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  • 1. Bogdanović, Renée Marie
    et al.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Michler, Christina
    Russmann, Vera
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Windhorst, Albert D
    Lammertsma, Adriaan A
    de Lange, Elisabeth C
    Voskuyl, Rob A
    Potschka, Heidrun
    (R)-[(11)C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: Evaluation in a rat epilepsy model2014In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 85, p. 104-112Article in journal (Refereed)
    Abstract [en]

    Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy. Brain uptake of (R)-[(11)C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders. In rats with drug-sensitive epilepsy, (R)-[(11)C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups. Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.

  • 2.
    Celerier, Evelyne
    et al.
    Laboratori of Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Doctor Aiguader 80, 08003 Barcelona, Spain.
    Ahdepil, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikander, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berrendero, Fernando
    Laboratori of Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Doctor Aiguader 80, 08003 Barcelona, Spain.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Maldonado, Rafael
    Laboratori of Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, C/Doctor Aiguader 80, 08003 Barcelona, Spain.
    Influence of the anabolic-androgenic steroid nandrolone on cannabinoid dependence.2006In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 50, no 7, p. 788-806Article in journal (Refereed)
    Abstract [en]

    The identification of the possible factors that might enhance the risk of developing drug addiction and related motivational disorders is crucial to reduce the prevalence of these problems. Here, we examined in mice whether the exposure to the anabolic-androgenic steroid nandrolone would affect the pharmacological and motivational effects induced by Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of Cannabis sativa. Mice received nandrolone using pre-exposure (during 14 days before THC treatment) or co-administration (1h before each THC injection) procedures. Both nandrolone treatments did not modify the acute anti nociceptive, hypothermic and hypolocomotor effects of THC or the development of tolerance after chronic THC administration. Nandrolone pre-exposure blocked THC- and food-induced conditioned place preference and increased the somatic manifestations of THC withdrawal precipitated by the CB1 cannabinoid antagonist rimonabant (SR141617A). The aversive effects of THC were not changed by nandrolone. Furthermore, nandrolone pre-exposure attenuated the anxiolytic-like effects of a low dose of THC without altering the anxiogenic-like effects of a high dose in the lit/dark box, open field and elevated plus-maze. Biochemical experiments showed that chronic nandrolone treatment did not modify CB1 receptor binding and GTP-binding protein activation in the caudate-putamen and cerebellum. Taken together, our results suggest that chronic nandrolone treatment alters behavioural responses related to cannabinoid addictive properties.

  • 3.
    Chapman, Colin D
    et al.
    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.
    Grillo, Claudia A
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Intranasal insulin in Alzheimer's disease: Food for thought2017In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, article id S0028-3908(17)30566-XArticle in journal (Refereed)
    Abstract [en]

    Accumulating evidence suggests that disrupted brain insulin signaling promotes the development and progression of Alzheimer's disease (AD), driving clinicians to target this circuitry. While both traditional and more modern antidiabetics show promise in combating insulin resistance, intranasal insulin appears to be the most efficient method of boosting brain insulin. Furthermore, intranasal delivery elegantly avoids adverse effects from peripheral insulin administration. However, there remain significant open questions regarding intranasal insulin's efficacy, safety, and potential as an adjunct or mono-therapy. Thus, this review aims to critically evaluate the present evidence and future potential of intranasal insulin as a meaningful treatment for AD.

  • 4. De Luca, Maria Antonietta
    et al.
    Bimpisidis, Zisis
    Melis, Miriam
    Marti, Matteo
    Caboni, Pierluigi
    Valentini, Valentina
    Margiani, G
    Pintori, N
    Polis, I
    Marsicano, Giovanni
    Parsons, Larry H
    Di Chiara, Gaetano
    Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid2015In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 99, p. 705-714Article in journal (Refereed)
  • 5. De Luca, Maria Antonietta
    et al.
    Solinas, Marcello
    Bimpisidis, Zisis
    Goldberg, Steven R
    Cannabinoid facilitation of behavioral and biochemical hedonic taste responses2012In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 63, p. 161-168Article in journal (Refereed)
  • 6.
    Elfverson, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Le Grevès, Pierre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chronic administration of the anabolic androgenic steroid nandrolone alters neurosteroid action at the sigma-1 receptor but not at the sigma-2 or NMDA receptors2011In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 61, no 7, p. 1172-1181Article in journal (Refereed)
    Abstract [en]

    Studies have shown that anabolic androgenic steroids (AASs) can induce profound changes to mental health. Commonly reported psychiatric side effects among AAS users include aggression, anxiety, depression, drug abuse and cognitive disabilities. In experimental animals, many of these effects have been associated with alterations in a number of neurotransmitter systems. We have observed that chronic administration of the AAS nandrolone (nandrolone decanoate) can affect excitatory amino acids as well as monoaminergic and peptidergic pathways in a way that is compatible with nandrolone-induced behavioural changes. The aim of the present work was to further explore the mechanisms underlying nandrolone-induced effects, with a particular focus on components known to be involved in aggression and cognitive function. Male rats were given daily injections of nandrolone decanoate for 14 days and the effects on neurosteroid interactions with sites on the N-methyl-D-aspartyl (NMDA) and sigma receptors were examined. These receptors were chosen because of their involvement in aggressive and cognitive behaviors and the hypothesis that nandrolone might affect the brain via interaction with neurosteroids. Radiolabelled [(3)H]ifenprodil was used in the binding studies because of its significant affinity for the NMDA and sigma receptors. The results indicated that [(3)H]ifenprodil binds to both sigma-1 and sigma-2 sites and can be displaced to a certain extent from both sites by the neurosteroids pregnenolone sulphate (PS), pregnanolone sulphate (3 alpha 5 beta S) and dehydroepiandrosterone sulphate (DHEAS). The remainder of the [(3)H]ifenprodil was displaced from the sigma-1 site by the sigma-1 receptor-selective ligand (+)-SKF 10,047. Chronic nandrolone treatment changed the sigma-1 receptor target for the neurosteroids but not for ifenprodil. The sigma-2 receptor site was unaltered by treatment with nandrolone decanoate. The results also indicated that the neurosteroid-induced allosteric modulation of the NMDA receptor subunit NR2B was not affected by nandrolone treatment. We conclude that chronic treatment with nandrolone changes the affinity of the neurosteroids PS, 3 alpha 5 beta S and DHEAS at the sigma-1 site but not at the sites on the sigma-2 receptor or the NMDA receptor subunit NR2B.

  • 7. Eng, W.
    et al.
    Atack, J. R.
    Bergström, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sanabria, S.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Dawson, G. R.
    Sciberras, D.
    Hargreaves, R. J.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Burns, H. D.
    Occupancy of human brain GABA(A) receptors by the novel alpha 5 subtype-selective benzodiazepine site inverse agonist alpha 5IA as measured using [C-11]flumazenil PET imaging2010In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 59, no 7-8, p. 635-639Article in journal (Refereed)
    Abstract [en]

    GABA(A) receptor alpha 5-selective inverse agonists enhance cognitive performance in pre-clinical species. However, a key aspect of the clinical development of such compounds is the demonstration that in man such compounds are devoid of the anxiogenic-like activity associated with non-selective inverse agonists such as FG 7142. The triazolophthalazine alpha 5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl) methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is an alpha 5-selective inverse agonist which enhances cognitive performance in rodents and encouragingly in human Phase I Safety and Tolerability studies it was devoid of the anxiogenic-like activity associated with FG 7142. However, in order to appropriately interpret this latter observation, it was considered important to demonstrate that the absence of anxiogenic-like activity occurs at significant levels of receptor occupancy. Consequently, the occupancy of human brain GABAA receptors was measured using [C-11]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg alpha 5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma alpha 5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an alpha 5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give 50% occupancy.

  • 8.
    Enoksson, Tomas
    et al.
    Brain and Mind Research Institute, The University of Sydney, NSW 2006, Australia.
    Bertran-Gonzalez, J
    University of Sydney.
    Christie, M J
    University of Sydney.
    Nucleus accumbens D2- and D1-receptor expressing medium spiny neurons are selectively activated by morphine withdrawal and acute morphine, respectively2012In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 62, no 8, p. 2463-2471Article in journal (Refereed)
    Abstract [en]

    Opioids are effective analgesic agents but serious adverse effects such as tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal involves numerous brain regions and includes suppression of dopamine release and activation of neurons in the ventral striatum. By contrast, acute opioids increase dopamine release. Like withdrawal, acute opioids also activate neurons in the ventral striatum, suggesting that different populations of ventral striatal neurons may be activated by withdrawal and acute opioid actions. Here, immunofluorescence for the activity-related immediate-early gene, c-Fos, was examined in transgenic reporter mouse lines by confocal microscopy to study the specific populations of ventral striatal neurons activated by morphine withdrawal and acute morphine. After chronic morphine, naloxone-precipitated withdrawal strongly increased expression of c-Fos immunoreactivity, predominantly in D2-receptor (D2R) medium-sized spiny neurons (MSNs) of the nucleus accumbens (NAc) core and shell regions. By contrast, a single injection of morphine exclusively activated c-Fos immunoreactivity in D1-receptor expressing (D1R) MSNs of the core and shell of the NAc. These results reveal a striking segregation of neuronal responses occurring in the two populations of MSNs of the NAc in response to morphine withdrawal and acute morphine.

  • 9.
    Fang, Xiaotian T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. PET Centre, Uppsala University Hospital, 751 85 Uppsala, Sweden.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University Hospital, 751 85 Uppsala, SwedenUppsala University Hospital, 751 85 Uppsala, Sweden.
    Yngve, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University Hospital, 751 85 Uppsala, SwedenUppsala University Hospital, 751 85 Uppsala, Sweden.
    Cato, Linda
    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.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [(11)C]ABP688 PET imaging and ex vivo immunoblotting2017In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 113, no Pt A, p. 293-300, article id S0028-3908(16)30459-2Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [(11)C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aβo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aβ pathology model using PET. Wild type C57/BL6 (wt) and AβPP transgenic mice (tg-ArcSwe), 4, 8, and 16 months old, were PET scanned with [(11)C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extracted postscan and mGluR5 and Aβ protofibril levels were assessed with immunoblotting and ELISA respectively. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [(11)C]ABP688 concentrations corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [(11)C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 months old tg-ArcSwe compared with wt mice. [(11)C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.

  • 10. Franck, Johan
    et al.
    Nylander, Ingrid
    Department of Clinical Neuroscience, Alcohol and Drug Dependence Research Section, Karolinska Hospital.
    Rosen, Annika
    Met-enkephalin inhibits 5-hydroxytryptamine release from the rat ventral spinal cord via delta opioid receptors1996In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 35, no 6, p. 743-749Article in journal (Refereed)
    Abstract [en]

    The effect of opioid receptor agonists and antagonists on the electrically evoked release of endogenous serotonin (5-hydroxytryptamine, 5-HT) was studied in superfused slices of the rat ventral lumbar spinal cord. Met-ENK (1 x 10(-8)M-1 x 10(-6)M) and DPDPE (1 x 10(-8)M-1 x 10(-6)M) reduced the evoked 5-Ht release in a concentration dependent fashion. DAMGO (1 x 10(-8)-1 x 10(-6)) and (-)-trans-(1S,2S)-U-50488 (1 x 10(-6)M) had no effect on the 5-HT release. The inhibitory effect of met-ENK was completely abolished by ICI-174,864, but neither by naloxonazine nor nor-binaltorphimine. Following i.c.v. treatment with 5,7-dihydroxytryptamine (5,7-DHT), the tissue concentration of 5-HT was reduced by 97%, whereas the concentration of noradrenaline was reduced by only 5%. The tissue concentration of met-ENK, as measured by radioimmunoassay, was not significantly altered. The results suggest that met-ENK is present in the rat ventral spinal cord mainly in non-serotonergic nerve terminals and exerts an inhibitory action on 5-HT release via delta opioid receptors.

  • 11.
    Gustafsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology2018In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 128, p. 482-491Article in journal (Refereed)
    Abstract [en]

    Pathophysiological impairment of the neurovascular unit, including the integrity and dynamics of the blood-brain barrier (BBB), has been denoted both a cause and consequence of neurodegenerative diseases. Pathological impact on BBB drug delivery has also been debated. The aim of the present study was to investigate BBB drug transport, by determining the unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain), in aged A beta PP-transgenic mice, alpha-synuclein transgenic mice, and wild type mice. Mice were dosed with a cassette of five compounds, including digoxin, levofloxacin (1 mg/kg, s.c.), paliperidone, oxycodone, and diazepam (0.25 mg/kg, s.c.). Brain and blood were collected at 0.5,1, or 3 h after dosage. Drug concentrations were measured using LC-MS/MS. The total brain-to-plasma concentration ratio was calculated and equilibrium dialysis was used to determine the fraction of unbound drug in brain and plasma for all compounds. Together, these three measures were used to determine the Kp,uu,brain value. Despite A beta or alpha-synuclein pathology in the current animal models, no difference was observed in the extent of drug transport across the BBB compared to wild type animals for any of the compounds investigated. Hence, the present study shows that the concept of a leaking barrier within neurodegenerative conditions has to be interpreted with caution when estimating drug transport into the brain. The capability of the highly dynamic BBB to regulate brain drug exposure still seems to be intact despite the presence of pathology. (C) 2017 The Authors. Published by Elsevier Ltd.

  • 12.
    Kindlundh-Högberg, Anna M. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Svenningsson, Per
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Quantitative mapping shows that serotonin rather than dopamine receptor mRNA expressions are affected after repeated intermittent administration of MDMA in rat brain2006In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 51, no 4, p. 838-847Article in journal (Refereed)
    Abstract [en]

    Ecstasy, (+/-)-3,4-methylenedioxy-metamphetamine (MDMA), is a popular recreational drug among young people. The present study aims to mimic MDMA intake among adolescents at dance clubs, taking repeated doses in the same evening on an intermittent basis. Male Sprague-Dawley rats received either 3 x 1 or 3 x 5 mg/kg/day (3 h apart) every seventh day during 4 weeks. We used real-time RT-PCR to determine the gene expression of serotonin 5HT(1A), 5HT(1B), 5HT(2A), 5HT(2C), 5HT(3), 5HT(6) receptors and dopamine D-1, D-2, D-3 receptors in seven brain nuclei. The highest dose of MDMA extensively increased the 5HT1(B)-receptor mRNA in the cortex, caudate putamen, nucleus accumbens, and hypothalamus. The 5HT(2A)-receptor mRNA was reduced at the highest MDMA dose in the cortex. The 5HT(2C) mRNA was significantly increased in a dose-dependent manner in the cortex and the hypothalamus, as well as the 5HT(3)-receptor mRNA was in the hypothalamus. The 5HT(6) mRNA level was increased in the forebrain cortex and the amygdala. Dopamine receptor mRNAs were only affected in the hypothalamus. In conclusion, this study provides evidence for a unique implication of serotonin rather than dopamine receptor mRNA levels, in response to repeated intermittent MDMA administration. We therefore suggest that serotonin regulated functions also primarily underlie repeated MDMA intake at rave parties.

  • 13.
    Lesniak, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Polish Acad Sci, Dept Neuropeptides, Mossakowski Med Res Ctr, PL-02106 Warsaw, Poland..
    Pick, Chaim G.
    Tel Aviv Univ, Dept Anat, Sackler Sch Med, IL-69978 Tel Aviv, Israel..
    Misicka, Aleksandra
    Polish Acad Sci, Dept Neuropeptides, Mossakowski Med Res Ctr, PL-02106 Warsaw, Poland.;Univ Warsaw, Fac Chem, PL-02093 Warsaw, Poland..
    Lipkowski, Andrzej W.
    Polish Acad Sci, Dept Neuropeptides, Mossakowski Med Res Ctr, PL-02106 Warsaw, Poland..
    Sacharczuk, Mariusz
    Polish Acad Sci, Inst Genet & Anim Breeding, Dept Cytogenet, PL-05552 Magdalenka, Poland..
    Biphalin protects against cognitive deficits in a mouse model of mild traumatic brain injury (mTBI)2016In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 101, p. 506-518Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is often a result of traffic accidents, contact sports or battlefield explosions. A mild form of traumatic brain injury (mTBI) is frequently underestimated, as the immediate physical symptoms decrease rapidly and conventional neuroimaging studies often do not show visible evidence of brain lesions. However, cognitive impairments persist for weeks, months or even years after the incident. Endogenous opioids were documented to play a role in thmodulation of mTBI pathology, whereas exogenous opioids were shown to possess neuroprotective properties. In the present study, biphalin, a dimeric enkephalin analog, improved cognitive performance in the Morris Water Maze and Novel Object Recognition tests in a mouse weight-drop model of mTBI. The effect of a single systemic injection of 10 mg/kg biphalin immediately after trauma was reversed by naltrexone, suggesting an opioid receptor-mediated mechanism. Biphalin also reduced cortical and hippocampal neurodegeneration, as shown by silver staining. Our data indicates that opioid receptor activation by biphalin may provide neuroprotection of post-traumatic neurodegeneration processes and may protect against memory impairments.

  • 14. Lim, M S
    et al.
    Birnir, Bryndis
    John Curtin School of Medical Research, Australian National University.
    Heterogeneity of functional GABA(A) receptors in rat dentate gyrus neurons revealed by a change in response to drugs during the whole-cell current time-course.2001In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 40, no 8, p. 1034-43Article in journal (Refereed)
    Abstract [en]

    We examined if the drug sensitivity of GABA(A) receptors in dentate gyrus granule neurons changed during the whole-cell current time-course. Effects of drugs on currents evoked immediately (the peak current) upon drug application and currents remaining about two seconds later (semi-plateau current) were compared. The apparent affinity for GABA (EC(50)) of the peak and the semi-plateau current were 14 and 4 microM, respectively. Bicuculline inhibited 50% of the peak and the semi-plateau current (IC(50)) at 7 and 36 microM, respectively, while 100 microM was required for full inhibition of the 100 microM GABA-evoked current. Zinc inhibited about 50% of the peak current with an IC(50) value of 94 microM whereas biphasic, but complete inhibition of the semi-plateau current was recorded with IC(50) values of 3 and 558 microM. The decay phase of the 100 microM GABA-evoked current was fitted by a fast (tau(1), 100-300 ms) and a slow (tau(2), 1-2 s) time-constants in all cells. The relative current amplitude associated with the fast (A1) and the slow (A2) component varied. The A1 current amplitude appeared more sensitive to bicuculline than the A2 current while the opposite was true for zinc. The results are consistent with heterogenous population of functional GABA(A) receptors in the dentate gyrus granule neurons.

  • 15.
    Machado, Ivana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Nacl Cordoba, Fac Ciencias Quim, Dept Farmacol, IFEC CONICET, Cordoba, Argentina..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lasaga, Mercedes
    UBA CONICET, Fac Med, Inst Invest Biomed INBIOMED, Buenos Aires, DE, Argentina..
    Scimonelli, Teresa
    Univ Nacl Cordoba, Fac Ciencias Quim, Dept Farmacol, IFEC CONICET, Cordoba, Argentina..
    IL-1 beta reduces GluAl phosphorylation and its surface expression during memory reconsolidation and cc-melanocyte-stimulating hormone can modulate these effects2018In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 128, p. 314-323Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory cytokines can affect cognitive processes such as learning and memory. Particularly, interleukin-beta (IL-beta) influences hippocampus-dependent memories. We previously reported that administration of IL-1 beta in dorsal hippocampus impaired contextual fear memory reconsolidation. This effect was reversed by the melanocortin alpha-melanocyte-stimulating hormone (a-MSH). Our results also demonstrated that IL-1 beta produced a significant decrease in glutamate release from dorsal hippo campus synaptosomes after reactivation of the fear memory. Therefore, we investigated whether IL-beta administration can affect GIuA1 AMPA subunit phosphorylation, surface expression, and total expression during reconsolidation of a contextual fear memory. Also, we studied the modulatory effect of alpha-MSH. We found that IL-beta reduced phosphorylation of this subunit at Serine 831 and Serine 845 60 min after contextual fear memory reactivation. The intrahippocampal administration of IL-beta after memory reactivation also induced a decrease in surface expression and total expression of GIuA1. alpha-MSH prevented the effect of IL-beta on GIuAI phosphorylation in Serine 845, but not in Serine 831. Moreover, treatment with alpha-MSH also prevented the effect of the cytokine on GluAl surface and total expression after memory reactivation. Our results demonstrated that IL-beta regulates phosphorylation of GIuAI and may thus play an important role in modulation of AMPAR function and synaptic plasticity in the brain. These findings further illustrate the importance of IL-beta in cognition processes dependent on the hippocampus, and also reinforced the fact that alpha-MSH can reverse IL-1 beta effects on memory reconsolidation. (C) 2017 Elsevier Ltd. All rights reserved.

  • 16.
    Nilsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stroth, Nikolas
    Zhang, Xiaoqun
    Qi, Hongshi
    Fälth, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sköld, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hoyer, Daniel
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svenningsson, Per
    Neuropeptidomics of mouse hypothalamus after imipramine treatment reveal somatostatin as a potential mediator of antidepressant effects2012In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 62, no 1, p. 347-357Article in journal (Refereed)
    Abstract [en]

    Excessive activation of the hypothalamic pituitary adrenal (HPA) axis has been associated with numerous diseases, including depression, and the tricyclic antidepressant imipramine has been shown to suppress activity of the HPA axis. Central hypothalamic control of the HPA axis is complex and involves a number of neuropeptides released from multiple hypothalamic subnuclei. The present study was therefore designed to determine the effects of imipramine administration on the mouse hypothalamus using a peptidomics approach. Among the factors found to be downregulated after acute (one day) or chronic (21 days) imipramine administration were peptides derived from secretogranin 1 (chromogranin B) as well as peptides derived from cerebellin precursors. In contrast, peptides SRIF-14 and SRIF-28 (1-11) derived from somatostatin (SRIF, somatotropin release inhibiting factor) were significantly upregulated by imipramine in the hypothalamus. Because diminished SRIF levels have long been known to occur in depression, a second part of the study investigated the roles of individual SRIF receptors in mediating potential antidepressant effects. SRA880, an antagonist of the somatostatin-1 autoreceptor (sst1) which positively modulates release of endogenous SRIF, was found to synergize with imipramine in causing antidepressant-like effects in the tail suspension test. Furthermore, chronic co-administration of SRA880 and imipramine synergistically increased BDNF mRNA expression in the cerebral cortex. Application of SRIF or L054264, an sst2 receptor agonist, but not 1,803807, an sst4 receptor agonist, increased phosphorylation of CaMKII and GluR1 in cerebrocortical slices. Our present experiments thus provide evidence for antidepressant-induced upregulation of SRIF in the brain, and strengthen the notion that augmented SRIF expression and signaling may counter depressive-like symptoms.

  • 17.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Structural plasticity of the brain to psychostimulant use2014In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 87, p. 115-124Article, review/survey (Refereed)
    Abstract [en]

    Over the past years it has become evident that repeated exposure to a variety of psychoactive stimulants, like amphetamine, cocaine, MDMA (3,4-methylenedioxy-N-methylamphetamine), methylphenidate and nicotine may produce profound behavioral changes as well as structural and neurochemical alterations in the brain that may persist long after drug administration has ceased. These stimulants have been shown to produce long-lasting enhanced embranchments of dendrites and increasing spine density in brain regions linked to behavioral sensitization and compulsive patterns characteristic of drug seeking and drug addiction. In this regard, addiction to stimulant drugs represents a compulsory behavior that includes drug seeking, drug use and drug craving, but is also characterized as a cognitive disorder. In this article, recent findings regarding the impact of central stimulants on plasticity in brain regions of relevance for addictive behavior will be highlighted. A particular focus will be given to changes in neuroplasticity that occur in areas related to memory and cognition. Possible routes for the reversal of altered brain plasticity will also be discussed. This article is part of the Special Issue entitled 'CNS Stimulants'. 

  • 18.
    Wood, Christian M.
    et al.
    School of Physiology, Pharmacology and Neuroscience, University of Bristol..
    Nicolas, Celine S.
    School of Physiology, Pharmacology and Neuroscience, University of Bristol.
    Choi, Sun-Lim
    School of Physiology, Pharmacology and Neuroscience, University of Bristol.
    Roman, Erika
    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.
    Fernandez-Teruel, Alberto
    Department of Psychiatry and Forensic Medicine, Institute of Neurosciences, Autonomous University of Barcelona.
    Kiianmaa, Kalervo
    Department of Alcohol, Drugs and Addiction, National Institute for Health and Welfare, POB 30 00271 Helsinki.
    Bienkowski, Przemyslaw
    Department of Pharmacology, Institute of Psychiatry and Neurology, Warsaw..
    de Jong, Trynke R.
    Department of Behavioural and Molecular Neuroendocrinology, University of Regensburg.
    Colombo, Giancarlo
    Neuroscience Institute, Section of Cagliari, National Research Council of Italy.
    Chastagnier, Denis
    Janvier Labs, CS4105 Le Genest-Saint-Isle.
    Wafford, Keith A
    Eli Lilly Research Laboratories, Windlesham.
    Collingridge, Graham L.
    School of Physiology, Pharmacology and Neuroscience, University of Bristol.
    Wildt, Sheryl J
    Envigo, 8520 Allison Pointe Boulevard, Indianapolis IN 46250.
    Conway-Campbell, Becky L
    Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building.
    Robinson, Emma S.J.
    School of Physiology, Pharmacology and Neuroscience, University of Bristol.
    Lodge, David
    School of Physiology, Pharmacology and Neuroscience, University of Bristol.
    Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour.2017In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 115, p. 128-138Article, review/survey (Refereed)
    Abstract [en]

    Modulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors.

  • 19. Zhang, Chao
    et al.
    Kong, Xiaohong
    Ning, Guangzhi
    Liang, Zhipin
    Qu, Tongjun
    Chen, Feiran
    Cao, Daigui
    Wang, Tianyi
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Feng, Shiqing
    All-trans retinoic acid prevents epidural fibrosis through NF-kappa B signaling pathway in post-laminectomy rats2014In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 79C, p. 275-281Article in journal (Refereed)
    Abstract [en]

    Laminectomy is a widely accepted treatment for lumbar disorders, and epidural fibrosis (EF) is a common complication. EF is thought to cause post-operative pain recurrence after laminectomy or discectomy. All-trans retinoic acid (ATRA) has shown anti-fibrotic, anti-inflammatory, and anti-proliferative functions. The object of this study was to investigate the effects of ATRA on the prevention of EF in post-laminectomy rats. In vitro, the anti-fibrotic effect of ATRA was demonstrated with cultured fibroblasts count, which comprised of those that were cultured with/without ATRA. In vivo, rats underwent laminectomy at the L1-L2 levels. We first demonstrated the beneficial effects using 0.05% ATRA compared to vehicle (control group). We found that a higher concentration of ATRA (0.1%) achieved dose-dependent results. Hydroxyproline content, Rydell score, vimentin-positive cell density, fibroblast density, inflammatory cell density and inflammatory factor expression levels all suggested better outcomes in the 0.1% ATRA rats compared to the other three groups. Presumably, these effects involved ATRA's ability to suppress transforming growth factor (TGF-β1) and interleukin (IL)-6 which was confirmed with reverse-transcriptase polymerase chain reaction (RT-PCR). Finally we demonstrated that ATRA down-regulated nuclear factor (NF)-κB by immunohistochemistry and western blotting for p65 and inhibition of κB (IκBα), respectively. Our findings indicate that topical application of ATRA can inhibit fibroblast proliferation, decrease TGF-β1 and IL-6 expression level, and prevent epidural scar adhesion in rats. The highest concentration employed in this study (0.1%) was the most effective. ATRA suppressed EF through down-regulating NF-κB signaling, whose specific mechanism is suppression of IκB phosphorylation and proteolytic degradation.

  • 20.
    Zhang, Xiaoqun
    et al.
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Andren, Per E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, MMS, Medical Mass Spectrometry.
    Chergui, Karima
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Svenningsson, Per
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Neurokinin B/NK3 receptors exert feedback inhibition on L-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease2008In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 54, no 7, p. 1143-1152Article in journal (Refereed)
    Abstract [en]

    Neurokinin B (NKB) and substance P (SP) act via NK(3) and NK(1) receptors. Using the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD), it was found that chronic, but not acute, administration of L-DOPA increases striatal NKB expression in the dopamine-depleted hemisphere. In contrast, both acute and chronic administrations of L-DOPA restore reduced levels of SP mRNA. Co-treatment with the NK(3) receptor antagonist, SB222200, and L-DOPA increased contralateral rotations compared to L-DOPA alone in L-DOPA primed rats. The NK(3)R agonist, senktide, increased the phosphorylation of tyrosine hydroxylase (TH) at Ser(19)-TH, a CaMKII site, and of Thr(286)-CaMKII in striatal slices. Senktide had no effect on P-Ser(31)-TH, a MAPK site, but reduced P-Ser(217/221)-MEK. Amperometry demonstrated that senktide increased evoked dopamine release. SB222200 blocked the effects of senktide. In striatal slices prepared from 6-OHDA-lesioned rats repeatedly treated with L-DOPA, senktide no longer increased P-Thr(286)-CaMKII, suggesting a role of NK(3)R on dopamine terminals under normal conditions. SB222200 increased P-Ser(217/221)-MEK only in dopamine-depleted slices, indicating an increased NK(3)R tone under Parkinsonism conditions. Altogether, these data demonstrate a differential regulation of NKB and SP by L-DOPA in an animal model of PD and indicate a unique role of NKB in long-term effects of L-DOPA. Behavioural, biochemical and amperometric data indicate that NKB/NK(3)R signalling stimulates dopamine transmission at the presynaptic site, but inhibits it at the postsynaptic site. The inhibitory influence of NKB/NK(3)R on dopamine transmission dominates in an animal model of PD and provides a feedback inhibition on actions mediated via L-DOPA.

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