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Karlsson, Urban
Publications (3 of 3) Show all publications
Klawonn, A., Fritz, M., Nilsson, A., Bonaventura, J., Shionoya, K., Mirrasekhian, E., . . . Engblom, D. (2018). Motivational valence is determined by striatal melanocortin 4 receptors. Journal of Clinical Investigation, 128(7), 3160-3170
Open this publication in new window or tab >>Motivational valence is determined by striatal melanocortin 4 receptors
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 7, p. 3160-3170Article in journal (Refereed) Published
Abstract [en]

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-149861 (URN)10.1172/JCI97854 (DOI)000437234600044 ()29911992 (PubMedID)
Note

Funding Agencies|European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain foundation; County Council of Ostergotland; National Institute on Drug Abuse Intramural Research Program [ZIA000069]; Lars Hiertas Minne Foundation

Available from: 2018-08-02 Created: 2018-08-02 Last updated: 2018-08-20
Yelhekar, T. D., Druzin, M., Karlsson, U., Blomqvist, E. & Johansson, S. (2016). How to Properly Measure a Current-Voltage Relation?: Interpolation vs. Ramp Methods Applied to Studies of GABA(A) Receptors. Frontiers in Cellular Neuroscience, 10(10)
Open this publication in new window or tab >>How to Properly Measure a Current-Voltage Relation?: Interpolation vs. Ramp Methods Applied to Studies of GABA(A) Receptors
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2016 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 10, no 10Article in journal (Refereed) Published
Abstract [en]

The relation between current and voltage, I-V relation, is central to functional analysis of membrane ion channels. A commonly used method, since the introduction of the voltage-clamp technique, to establish the I-V relation depends on the interpolation of current amplitudes recorded at different steady voltages. By a theoretical computational approach as well as by experimental recordings from GABA(A) receptor mediated currents in mammalian central neurons, we here show that this interpolation method may give reversal potentials and conductances that do not reflect the properties of the channels studied under conditions when ion flux may give rise to concentration changes. Therefore, changes in ion concentrations may remain undetected and conclusions on changes in conductance, such as during desensitization, may be mistaken. In contrast, an alternative experimental approach, using rapid voltage ramps, enable I-V relations that much better reflect the properties of the studied ion channels.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2016
Keywords
current-voltage relation; voltage clamp; reversal potential; conductance; concentration changes; interpolation; voltage ramp; ion channel
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125294 (URN)10.3389/fncel.2016.00010 (DOI)000369141200001 ()26869882 (PubMedID)
Note

Funding Agencies|Swedish Research Council [22292]; Gunvor och Josef Aners Stiftelse

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2017-11-30
Ottosson, N., Wu, X., Nolting, A., Karlsson, U., Lund, P.-E., Ruda, K., . . . Elinder, F. (2015). Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability. Scientific Reports, 5(13278)
Open this publication in new window or tab >>Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 13278Article in journal (Refereed) Published
Abstract [en]

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121307 (URN)10.1038/srep13278 (DOI)000359905300001 ()26299574 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; ALF; County Council of Ostergotland

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-01-25Bibliographically approved
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