Biological research on drug dependence
Description
The research program comprises of three parts. One research line addresses the impact of addictive drugs (anabolic androgenic steroids, opioids, GHB etc.), but also hormones (growth hormone etc.), on important biochemical and physiological processes that are associated with drug dependence, behaviour and cognition. The effects of these substances on hippocampal function and e.g. learning and memory in animal models are examined. Most recently for example methadone and the party drug GHB was assessed. Extensive studies of the recently observed beneficial effects of growth hormone on cognitive functions is performed at present applying the Water maze in conjunction with various neurobiological techniques (PI Mathias Hallberg, previously prof Fred Nyberg served as the director of the project).
A second research line is addressing the peptide angiotensin IV that is known to improve cognitive functions in animal models and is proposed to exert its action through inhibiting the insulin regulated aminopeptidase (PI Mathias Hallberg). New unique drug-like angiotensin IV mimics have been discovered in close collaboration with medicinal chemists (Prof Mats Larhed). These molecules that could serve as leads in drug discovery processes exhibit high inhibitory capacity and selectivity and promote the development of dendritic spines, a property that is strongly associated with cognitive improvements. Hence, in parallel to the studies of the often adverse effects on cognition of addictive and abused substances in animal models and the studies of physiological and biochemical parameters related to behaviour, drug dependence and cognition, the ambition is to discover drug-like substances with the capacity to improve cognition; memory and learning.
The third research line is devoted to finding new analgesics that exert their actions by interacting with macromolecular targets in the renin-angiotensin and tachykinin systems. We study substance P 1-7 in collaboration with Assoc Prof Anja Sandström and in depth the role of angiotensin II and especially the AT2 receptor in neuropathic pain. Receptor assays specific for the AT1, AT2 and AT4 receptors are used to guide the synthesis and design of non-peptide metabolically stable bioavailable receptor ligands (PI Mathias Hallberg).
Selected publications
Svensson A-L, Bucht N, Hallberg M, Nyberg F. (2008) Reversal of opiate-induced apoptosis by human recombinant growth hormone in mice foetus primary hippocampal neuronal cell-cultures. Proc Natl Acad Sci USA. 105: 7304-7308.
Andersson H, Demaegdt H, Vauquelin G, Lindeberg G, Karlén A, Hallberg M. (2008) Ligands to the (IRAP)/AT4 receptor encompassing a 4-hydroxydiphenylmethane scaffold replacing Tyr2. Bioorg Med Chem. 16: 6924-6935.
Nyberg F, Hallberg M. (2013) Growth hormone and cognitive function. Nature Rev Endocrinology. 9: 357-365.
Hallberg M. (2015) Neuropeptides; metabolism to bioactive fragments and the pharmacology of their receptors. Med Res Rev. 35: 464-519.
Diwakarla S, Nylander E, Grönbladh A, Vanga SR, Khan YS, Gutiérrez-de-Terán H, Ng L, Sävmarker J, Lundbäck T, Jenmalm-Jensen A, Andersson H, Engen K, Rosenström U, Larhed M, Åqvist J, Chai SY, Hallberg M. (2016) Binding to and inhibition of insulin-regulated aminopeptidase (IRAP) by macrocyclic disulfides enhance spine density. Molecular Pharmacol. 89: 413-424.
Diwakarla S, Nylander E, Grönbladh A, Vanga S, Khan Y, Gutiérrez-de-Terán H, Savmarker J, Ng L, Pham V, Lundbäck T, Jenmalm-Jensen A, Svensson R, Artursson P, Zelleroth S, Engen K, Rosenström U, Larhed M, Aqvist J, Chai S Y, Hallberg M. (2016) Aryl sulfonamide inhibitors of insulin-regulated aminopeptidase enhance spine density in primary hippocampal neuron cultures. ACS Chem Neurosci. 7: 1383-1392.
Grönbladh A, Nylander E, Hallberg M. (2016) The neurobiology and addiction potential of anabolic androgenic steroids and effects of growth hormone. Brain Res Bull. 126:127-137.
Nylander E, Grönbladh A, Zelleroth S, Diwakarla S, Nyberg F, Hallberg M. (2016) Growth hormone is protective against acute methadone-induced toxicity by modulating the NMDA receptor complex.
Neuroscience. 339: 538-547.
Hallberg M, Sumners C, Steckelings UM, Hallberg A. (2018) Small-molecule AT2 receptor agonists. Med Res Rev. 38:602-624.
Hallberg M, Sandström A. (2018) From the anti-nociceptive substance P metabolite substance P (1-7) to small peptidemimetics. Curr Protein Pept Sci, doi: 10.2174/1389203719666180508122019.
Publications
Inhibition of Insulin-Regulated Aminopeptidase by Imidazo[1,5-α]pyridines; Synthesis and Evaluation
Part of International Journal of Molecular Sciences, 2024
Part of Hormones and Behavior, 2024
- DOI for The decanoate esters of nandrolone, testosterone, and trenbolone induce steroid specific memory impairment and somatic effects in the male rat
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Part of International Journal of Molecular Sciences, 2024
N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands
Part of European Journal of Medicinal Chemistry, 2024
DNA methylation at DLGAP2 and risk for relapse in alcohol dependence during acamprosate treatment
Part of Drug And Alcohol Dependence, 2024
Part of Behavioural Brain Research, 2022
- DOI for Nandrolone decanoate and testosterone undecanoate differently affect stress hormones, neurotransmitter systems, and general activity in the male rat
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Part of Current Issues in Molecular Biology, p. 5000-5012, 2022
Part of Neural Regeneration Research, p. 2431-2433, 2022
2-Alkyl substituted benzimidazoles as a new class of selective AT2 receptor ligands
Part of Bioorganic & Medicinal Chemistry, 2022
Angiotensin II AT2 receptor ligands with phenylthiazole scaffolds
Part of Bioorganic & Medicinal Chemistry, 2022
Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum
Part of Translational Psychiatry, 2022
Part of eNeuro, 2021
Part of Journal of Steroid Biochemistry and Molecular Biology, 2021
- DOI for Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures
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Assessing Cell Viability Effects of Opioids in Primary Cortical Cells from Rat.
Part of Methods in Molecular Biology, p. 171-180, 2021
Part of eLIFE, 2021
The effects of morphine, methadone, and fentanyl on mitochondria: A live cell imaging study
Part of Brain Research Bulletin, p. 126-134, 2021
Part of Frontiers in Genetics, 2021
Part of Experimental Brain Research, p. 2221-2232, 2021
Part of European Journal of Neuroscience, p. 5560-5573, 2021
- DOI for Coordinated expression of the renin-angiotensin genes in the lumbar spinal cord: Lateralization and effects of unilateral brain injury
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Unilateral brain injury to pregnant rats induces asymmetric neurological deficits in the offspring
Part of European Journal of Neuroscience, p. 3621-3633, 2021
Part of Journal of Neurotrauma, p. 1679-1688, 2021
N-(Methyloxycarbonyl)thiophene sulfonamides as high affinity AT2 receptor ligands
Part of Bioorganic & Medicinal Chemistry, 2021
Part of European Journal of Pharmacology, 2021
Part of Molecular Psychiatry, p. 3884-3895, 2021
- DOI for Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
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Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence
Part of Molecular Psychiatry, p. 4367-4382, 2021
Part of European Journal of Pharmacology, 2020
- DOI for Direct stimulation of angiotensin II type 2 receptor reduces nitric oxide production in lipopolysaccharide treated mouse macrophages
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Part of Metabolomics, 2020
- DOI for Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver
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Growth hormone increases dendritic spine density in primary hippocampal cell cultures
Part of Growth Hormone & IGF Research, p. 42-47, 2020
Part of ChemistryOpen, p. 325-337, 2020
Macrocyclic Peptidomimetics as Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
Part of RSC Medicinal chemistry, p. 234-244, 2020
Growing knowledge: How growth hormone improves learning
Part of Acta Physiologica, 2020
Part of Biomolecules, 2020
Part of ACS Medicinal Chemistry Letters, p. 1429-1434, 2020
Part of Journal of Neurochemistry, p. 485-494, 2020
Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry
Part of Brain Communications, 2020
Part of Brain Communications, 2020
Correlations between sex-related hormones, alcohol dependence and alcohol craving
Part of Drug And Alcohol Dependence, p. 183-190, 2019
Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse
Part of American Journal of Psychiatry, p. 146-155, 2019
Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord
Part of Restorative Neurology and Neuroscience, p. 87-96, 2019
Part of Cerebral Cortex, p. 1736-1751, 2019
High affinity rigidified AT(2) receptor ligands with indane scaffolds
Part of MedChemComm, p. 2146-2160, 2019
Part of Brain Research, p. 182-189, 2019
Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures
Part of Neuroscience, p. 172-183, 2019
Part of ChemistryOpen, p. 114-125, 2019
Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics.
Part of Molecular Neurobiology, p. 7049-7061, 2018
Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord
Part of Brain Research, p. 78-83, 2018
Part of Journal of Neurotrauma, 2018
Part of Journal of Neurotrauma, 2018
Part of Journal of Neurotrauma, 2018
Part of Bioorganic & Medicinal Chemistry Letters, p. 519-522, 2018