| 101. |
- Taqi, Malik Mumtaz, et al.
(författare)
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Prodynorphin promoter SNP associated with alcohol dependence forms noncanonical AP-1 binding site that may influence gene expression in human brain
- 2011
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1385, s. 18-25
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Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphism (rs1997794) in promoter of the prodynorphin gene (PDYN) associated with alcohol-dependence may impact PDYN transcription in human brain. To address this hypothesis we analyzed PDYN mRNA levels in the dorsolateral prefrontal cortex (dl-PFC) and hippocampus, both involved in cognitive control of addictive behavior and PDYN promoter SNP genotype in alcohol-dependent and control human subjects. The principal component analysis suggested that PDYN expression in the dl-PFC may be related to alcoholism, while in the hippocampus may depend on the genotype. We also demonstrated that the T, low risk SNP allele resides within noncanonical AP-1-binding element that may be targeted by JUND and FOSS proteins, the dominant AP-1 constituents in the human brain. The T to C transition abrogated AP-1 binding. The impact of genetic variations on PDYN transcription may be relevant for diverse adaptive responses of this gene to alcohol.
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| 102. |
- Tay, Nicole, et al.
(författare)
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Allele-Specific Methylation of SPDEF : A Novel Moderator of Psychosocial Stress and Substance Abuse
- 2019
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Ingår i: American Journal of Psychiatry. - : AMER PSYCHIATRIC PUBLISHING, INC. - 0002-953X .- 1535-7228. ; 176:2, s. 146-155
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population.Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study.Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use.Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.
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| 103. |
- Vukojevic, Vladana, et al.
(författare)
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Fluorescence Imaging with Single-Molecule Sensitivity and Fluorescence Correlation Spectroscopy of Cell-Penetrating Neuropeptides
- 2011
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Ingår i: Neuropeptides. - Totowa, NJ : Humana Press. - 9781617793097 ; 789, s. 147-70
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Bokkapitel (refereegranskat)abstract
- Neuropeptide plasma membrane interactions in the absence of a corresponding specific receptor may result in neuropeptide translocation into the cell. Trans location across the plasma membrane may represent a previously unknown mechanism by which neuropeptides can signal information to the cell interior. We introduce here two complementary optical methods with single-molecule sensitivity, fluorescence imaging with avalanche photodiode detectors (APD imaging) and fluorescence correlation spectroscopy (FCS), and demonstrate how they may be applied for the analysis of neuropeptide ability to penetrate into live cells in real time. APD imaging enables us to visualize fluorescently labeled neuropeptide molecules at very low, physiologically relevant concentrations, whereas FCS enables us to characterize quantitatively their concentration and diffusion properties in different cellular compartments. Application of these methodologies for the analysis of the endogenous opioid peptide dynorphin A (Dyn A), a ligand for the kappa-opioid receptor (KOP), demonstrated that this neuropeptide may translocate across the plasma membrane of living cells and enter the cellular interior without binding to its cognate receptor.
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| 104. |
- Walker, Brendan M., et al.
(författare)
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Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence
- 2012
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Ingår i: Alcohol. - : Elsevier BV. - 0741-8329 .- 1873-6823. ; 46:4, s. 359-370
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Tidskriftsartikel (refereegranskat)abstract
- This review represents the focus of a symposium that was presented at the "Alcoholism and Stress: A Framework for Future Treatment Strategies" conference in Volterra, Italy on May 3-6, 2011 and organized/chaired by Dr. Brendan M. Walker. The primary goal of the symposium was to evaluate and disseminate contemporary findings regarding the emerging role of kappa-opioid receptors (KORs) and their endogenous ligands dynorphins (DYNs) in the regulation of,escalated alcohol consumption, negative affect and cognitive dysfunction associated with alcohol dependence, as well as DYN/KOR mediation of the effects of chronic stress on alcohol reward and seeking behaviors. Dr. Glenn Valdez described a role for KORs in the anxiogenic effects of alcohol withdrawal. Dr. Jay McLaughlin focused on the role of KORs in repeated stress-induced potentiation of alcohol reward and increased alcohol consumption. Dr. Brendan Walker presented data characterizing the effects of KOR antagonism within the extended amygdala on withdrawal-induced escalation of alcohol self-administration in dependent animals. Dr. Georgy Bakalkin concluded with data indicative of altered DYNs and KORs in the prefrontal cortex of alcohol dependent humans that could underlie diminished cognitive performance. Collectively, the data presented within this symposium identified the multifaceted contribution of KORs to the characteristics of acute and chronic alcohol-induced behavioral dysregulation and provided a foundation for the development of pharmacotherapeutic strategies to treat certain aspects of alcohol use disorders.
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| 105. |
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| 106. |
- Watanabe, Hiroyuki, et al.
(författare)
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Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate : a Putative Molecular Basis for Lateralization of Emotions and Pain
- 2015
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Ingår i: Cerebral Cortex. - United kingdom : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 25:1, s. 97-108
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Tidskriftsartikel (refereegranskat)abstract
- Lateralization of processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria and pain, the m-, d- and k-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and five “classical” neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg and Met-enkephalin-Arg-Phe, preferential d-/m- and k-/m-opioid agonists demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B strongly correlated with Leu-enkephalin-Arg in the left but not right ACC suggesting different mechanisms of conversion of this k-opioid agonist to d-/m-opioid ligand in the two hemispheres; in the right ACC dynorphin B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlyes in part lateralization of higher functions including positive and negative emotions and pain in the human brain.
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| 107. |
- Watanabe, Hiroyuki, et al.
(författare)
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FOSB proteins in the orbitofrontal and dorsolateral prefrontal cortices of human alcoholics
- 2009
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 14:3, s. 294-297
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor DeltaFosB is accumulated in the addiction circuitry, including the orbitofrontal and medial prefrontal cortices of rodents chronically exposed to ethanol or other drugs of abuse, and has been suggested to play a direct role in addiction maintenance. To address this hypothesis in the context of substance dependence in humans, we compared the immunoreactivities of FOSB proteins in the orbitofrontal and dorsolateral prefrontal cortices (OFC and DLPFC respectively) between controls and alcoholics using semiquantitative immunoblotting. In both structures, we detected three forms of FOSB, one of which was DeltaFOSB, but in neither case did their immunoreactivities differ between the groups. Our results indicate that the DeltaFOSB immunoreactivity in the human brain is very low, and that it is not accumulated in the OFC and DLPFC of human alcoholics, suggesting that it may not be directly involved in addiction maintenance, at least not in ethanol dependence.
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| 108. |
- Watanabe, Hiroyuki, et al.
(författare)
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Ipsilesional versus contralesional postural deficits induced by unilateral brain trauma : a side reversal by opioid mechanism
- 2020
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Ingår i: Brain Communications. - : Oxford University Press. - 2632-1297. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- Unilateral traumatic brain injury and stroke result in asymmetric postural and motor deficits including contralateral hemiplegia and hemiparesis. In animals, a localized unilateral brain injury recapitulates the human upper motor neuron syndrome in formation of hindlimb postural asymmetry with contralesional limb flexion and the asymmetry of hindlimb nociceptive withdrawal reflexes. The current view is that these effects are developed due to aberrant activity of motor pathways that descend from the brain into the spinal cord. These pathways and their target spinal circuits may be regulated by local neurohormonal systems that may also mediate effects of brain injury. Here we evaluate if a unilateral traumatic brain injury induces hindlimb postural asymmetry, a model of postural deficits, and if this asymmetry is spinally encoded and mediated by the endogenous opioid system in rats. A unilateral right-sided controlled cortical impact, a model of clinical focal traumatic brain injury was centered over the sensorimotor cortex and was observed to induce hindlimb postural asymmetry with contralateral limb flexion. The asymmetry persisted after complete spinal cord transection, implicating local neurocircuitry in the development of the deficits. Administration of the general opioid antagonist naloxone and µ-antagonist β-funaltrexamine blocked formation of postural asymmetry. Surprisingly, κ-antagonists nor-binaltorphimine and LY2444296 did not affect the asymmetry magnitude but reversed the flexion side; instead of contralesional (left) hindlimb flexion the ipsilesional (right) limb was flexed. The postural effects of the right-side cortical injury were mimicked in animals with intact brain via intrathecal administration of the opioid κ-agonist U50,488 that induced hindlimb postural asymmetry with left limb flexion. The δ-antagonist naltrindole produced no effect on the contralesional (left) flexion but inhibited formation of the ipsilesional (right) limb flexion in brain-injured rats that were treated with κ-antagonist. The effects of the antagonists were evident before and after spinal cord transection. We concluded that the focal traumatic brain injury-induced postural asymmetry was encoded at the spinal level, and was blocked or its side was reversed by administration of opioid antagonists. The findings suggest that the balance in activity of the mirror symmetric spinal neural circuits regulating contraction of the left and right hindlimb muscles is controlled by receptors; and that this equilibrium is impaired after unilateral brain trauma through side-specific opioid mechanism.
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| 109. |
- Watanabe, Hiroyuki, et al.
(författare)
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Left-right side-specific neuropeptide mechanism mediates contralateral responses to a unilateral brain injury
- 2021
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Ingår i: eNeuro. - : Society for Neuroscience. - 2373-2822. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contra- and ipsilesional side-specific postural and sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contra- and ipsilesional hindlimb responses to the left- and right-sided injury in rats. UBI induced hindlimb postural asymmetry (HL-PA) with the contralesional hindlimb flexion, and activated contralesional withdrawal reflex of extensor digitorum longus (EDL) evoked by electrical stimulation and recorded with EMG technique. No effects on the interossei (Int) and peroneaus longus (PL) were evident. The general opioid antagonist naloxone blocked postural effects, did not change EDL asymmetry while uncovered cryptic asymmetry in the PL and Int reflexes induced by UBI. Thus the spinal opioid system may either mediate or counteract the injury effects. Strikingly, effects of selective opioid antagonists were the injury side-specific. The mu- and kappa-antagonists beta-funaltrexamine and nor-binaltorphimine, respectively, reduced postural asymmetry after the right but not left UBI. In contrast, the delta-antagonist naltrindole inhibited HL-PA after the left but not right side brain injury. The opioid gene expression and opioid peptides were lateralized in the lumbar spinal cord, and coordination between expression of the opioid and neuroplasticity-related genes was impaired by UBI that together may underlie the side-specific effects of the antagonists. We suggest that mirror-symmetric neural circuits that mediate effects of left and right brain injury on the contralesional hindlimbs are differentially controlled by the lateralized opioid system. Significance statement Functional specialization of the left and right hemispheres is an organizing principle of the brain. Lasting regulation of lateralized processes may be accomplished by paracrine neurohormonal mechanisms that preferentially operate in the left or right hemisphere. Our findings support this hypothesis by demonstration that mirror-symmetric neural circuits that control the left and right hindlimbs may be regulated by the left- and right-side specific neuropeptide mechanisms. Neuropeptides may differentially target the left and right counterparts of these circuits, and in this way control the left-right balance in their functional performance. This bipartite mechanism may be based on lateralization of the neuropeptide systems, and may operate in the spinal cord or control neural pathways descending from the brain to contralateral motoneurons.
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| 110. |
- Watanabe, Hiroyuki, et al.
(författare)
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Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23
- 2012
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Ingår i: Peptides. - : Elsevier. - 0196-9781 .- 1873-5169. ; 35:2, s. 306-310
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Tidskriftsartikel (refereegranskat)abstract
- We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both opioid activities and non-opioid neurodegenerative actions. It has been reported that Dyn A administered intrathecally (i.t.) in femtomolar doses into mice produces nociceptive behaviors consisting of hindlimb scratching along with biting and licking of the hindpaw and tail (SBL responses) through a non-opioid mechanism. We here evaluated the potential of the three mutant peptides to produce similar behaviors. Compared to the wild type (WT)-peptide, the relative potency of Dyn A R6W, L5S and R9C peptides for SBL responses was 50-, 33- and 2-fold higher, and Dyn A R6W and L5S induced the SBL responses at a 10-30-fold lower doses. Dyn A R6W was the most potent peptide. The SBL responses induced by Dyn A R6W were dose dependently inhibited by morphine (i.p.; 0.1-1 mg/kg) or MK-801, an NMDA ion channel blocker (i.t. co-administration; 5-7.5 nmol). CP-99,994, a tachykinin NK1 receptor antagonist (i.t. co-administration; 2 nmol) and naloxone (i.p.; 5 mg/kg) failed to block effects of Dyn A R6W. Thus, similarly to Dyn A WT, the SBL responses induced by Dyn A R6W may involve the NMDA receptor but are not mediated through the opioid and tachykinin NK1 receptors. Enhanced non-opioid excitatory activities of Dyn A mutants may underlie in part development of SCA23.
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