Biological research on drug dependence

Massa piller som rasar ner i olika färger

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).

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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).

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.

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