locus coeruleus are innervating the ventral hippocampus and are thought to play an essential role for efficient cognitive function. Moreover, these VTA projections are hypothesized to be part of a functional loop, in which dopamine regulates memory storage. It is hypothesized that when a novel stimulus is encountered and recognized as novel, increased dopamine activity in the hippocampus induces long-term potentiation and long-term storage of memories. We here demonstrate the importance of increased release of dopamine and norepinephrinein the rat ventral hippocampus on recognition memory, using microdialysis combined to a modified novel object recognition test. We found that presenting rats to a novel object significantly increased dopamine and norepinephrine output in the ventral hippocampus. Two hours after introducing the first object, a second object (either novel or familiar) was placed in the same position as the first object. Presenting the animals to a second novel object significantly increased dopamine and norepinephrine release in the ventral hippocampus, compared to a familiar object. In conclusion, this study suggests that dopamine and norepinephrine output in the ventral hippocampus has a crucial role in recognition memory and signals novelty.
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| 24. |
- Wang, Qianyu, et al.
(författare)
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Intradermal Glycine Detection with a Wearable Microneedle Biosensor : The First In Vivo Assay
- 2022
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 94:34, s. 11856-11864
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Tidskriftsartikel (refereegranskat)abstract
- Glycine (GLY) is gaining importance in medical diagnoses due to its relationship with multiple physiological functions. Today, GLY is exclusively analyzed using instrumentation centralized in clinical labs, and a tangible point-of-care tool that gathers real-time data from the patient for effective and fast evaluations is lacking. Relevant clinical advances are expected as soon as the rapid provision of both punctual and continuous measurements is possible. In that context, this work presents a microneedle (MN)-based biosensor for intradermal GLY detection in interstitial fluid (ISF). The MN tip is externally tailored to detect GLY levels through the hydrogen peroxide formed in its reaction with a quinoprotein-based GLY oxidase enzyme. The analytical performance of the MN biosensor indicates a fast response time (<7 s); acceptable reversibility, reproducibility, and stability; as well as a wide linear range of response (25-600 μM) that covers the physiological levels of GLY in ISF. The MN biosensor conveniently exhibits high selectivity for GLY over other compounds commonly found in ISF, and the response is not influenced by temperature, pH, or skin insertions. Validated intradermal measurements of GLY were obtained at the in vitro (with pieces of rat skin), ex vivo (on-body tests of euthanized rats) and in vivo (on-body tests of anesthetized rats) levels, demonstrating its ability to produce accurate physiological data. The developed GLY MN biosensor is skin-wearable and provides reliable, real-time intradermal GLY measurements in ISF by means of a minimally invasive approach.
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