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  • 1.
    Abelson, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Höglund, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats2002In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 317, no 2, p. 93-6Article in journal (Refereed)
    Abstract [en]

    The local anesthetic lidocaine suppresses different pain conditions when administered systemically. Part of the antinociceptive effect appears to be mediated via receptor mechanisms. We have previously shown that muscarinic and nicotinic agonists that produce antinociception increase the intraspinal release of acetylcholine. In the present study it was hypothesized that systemically administered lidocaine is acting through the same mechanisms as cholinergic agonists and affects the intraspinal release of acetylcholine. Microdialysis probes were placed in anesthetized rats for sampling of acetylcholine. Ten and 30 mg/kg lidocaine injected intravenously significantly increased the intraspinal release of acetylcholine. The effect of lidocaine could be reduced by pretreatment with intraspinally administered atropine or mecamylamine. Our results suggest that the antinociceptive effect produced by systemically administered lidocaine is mediated through an action on muscarinic and nicotinic receptors.

  • 2.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pickering, Chris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Motivation for sucrose in sated rats is predicted by low anxiety-like behavior2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 454, no 3, p. 193-197Article in journal (Refereed)
    Abstract [en]

    Anxiety has been implicated in obesity and in the overconsumption of highly palatable foods such as those high in fat, sugar, or both. Also, the novelty-seeking trait has been associated with failure in weight-loss programs. The aim of this study was to investigate the associations of experimental anxiety and the self-administration of sucrose and high fat pellets in non-food deprived rats across different operant schedules. Male Wistar rats were subjected to the elevated plus-maze test (EPM) of anxiety-like behavior. The rats were tested for fixed ratio 5 (FR5) and progressive ratio (PR) operant responding for 50% sucrose, 95% sucrose, and high-fat pellets. PR active lever press response for 95% sucrose, but not the other pellet types, was correlated to % time spent on open arms (P=0.019) in the EPM. On the FR5 schedule, activity (closed arm entries) was correlated to the self-administration of 50% sucrose (P=0.027) and high-fat (P=0.002). This indicates an association of novelty-induced activity and self-administration of palatable food in sated rats, as well as a specific association of PR lever press response for 95% sucrose and low anxiety-like behavior. It has been argued that such active lever press response on PR may be interpreted as craving for the reinforcer; thus, our findings indicate an inverse relationship of experimental anxiety and craving for sucrose. This connection may have implications for human situations, since anxiety and novelty-seeking have been associated with obesity and failure in weight-loss programs.

  • 3.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chavan, Rohit A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Exposure to a high-fat high-sugar diet causes strong up-regulation of proopiomelanocortin and differentially affects dopamine D1 and D2 receptor gene expression in the brainstem of rats2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 559, p. 18-23Article in journal (Refereed)
    Abstract [en]

    A strong link between obesity and dopamine (DA) has been established by studies associating body weight status to variants of genes related to DA signalling. Human and animal studies investigating this relationship have so far focused mainly on the role of DA within the mesolimbic pathway. The aim of this study was to investigate potential DA receptor dysregulation in the brainstem, where these receptors play a potential role in meal termination, during high-fat high-sugar diet (HFHS) exposure. Expression of other key genes, including proopiomelanocortin (POMC), was also analyzed. We randomized rats into three groups; ad libitum access to HFHS (n=24), restricted HFHS access (n=10), or controls (chow-fed, n=10). After 5 weeks, brainstem gene expression was investigated by qRT-PCR. We observed an increase in POMC expression in ad libitum HFHS-fed rats compared to chow-fed controls (p<0.05). Further, expression of DA D2 receptor mRNA was down-regulated in the brainstem of the HFHS ad libitum-fed rats (p<0.05), whereas expression of the DA D1 receptor was upregulated (p<0.05) in these animals compared to chow-fed rats. In control experiments, we observed no effect relative to chow-fed controls on DA-receptor or POMC gene expression in the hypothalamus of HFHS diet-exposed rats, or in the brainstem of acutely food deprived rats. The present findings suggest brainstem POMC to be responsive to palatable foods, and that DA dysregulation after access to energy-dense diets occurs not only in striatal regions, but also in the brainstem, which could be relevant for overeating and for the development and maintenance of obesity.

  • 4.
    Amandusson, Åsa
    et al.
    Linköpings Universitet.
    Hermansson, O
    Blomqvist, A
    Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat1995In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 196, no 1-2, p. 25-28Article in journal (Refereed)
    Abstract [en]

    Using an immunohistochemical technique, we demonstrate that large numbers of neurons in the laminar spinal trigeminal nucleus and spinal gray matter of the female rat express estrogen receptors (ER). Densely packed ER-immunoreactive neurons were present in lamina II, but labeled neurons were also present in lamina I, the neck of the dorsal horn, and in lamina X. Labeling was present throughout the length of the spinal cord, with the exception of segments caudal to S1, which were unlabeled. The distribution of ER-containing neurons to areas that are involved in processing of primary afferent nociceptive information suggests that the pain modulatory effects of estrogen may be exerted at the spinal level.

  • 5.
    Andreou, Dimitrios
    et al.
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Soderman, Erik
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sedvall, Goran C.
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Terenius, Lars
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Agartz, Ingrid
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden.;Univ Oslo, Inst Clin Med, NORMENT, Oslo, Norway.;Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway..
    Jonsson, Erik G.
    Karolinska Hosp & Inst, HUBIN Project, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden..
    Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis2016In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 619, p. 126-130Article in journal (Refereed)
    Abstract [en]

    Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.

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  • 6.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Kindlundh-Högberg, Anna M. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 412, no 2, p. 168-172Article in journal (Refereed)
    Abstract [en]

    Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague–Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1 h before and 3 h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.

  • 7. Blennow, Kaj
    et al.
    Zetterberg, Henrik
    Minthon, Lennart
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Strid, Stig
    Annas, Peter
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Andreasen, Niels
    Longitudinal stability of CSF biomarkers in Alzheimer's disease2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 419, no 1, p. 18-22Article in journal (Refereed)
    Abstract [en]

    Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181) and the 42 amino acid isoform of β-amyloid (Aβ42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (±S.D.) 76.1 ± 7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4–6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p < 0.0001), for all three markers. We conclude that T-tau, P-tau and Aβ42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Aβ immunotherapy and tau phosphorylation inhibitors.

  • 8.
    Brolin, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zelleroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Diwakarla, Shanti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gröndbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration2017In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 646, p. 15-20Article in journal (Refereed)
    Abstract [en]

    In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.

  • 9.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Exploring a new approach to treating brain injury: Anti-inflammatory effect of pulsed electromagnetic fields2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 519, no 1, p. 1-3Article in journal (Other academic)
  • 10.
    Emanuelsson, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norlin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Protective effects of 27-and 24-hydroxycholesterol against staurosporine-induced cell death in undifferentiated neuroblastoma SH-SY5Y cells2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 525, no 1, p. 44-48Article in journal (Refereed)
    Abstract [en]

    Alterations in cholesterol metabolism have been linked to several neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis and Parkinson's disease. Brain cholesterol is metabolized to the oxysterols 24-hydroxycholesterol and 27-hydroxycholesterol. Disturbed levels of these oxysterols are found in neurodegenerative conditions. In the current study we examined the effects of 27- and 24-hydroxycholesterol on viability of human neuroblastoma SH-SY5Y cells treated with staurosporine, a toxic substance that induces apoptosis. Analyses using MTT assay and measurement of lactate dehydrogenase release showed that presence of 27-hydroxycholesterol counteracted the toxic effects of staurosporine on these cells. Also, 27-hydroxycholesterol significantly decreased the staurosporine-mediated induction of caspase-3 and -7, known to be important in apoptotic events. 24-Hydroxycholesterol had similar effects on viability as 27-hydroxycholesterol in low concentrations, although in higher concentrations this oxysterol exacerbated the toxic effects of staurosporine. From these findings it may be concluded that effects of oxysterols on cellular viability are strongly dependent on the concentration and on the type of oxysterol. Previous studies on oxysterols have reported that these compounds are pro-apoptotic or trigger pathological changes that result in neurodegeneration. The present data indicate that, during some conditions, oxysterols may have neuroprotective effects.

  • 11.
    Emilsson, Lina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Saetre, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Balciuniene, Jorune
    Castensson, Anja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Cairns, Nigel
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer's disease patients2002In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 326, no 1, p. 56-60.Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the industrialised world. The two monoamine oxidase (MAO) enzymes, monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB), are important in the metabolism of monoamine neurotransmitters. AD and ageing have been shown to increase enzyme activity for both MAOA and MAOB. An increase (rather than decrease) of enzyme activity is a rare event in a disease that results in a decrease in the number of cells in the brain. The mechanism, transcriptional or post-transcriptional, responsible for the increase in protein activity, is not known. In this study, we investigate for the first time the messenger RNA (mRNA) expression levels of both MAOA and MAOB in 246 cortical brain samples obtained at autopsy from 62 AD patients and 61 normal controls. We found a significant increase in mRNA levels for both MAOA (P=0.001) and MAOB (P=0.002) in disease brain tissue. This indicates that both MAO enzymes might be important in the progression of AD.

  • 12.
    Enhamre, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 523, no 1, p. 82-86Article in journal (Refereed)
    Abstract [en]

    Previous studies have indicated that both growth hormone (GH) deficiency and diabetes are conditions associated with impairments in learning and memory processes. In this study, we investigated the effect of streptozotocin-induced diabetes on spatial learning in mice using the Barnes maze (BM). The expression of the GH receptor (GHR) gene transcript in areas of the brain associated with learning and memory were examined. The results indicated that the GHR gene transcript is up-regulated in the prefrontal cortex (PFC) of diabetic mice compared to controls. In addition, there was a significant correlation between the expression of GHR mRNA and performance in the BM during the acquisition phase in diabetic but not control mice. These results suggest that diabetes induces an imbalance in the GH/IGF-1 system leading to altered activity in the PFC and associated cognitive deficiencies.

  • 13. Erhardt, S
    et al.
    Blennow, K
    Nordin, C
    Skogh, E
    Lindström, Leif H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Engberg, G
    Kynurenic acid levels are elevated in the cerebrospinal fluid of patientswith schizophrenia2001In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 313, no 1-2, p. 96-98Article in journal (Refereed)
    Abstract [en]

    Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl d-aspartate-receptor. Mounting evidence indicate that the compound is significantly involved in basal neurophysiological processes in the brain. In the present investigation, cerebrospinal fluid (CSF) level of kynurenic acid was analyzed in 28 male schizophrenic patients and 17 male healthy controls by means of high pressure liquid chromatography and fluorescence detection. Schizophrenic patients showed elevated CSF levels of kynurenic acid (1.67±0.27 nM) compared to the control group (0.97±0.07 nM). Furthermore, CSF levels of kynurenic acid in schizophrenic patients were also found to correlate with age. The present finding is indicative of a contribution of kynurenic acid in the pathogenesis of schizophrenia.

  • 14.
    Fernandez, Manuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Fischer, Håkan
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Brain function in a patient with torture related post-traumatic stress disorder before and after fluoxetine treatment: a positron emission tomography provocation study2001In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 297, no 2, p. 101-104Article in journal (Refereed)
    Abstract [en]

    We report positron emission tomographic measurements of regional cerebral blood flow (rCBF) in a male patient with war and torture related post-traumatic stress disorder (PTSD) during symptom provocation. The subject was exposed to war related sounds before and after treatment with a selective serotonin reuptake inhibitor (SSRI; Fluoxetine; Fontex((R))). Therapy reduced PTSD symptoms, provoked anxiety and heart rate. Before treatment trauma reminders resulted in decreased rCBF in the insula, prefrontal, and inferior frontal cortices. Increased activity was evident in the cerebellum, precuneus and supplementary motor cortex. This was normalized after SSRI administration. Prefrontal and cingulate rCBF correlated with heart rate. Hence, the anxiolytic effect of SSRI for PTSD could be mediated by prefrontal and paralimbic cortices. Data suggest that SSRI treatment normalize provocation induced rCBF alterations in areas involved in memory, emotion, attention and motor-control.

  • 15. Fernell, E.
    et al.
    Karagiannakis, A.
    Edman, G.
    Bjerkenstedt, L.
    Wiesel, Frits Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Venizelos, N.
    Aberrant amino acid transport in fibroblasts from children with autism2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 418, no 1, p. 82-86Article in journal (Refereed)
    Abstract [en]

    Autism is a developmental, cognitive disorder clinically characterized by impaired social interaction, communication and restricted behaviours. The present study was designed to explore whether an abnormality in transport of tyrosine and/or alanine is present in children with autism. Skin biopsies were obtained from 11 children with autism (9 boys and 2 girls) fulfilling the DSM-IV diagnostic criteria for autistic disorder and 11 healthy male control children. Transport of amino acids tyrosine and alanine across the cell membrane of cultured fibroblasts was studied by the cluster tray method. The maximal transport capacity, V(max) and the affinity constant of the amino acid binding sites, K(m), were determined. Significantly increased V(max) for alanine (p=0.014) and increased K(m) for tyrosine (p=0.007) were found in children with autism. The increased transport capacity of alanine across the cell membrane and decreased affinity for transport sites of tyrosine indicates the involvement of two major amino acid transport systems (L- and A-system) in children with autism. This may influence the transport of several other amino acids across the blood-brain-barrier. The significance of the findings has to be further explored.

  • 16.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Alaie, Iman
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Björkstrand, Johannes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Wallenquist, Ulrika
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Ågren, Thomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Morell, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Enlargement of visual processing regions in social anxiety disorder is related to symptom severity2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 583, p. 114-119Article in journal (Refereed)
    Abstract [en]

    Social anxiety disorder (SAD) is associated with altered brain function and structure, but most structural studies include small samples and findings are mixed. This study compared regional gray matter volume between 48 SAD patients and 29 healthy controls (HC) as well as the relationship between volume and symptom severity. Structural magnetic resonance images from SAD patients and HC were evaluated using standard voxel-based morphometry (VBM) processing in the SPM8 software package. Social anxiety symptom severity was rated in SAD patients by a clinician using the Liebowitz Social Anxiety Scale (LSAS). SAD patients had greater regional gray matter volume in the lingual gyrus and lateral occipital cortex than the controls, and within the SAD group a positive correlation was found between symptom severity and regional gray matter volume in the lingual gyrus and the retrosplenial cortex. These findings replicate and extend earlier reports of enlarged visual processing areas in SAD. Increased gray matter volume in regions involved in visual processing and self-consciousness could underlie, or be the result of, abnormal emotional information processing and self-focused attention previously demonstrated in patients with SAD.

  • 17.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Howner, Katarina
    Fischer, Hakan
    Eskildsen, Simon Fristed
    Kristiansson, Marianne
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Cortical thickness alterations in social anxiety disorder2013In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 536, p. 52-55Article in journal (Refereed)
    Abstract [en]

    Social anxiety disorder (SAD) has been associated with aberrant processing of socio-emotional stimuli and failure to adaptively regulate emotion, corroborated by functional neuroimaging studies. However, only a few studies of structural brain abnormalities in SAD have been reported, and among these only one investigated cortical thickness. In the present study we used magnetic resonance imaging (MRI) in conjunction with an automated method to measure cortical thickness in patients with SAD (n=14) and healthy controls (n=12). Results showed significantly increased thickness of the left inferior temporal cortex in SAD patients relative to controls. Within the patient group, a negative association was found between social anxiety symptom severity and thickness of the right rostral anterior cingulate cortex. The observed alterations in brain structure may help explain previous findings of dysfunctional regulation and processing of emotion in SAD.

  • 18.
    Giacobini, MaiBritt M J
    et al.
    Department of Histology and Neurobiology, Karolinska Institute, Stockholm Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Funa, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Westermark, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Olson, L
    Department of Histology and Neurobiology, Karolinska Institute, Stockholm Sweden.
    Differential effects of platelet-derived growth factors on fetal hippocampal and cortical grafts: evidence from intraocular transplantation in rats1992In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 136, no 2, p. 227-231Article in journal (Refereed)
    Abstract [en]

    Effects of platelet-derived growth factor-AA (PDGF-AA) and platelet-derived growth factor-BB (PDGF-BB) on developing parietal cortex (E16) and hippocampal (E18-E19) grafts were studied using the in vivo method of intraocular transplantation. Survival and growth of grafts in the anterior eye chamber of adult host rats under the influence of regular treatments with 0.5 ng (in a 100 ng/ml concentration) PDGF-AA or PDGF-BB was followed and compared to those receiving vehicle solution alone (0.5 mg HSA/ml Hanks). Both PDGF-AA and PDGF-BB increased the volume of transplanted cortical grafts. PDGF-BB also exerted trophic effects on grafted hippocampal tissue whereas PDGF-AA seemed to inhibit hippocampal growth. Histological and immunohistochemical studies revealed an increase in the density of astroglial elements in PDGF-AA- and PDGF-BB-treated cortical grafts whereas the PDGF-AA- and PDGF-BB-treated hippocampal grafts maintained a cytoarchitecture closely resembling that of control grafts. These findings support in vitro experiments showing that developing glial cells are stimulated by PDGFs and we further propose regional differences of action of PDGFs in the developing central nervous system.

  • 19.
    Giedraitis, Vilmantas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Glaser, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sarajärvi, Timo
    Brundin, RoseMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gunnarsson, Malin Degerman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schjeide, Brit-Maren
    Tanzi, Rudolph E
    Helisalmi, Seppo
    Pirttilä, Tuula
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Soininen, Hilkka
    Bertram, Lars
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hiltunen, Mikko
    CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid2010In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 469, no 2, p. 265-267Article in journal (Refereed)
    Abstract [en]

    Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers.

  • 20.
    Giedraitis, Vilmantas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Sundelöf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Irizarry, Michael C
    Gårevik, Nina
    Hyman, Bradley T
    Wahlund, Lars-Olof
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 427, no 3, p. 127-131Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta (A beta) with 40 (A beta 40) and 42 (A beta 42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF A beta 42 is decreased in AD, some studies have reported changed plasma A beta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of A beta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma A beta. We have measured A beta 40 and A beta 42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n= 18). We observed a clear correlation between CSF and plasma levels for both A beta 40 and A beta 42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of A beta 42 in AD CSF, whereas there were no significant differences in plasma A beta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma A beta may be disrupted with the initiation of amyloid deposition in the brain.

  • 21. Hensch, Tilman
    et al.
    Wargelius, Hanna-Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Herold, Ulf
    Strobel, Alexander
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Brocke, Burkhard
    Electrophysiological and behavioral correlates of polymorphisms in the transcription factor AP-2beta coding gene2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 436, no 1, p. 67-71Article in journal (Refereed)
    Abstract [en]

    Transcription factor AP-2beta may influence brain monoaminergic systems by regulating target genes. Several monoaminergic genes, including the serotonin transporter gene, have AP-2beta binding sites. Late auditory-evoked potentials (P1, N1/P2) and impulsiveness-related personality traits are correlated, and both are modulated by monoaminergic neurotransmission. The present study assesses the impact of two AP-2beta polymorphisms (VNTRs within intron 1 and 2) together with the serotonin transporter polymorphism 5-HTTLPR on late auditory-evoked potentials and personality for the first time. EEG was recorded from 91 male subjects at central electrode positions while tones of six intensity levels were presented. Additionally, subjects completed personality questionnaires. Both AP-2beta polymorphisms revealed significant main effects on P1, and haplotype analysis confirmed the contribution of both AP-2beta-polymorphisms. Additionally, AP-2beta and 5-HTTLPR showed interactions with respect to P1. 5-HTTLPR revealed a main effect on N1/P2 but not P1. Impulsiveness showed an association with intron 1 VNTR. The results are discussed with respect to differential impact of AP-2beta polymorphisms and 5-HTTLPR on the monoaminergic systems. The findings promote replication in a larger sample and suggest a potential usefulness of AP-2beta polymorphisms in explaining or predicting central nervous diseases, drug effects and side effects.

  • 22. Kastrup, Y
    et al.
    Hallbeck, M
    Amandusson, A
    Hirata, S
    Hermanson, O
    Blomqvist, A
    Progesterone receptor expression in the brainstem of the female rat1999In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 275, no 2, p. 85-88Article in journal (Refereed)
    Abstract [en]

    By using in situ hybridization and immunohistochemistry, the presence of neurons expressing progesterone receptor mRNA (PR mRNA) and progesterone receptor-like immunoreactivity (PR-LI) was examined in the brainstem and spinal cord of female rats. Neurons expressing PR mRNA and PR-LI were seen in the ventrolateral medulla, the parvocellular reticular formation and the nucleus of the solitary tract. PR mRNA, but not PR-LI, was seen in the hypoglossal nucleus, the inferior olive, the locus coeruleus and the parabrachial nucleus. No consistent labeling was present in the spinal cord. These findings show that progesterone receptors are expressed in brainstem areas involved in various functions, including autonomic regulation and pain modulation.

  • 23.
    Kindlundh, Anna M S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rahman, Sadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Increased dopamine transporter density in the male rat brain following chronic nandrolone decanoate administration2004In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 356, no 2, p. 131-134Article in journal (Refereed)
    Abstract [en]

    Adolescent males currently employ anabolic-androgenic steroids (AAS) to become intoxicated, besides the traditional desires of an improved physical appearance and enhanced sports performance. Several studies indicate that AAS affect the brain reward system. Recently chronic administration with nandrolone decanoate to male rats has been shown to increase the dopamine transporter (DAT) density in the striatum visualised in vivo by positron emission tomography. The present study aimed to investigate if the increased DAT density could be confirmed using in vitro autoradiography following a comparable regimen of nandrolone treatment. Specific binding of 50 pM [125I] RTI-55 in the presence of 1 microM citalopram was used to label DAT. Two weeks of nandrolone decanoate administration at the supra-therapeutic doses 1, 5 and 15 mg/kg per day increased DAT density in the caudate putamen at all three doses. In conclusion, this study confirms that chronic nandrolone administration increases dopamine transporter density in the CPU and therefore supports the theory that AAS affects the dopamine system in the male rat brain.

  • 24. Koomoa, Dana-Lynn T.
    et al.
    Go, Ramon Christopher V.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bachmann, André S.
    Expression profile of PRAF2 in the human brain and enrichment in synaptic vesicles2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 436, no 2, p. 171-176Article in journal (Refereed)
    Abstract [en]

    PRA1 domain family, member 2 (PRAF2) is a novel 19-kDa protein with a prenylated Rab acceptor 1 (PRA1) motif and four transmembrane domains. Our previous studies revealed that PRAF2 is highly expressed in the brain and serves as a candidate prognostic marker in neuroblastoma (NB). PRAF2 is related to proteins PRAF1 (PRA1, prenylin, Yip3) and PRAF3 (GTRAP3-18, JWA, Arl6-IP5), both of which are enriched in the brain and implicated in cellular transport and endo/exocytic vesicle trafficking. However, the function for PRAF2 remains unknown. In this study, we analyzed the distribution and localization of PRAF2 in the mature human brain using two new antibodies specific for the protein. Analysis by immunohistochemistry revealed that in the human cerebellum, the PRAF2 protein was strongly expressed in Purkinje cells and, more moderately, in cells of the molecular and the granular layers. In the cerebral cortex, hippocampus, and lateral ventricles, PRAF2 protein was detected in neuronal cells, but not in non-neuronal cells. Intriguingly, immunoblot analysis revealed that PRAF2 is enriched in synaptic vesicles (SVs) prepared from rat brains. The expression of PRAF2 in specific regions of the brain including SVs suggest an important physiological function for this novel protein, possibly by participating in multiple aspects of SV maturation, transport, and signal transmission.

  • 25.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tafreshiha, Atieh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Insulin enhances GABAA receptor-mediated inhibitory currents in rat central amygdala neurons2018In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 671, p. 76-81Article in journal (Refereed)
    Abstract [en]

    Insulin, a pancreatic hormone, can access the central nervous system, activate insulin receptors distributed in selective brain regions and affect various cellular functions such as neurotransmission. We have previously shown that physiologically relevant concentration of insulin potentiates the GABAA receptor-mediated tonic inhibition and reduces excitability of rat hippocampal CA1 neurons. The central nucleus of the amygdala (CeA) comprises heterogeneous neuronal populations that can respond to hormonal stimulus. Using quantitative PCR and immunofluorescent labeling, we report that the mRNA and protein of the insulin receptor are abundantly expressed in the rat CeA. The insulin receptor mRNA is also detected in the CeA from post-mortem human brain samples. Furthermore, our whole-cell patch-clamp recordings show that the application of insulin (5 and 50 nM) selectively enhances the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat CeA neurons. Our findings reveal that GABAergic synaptic transmission is a target in the CeA for insulin receptor signaling that may underlie insulin modulation of emotion- and feeding-related behaviors.

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    Insulin enhances GABAA receptor-mediated inhibitory currents in rat central amygdala neurons
  • 26. Li, Lili
    et al.
    Wang, Bo
    Gao, Tianle
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hao, Jing-Xia
    Vlodavsky, Israel
    Wiesenfeld-Hallin, Zsuzsanna
    Xu, Xiao-Jun
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase overexpression reduces carrageenan-induced mechanical and cold hypersensitivity in mice2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 511, no 1, p. 4-7Article in journal (Refereed)
    Abstract [en]

    Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice.

  • 27. Lim, M S F
    et al.
    Lindquist, C E L
    Birnir, B
    John Curtin School of Medical Research, Australian National University.
    Effects of pentobarbital on GABA-activated currents in acutely-isolated rat dentate gyrus granule neurons.2003In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 353, no 2, p. 139-42Article in journal (Refereed)
    Abstract [en]

    Granule neurons from the rat dentate gyrus were acutely isolated and whole-cell currents recorded. Maximal enhancement of 7 microM gamma-aminobutyric acid (GABA; EC30) evoked currents was obtained with 100 microM pentobarbital where the peak-current was 2.1+/-0.2 of control. One hundred microM pentobarbital alone evoked no current response whereas 1 mM pentobarbital elicited a current response that was 0.4+/-0.2 of the 100 microM GABA-activated peak current. In 100 microM pentobarbital, the GABA EC50 value shifted from 14 to 3 microM but the peak-saturating-current value was not altered. An off-current was recorded on removal of 100 microM and higher pentobarbital concentrations. Ten mM pentobarbital abolished the peak-current response to 7 and 100 microM GABA. The results show that in the granule neurons the drug potency differs for the different effects of pentobarbital at GABAA receptors with the modulatory and inhibitory effects requiring lower concentrations than the direct activation of the receptors.

  • 28.
    Magnusson, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hånell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nandrolone decanoate administration elevates hippocampal prodynorphin mRNA expression and impairs Morris water maze performance in male rats2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 467, no 3, p. 189-193Article in journal (Refereed)
    Abstract [en]

    The misuse of anabolic androgenic steroids has in several reports been associated with effects resulting in altered behavior and cognition. This study used the Morris water maze task to investigate the effect of high doses of the anabolic androgenic steroid nandrolone on spatial learning and memory in male rats. The results on day two of the experiment and during the final probe trial indicated significant memory impairment compared with controls. The hippocampus, a brain region associated with cognitive function, was analyzed for mRNA expression of prodynorphin, the precursor of dynorphinergic peptides. The results indicated that the transcription levels of prodynorphin were significantly elevated in the animals treated with nandrolone compared with controls. Thus, the findings suggest that administration of nandrolone to male rats impairs memory function, possibly via dynorphinergic actions.

  • 29.
    Nilsson, Kent W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Damberg, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Öhrvik, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Lindström, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Anckarsäter, Henrik
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Genes encoding for AP-2beta and the Serotonin Transporter are associated with the Personality Character Spiritual Acceptance2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 411, no 3, p. 233-237Article in journal (Refereed)
    Abstract [en]

    In several twin studies the relative contribution of genetic factors for personality traits has amounted to figures between 40 and 60%. In the present study we investigated to which degree polymorphisms in the 5-HTT and AP-2beta genes are implicated in the neural processes involved in the formation of Temperament and Character traits, as estimated by Cloninger's TCI. Considering the background of previous reports, associations with the character Self-Transcendence and its sub-scale Spiritual Acceptance in particular, were of interest. A stratified random sample of 200 individuals (total population=5173), matched for age, gender and risk behaviors, from volunteering 16- and 19-year-old adolescents students in Sweden was investigated. Cloninger's TCI inventory was used for investigation of temperament and character traits. Blood samples were used for analyses of a promoter serotonin transporter polymorphism (5-HTTLPR) and an intron 2 polymorphism in the transcription factor AP-2beta gene. Among boys individuals with presence of the short 5-HTTLPR genotype showed lower scores, whereas individuals with presence of the short AP-2beta genotype showed higher scores of personality character Self-Transcendence and its sub-scale Spiritual Acceptance. Among girls no effect of either genotype was found. Both among boys and girls, significant interactive effects were found between 5-HTTLPR and AP-2beta genotypes, with regard to Self-Transcendence and Spiritual acceptance. Boys and girls with the combination of presence of the short 5-HTTLPR, and homozygosity for the long AP-2beta genotype scored significantly lower on Self-Transcendence and Spiritual Acceptance.

  • 30.
    Pannee, Josef
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Tornqvist, Ulrika
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Westerlund, Anni
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brinkmalm, Gunnar
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Persson, Rita
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Gobom, Johan
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Svensson, Johan
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med, SE-41345 Gothenburg, Sweden; Skaraborg Cent Hosp, Dept Endocrinol, SE-54185 Skovde, Sweden.
    Johansson, Per
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med, SE-41345 Gothenburg, Sweden; Skaraborg Cent Hosp, Dept Neuropsychiat, SE-52185 Falkoping, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden; UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Portelius, Erik
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.
    The amyloid-beta degradation pattern in plasma A possible tool for clinical trials in Alzheimer's disease2014In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 573, p. 7-12Article in journal (Refereed)
    Abstract [en]

    Amyloid beta (A beta) is the main component of plaques, the central neuropathological hallmark in Alzheimer's disease (AD). A beta is derived from the amyloid precursor protein (APP) by beta- and gamma-secretase-mediated cleavages. A large number of A beta peptides are found in cerebrospinal fluid and these peptides are produced in specific metabolic pathways, which are important for diagnosis, in drug development and to explore disease pathogenesis. To investigate whether a similar pattern could be found also in blood samples, an immunoprecipitation (IP) based method for enrichment of A beta peptides from human plasma was developed. The peptides were analyzed using matrix-assisted-laser-desorption/ionization time-of-flight/time-of-flight mass spectrometry for A beta profiling and selected reaction monitoring (SRM) for MS quantification of A beta 1-38, A beta 1-40 and A beta 1-42 using tripe quadrupole MS. Sixteen N- or C-terminally truncated A beta peptides were reproducibly detected in human plasma, of which 11 were verified by tandem MS. In a pilot study including 9 AD patients and 10 controls, where A beta 1-38, A beta 1-40 and A beta 1-42 were quantified using SRM, no AD-associated change in plasma levels of the peptides were observed. Using MS-based measurement techniques, we show that several A beta peptides can be monitored in a single analysis and the developed methods have the potential to be used as a read out in clinical trials of drugs affecting APP processing or A beta homeostasis.  

  • 31. Persson, M. L.
    et al.
    Johansson, J
    Vumma, R
    Raita, J
    Bjerkenstedt, L
    Wiesel, F.-A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Venizelos, N
    Aberrant amino acid transport in fibroblasts from patients with bipolar disorder2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 457, no 1, p. 49-52Article in journal (Refereed)
    Abstract [en]

    Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n = 10) and healthy controls (n = 10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (V-max) and affinity constant (K-m) were determined. A significantly lower V-max for tyrosine (p = 0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in K-m for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low V-max) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

  • 32.
    Ploj, Karolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term effects on brain opioid and opioid receptor like-1 receptors after short periods of maternal separation in rats2003In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 345, no 3, p. 195-197Article in journal (Refereed)
    Abstract [en]

    Short periods of maternal separation of neonatal rats are known to induce attenuated behavioural and neuroendocrine responses to stress in adult life. The present study was carried out to evaluate whether 15 min separation from the dam during postnatal days 1-21 (MS15) can induce long-term changes in brain opioid (kappa- and delta-receptors) and opioid receptor-like 1 (ORL1) densities in male Sprague-Dawley rats. Receptor autoradiography indicated that MS15 rats had increased delta-receptor density in the basomedial amygdala compared to animal facility reared rats 2 months after MS15. No differences in brain kappa- or ORL1-receptor density were found. The results indicate that a manipulation early in life can induce persistent neurochemical changes in the delta-opioid receptor system, which suggests involvement of delta-opioid receptors in the altered emotional processing in these rats.

  • 33. Putula, Jaana
    et al.
    Turunen, Pauli M
    Jäntti, Maria H
    Ekholm, Marie E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Kukkonen, Jyrki P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Agonist ligand discrimination by the two orexin receptors depends on the expression system2011In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 494, no 1, p. 57-60Article in journal (Refereed)
    Abstract [en]

    Despite the recent successes in producing orexin receptor subtype-selective antagonists, these are not commonly available, and therefore, agonist ligands are regularly used to ascribe cell and tissue responses to OX(1) or OX(2) receptors. In the current study, we have compared the native "subtype-selective" agonist, orexin-B, and its reputedly enhanced synthetic variant, Ala(11), d-Leu(15)-orexin-B, in two different recombinant cell lines. Ca(2+) elevation was used as readout, and the two "selective" ligands were compared to the subtype-non-selective orexin-A, as is customary with these ligands. In transiently transfected HEK-293 cells, orexin-B showed 9-fold selectivity for the OX(2) receptor and Ala(11), d-Leu(15)-orexin-B 23-fold selectivity, when the potency ratios of ligands were compared between OX(1) and OX(2). In stable CHO-K1 cells, the corresponding values were only 2.6- and 14-fold, respectively. In addition to being low, the selectivity of the ligands was also variable, as indicated by the comparison of the two cell lines. For instance, the relative potency of Ala(11), d-Leu(15)-orexin-B at OX(2) in CHO cells was only 2.3-fold higher than its relative potency at OX(1) in HEK-293 cells; this indicates that Ala(11), d-Leu(15)-orexin-B does not show high enough selectivity for OX(2) to be useful for determination of receptor subtype expression. Comparison of the potencies of orexin-A and -B with respect to a number of published responses in OX(1)-expressing CHO cells, demonstrates that these show great variation: i.e., orexin-A is 1.6-18-fold more potent than orexin-B, depending on the response assessed. These data together suggest that orexin receptor ligands show signal trafficking, which makes agonist-based pharmacology unreliable.

  • 34. Schmelz, M.
    et al.
    Schmidt, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Microneurographic single-unit recordings to assess receptive properties of afferent human C-fibers2010In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 470, no 3, p. 158-161Article, review/survey (Refereed)
    Abstract [en]

    Action potentials in unmyelinated peripheral axons can be recorded in awake humans by microneurography with small electrodes placed in a peripheral nerve. This technique provides extracellular recordings of single C-fibers and thus enables characterization of their sensory and axonal properties. By using microneurographical basic properties of afferent C-fibers such as conduction velocities, innervation territories, sensory thresholds and chemical responsiveness were measured. Moreover, axonal excitability changes induced by repetitive activation were assessed. Sensory and axonal properties of the different fiber classes cluster. Based on those specific properties, unitary functional classes of nociceptors (such as polymodal nociceptors and mechano-insensitive nociceptors) and non-nociceptors (such as tactile afferents and warm fibers) were classified. With normal data available, sensitization and desensitization of afferent fibers have been found in pathophysiologic states as detected in chronic pain patients. As subjects and patients are awake during the recording, microneurography provides a unique tool to correlate the discharge behaviour of afferent nerve fibers with the sensation evoked by certain stimuli.

  • 35.
    Stiller, C O
    et al.
    Division of Pharmacology, Department of Physiology and Pharmacology, Karolinska Institute.
    Bergquist, Jonas
    Institute of Clinical Neuroscience, Department of Psychiatry and Neurochemistry, Göteborg University, Mölndal Hospital.
    Beck, O
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Hospital.
    Ekman, R
    Institute of Clinical Neuroscience, Department of Psychiatry and Neurochemistry, Göteborg University, Mölndal Hospital.
    Brodin, E
    Division of Pharmacology, Department of Physiology and Pharmacology, Karolinska Institute.
    Local administration of morphine decreases the extracellular level of GABA in the periaqueductal gray matter of freely moving rats.1996In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 209, no 3, p. 165-8Article in journal (Refereed)
    Abstract [en]

    Opioids are generally believed to activate descending pain inhibitory pathways from the periaqueductal gray matter (PAG). Since opioids exert an inhibitory effect on neural excitability and transmitter release, an opioid-mediated inhibition of tonically active inhibitory gamma-aminobutyric acid (GABA) neurons has been suggested to mediate this effect. The aim of the present microdialysis study was to investigate the effect of local administration of morphine on the extracellular GABA level in the PAG of awake rats. The recently developed and highly sensitive method of capillary electrophoresis with laser-induced fluorescence detection was used for GABA determination in microdialysate samples obtained from the PAG of freely moving rats. The basal GABA level was 54.5 +/- 6.6 nM (n = 8; mean +/- SEM). Perfusion of the dialysis probe with morphine (100 microM) for 30 min significantly decreased the GABA level to 28.2 +/- 4.2 nM (n = 8; P < 0.05). The effect of morphine was reversed by coperfusion with naloxone (100 microM in the perfusion fluid). The present results thus provide direct experimental evidence for an opioid-induced inhibition of tonic GABA release in the PAG, which may in turn lead to a disinhibition of descending pain inhibitory pathways.

  • 36.
    Tan-No, Koichi
    et al.
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Shimoda, Masakazu
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Watanabe, Kenya
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Nakagawasai, Osamu
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Niijima, Fukie
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Kanno, Syu-Ichi
    Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Ishikawa, Masaaki
    Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tadano, Takeshi
    Department of Pharmacology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
    Involvement of the p53 tumor-suppressor protein in the development of antinociceptive tolerance to morphine2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 450, no 3, p. 365-368Article in journal (Refereed)
    Abstract [en]

    The present study was designed to determine whether the p53 tumor-suppressor protein is involved in the development of antinociceptive tolerance to morphine. When the doses of morphine (mg/kg per injection) were subcutaneously given into mice as pretreatment twice daily for 2 days (first day (30) and second day (60)), intrathecal (i.t.) administration of morphine (0.1nmol) was inactive due to antinociceptive tolerance in the 0.5% formalin test on the third day. Tolerance to i.t. morphine was significantly suppressed by i.t. injection of pifithrin-alpha (1 and 10nmol), an inhibitor of p53 activation, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) (1 and 10nmol), a non-selective caspase inhibitor, or N(G)-nitro-l-arginine methyl ester (l-NAME) (2 and 20nmol), a non-selective inhibitor of nitric oxide synthase, 5min before each morphine treatment during the induction, with none given on the test day. Moreover, p53 expression in the spinal cord had increased significantly 14h after the last morphine administration. These results indicate that the increased expression and activation of p53, and the nitric oxide and caspase systems related to p53 may contribute to the development of antinociceptive tolerance to morphine in the mouse spinal cord.

  • 37. Vumma, Ravi
    et al.
    Wiesel, Frits-Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Flyckt, Lena
    Bjerkenstedt, Lars
    Venizelos, Nikolaos
    Functional characterization of tyrosine transport in fibroblast cells from healthy controls2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 434, no 1, p. 56-60Article in journal (Refereed)
    Abstract [en]

    Human fibroblast cells are an advantageous model to study the transport of amino acids across cell membranes, since one can control the environmental factors. A major problem in all earlier studies is the lack of precise and detailed knowledge regarding the expression and functionality of tyrosine transporters in human fibroblasts. This motivated us to perform a systematic functional characterization of the tyrosine transport in fibroblast cells with respect to the isoforms of system-L (LAT1, LAT2, LAT3, LAT4), which is the major transporter of tyrosine. Ten (n=10) fibroblast cell lines from healthy volunteers were included in the study. Uptake of L-[U-14C] tyrosine in fibroblasts was measured using the cluster tray method in the presence and absence of excess concentrations of various combinations of inhibitors. This study demonstrated that LAT1 is involved in 90% of total uptake of tyrosine and also around 51% of alanine. Not more than 10% can be accounted for by LAT2, LAT3 and LAT4 isoforms. LAT2 seems to be functionally weak in uptake of tyrosine while LAT3 and LAT4 contributed around 7%. 10% could be contributed by system-A (ATA2 isoform). Alanine consequently inhibited the tyrosine transport by up to 60%. Tyrosine transport through the LAT1 isoform has a higher affinity compared to system-L. In conclusion, the LAT1 isoform is the major transporter of tyrosine in human fibroblast cells. Competition between tyrosine and alanine for transport is shown to exist, probably between LAT1 and LAT2 isoforms. This study established fibroblast cells as a suitable experimental model for studying amino acid transport defects in humans.

  • 38.
    Wallin, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Blomberg, Helmut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hynninen, Pirkko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Intraneural stimulation as a method to study sympathetic function in the human skin.1983In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 36, no 2, p. 189-194Article in journal (Refereed)
    Abstract [en]

    Intraneural electrical stimulation of sympathetic postganglionic axons was made in human skin nerves combined with recordings of skin resistance and a photoelectric pulse plethysmogram within the innervation zone. Tungsten microelectrodes were used first to record multiunit sympathetic activity in sural or median nerves. After blocking the nerve with local anaesthetics proximal to the recording site the electrodes were then used for intraneural stimulation. Stimulation led to reduction of skin resistance which was frequency dependent. A short train of stimuli reduced skin resistance transiently and the response was potentiated by a single stimulus delivered up to 2.5 min. prior to the train. Vasoconstrictor responses did not always occur and were relatively independent of stimulation frequency. The method may be useful for physiological and pathophysiological studies of sympathetic neuroeffector transmission in man.

  • 39.
    Wang, Chao
    et al.
    Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden.
    Iashchishyn, Igor A.
    Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden.
    Kara, John
    Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden.
    Fodera, Vito
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Vetri, Valeria
    Univ Palermo, Dipartimento Fis & Chim, I-90128 Palermo, Italy;Univ Palermo, Aten Ctr, I-90128 Palermo, Italy.
    Sancataldo, Giuseppe
    Univ Palermo, Dipartimento Fis & Chim, I-90128 Palermo, Italy;Univ Palermo, Aten Ctr, I-90128 Palermo, Italy.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Morozova-Roche, Ludmilla A.
    Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden.
    Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model2019In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 699, p. 199-205Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer's and Parkinson's. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer's as demonstrated recently in the human brain tissues. Here by using immunohistochemistry in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post- TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochemistry we have shown that S100A9 was produced by both neuronal and microglial cells. However, A beta peptide deposits characteristic for Alzheimer's disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously observed in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and atomic force microscopy we demonstrated that in vitro S100A9 self- assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temperature and reduction/oxidation, which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.

  • 40.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Husic, Ena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Gunnar
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Developmental expression of IL-33 in the mouse brain2013In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 555, p. 171-176Article in journal (Refereed)
    Abstract [en]

    IL-33 has important functions in inflammatory and autoimmune diseases. In the brain, models of experimental encephalomyelitis are accompanied by up-regulation of IL-33 expression, and the cytokine is seen as an amplifier of the innate immune response. Little is known, however, about IL-33 the normal brain in adult life, or during development. We have analyzed the expression of IL-33 in the mouse brain during embryonic and postnatal development. Here we report that IL-33 expression was first detected in the CNS during late embryogenesis. From postnatal day 2 (P2) until P9 the expression increased and was strongest in the cerebellum, pons and thalamus, as well as in olfactory bulbs. Expression of IL-33 then became weaker and declined until P23, and it was not present in the adult brain. Both astrocytes and oligodendrocyte precursors expressed IL-33. The vast majority of IL-33 positive cells in the brain displayed nuclear staining, and this was found to be the case also in vitro, using mixed glial cultures. Our data suggest that IL-33 expression is under tight regulation in the normal brain. Its detection during the first three weeks of postnatal life coincides with important parts of the CNS developmental programs, such as general growth and myelination. This opens the possibility that IL-33 plays a role also in the absence of an inflammatory response.

  • 41. Zelano, Johan
    et al.
    Plantman, Stefan
    Hailer, Nils P.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cullheim, Staffan
    Altered expression of nectin-like adhesion molecules in the peripheral nerve after sciatic nerve transection2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 449, no 1, p. 28-33Article in journal (Refereed)
    Abstract [en]

    Following axotomy several processes involving cell-cell interaction occur, such as loss of synapses, axon guidance, and remyelination. Two recently discovered families of cell-cell adhesion molecules, nectins and nectin-like molecules (necls) are involved in such processes in vitro and during development, but their roles in nerve injury have been largely unknown until recently. We have previously shown that axotomized motoneurons increase their expression of nectin-1 and nectin-3 and maintain a high expression of necl-1. We here investigate the expression of potential binding partners for motoneuron nectins and necls in the injured peripheral nerve. In situ hybridization (ISH) revealed a decreased signal for necl-1 mRNA in the injured nerve, whereas no signal for necl-2 was detected before or after injury. The signals for necl-4 and necl-5 mRNA both increased in the injured nerve and necl immunoreactivity displayed a close relation to axon and Schwann cell markers. Finally, signal for mRNA encoding necl-5 increased in axotomized spinal motoneurons. We conclude that peripheral axotomy results in altered expression of several necls in motoneurons and Schwann cells, suggesting involvement of the molecules in regeneration.

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