Laura Friis Eghorn

September 2010 – present:
PhD student, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen

September 2005 – August 2010:
M.Sc (Pharm), Faculty of Pharmaceutical Sciences, University of Copenhagen

Radioactive Isotopes and Ionizing Radiation, University of Copenhagen (2011)
Laboratory Animal Science (FELASA cat. C), University of Copenhagen (2010)

2011: DRA equipment grant (15,000 dkr)
2010: H. C. Ørsted’s medalist

Project title
Neuropharmacological studies of the putative γ-hydroxybutyric acid (GHB) receptor

Background
γ-hydroxybutyric acid (GHB) is a metabolite of γ-aminobutyric acid (GABA) and a putative neuromodulator in the mammalian brain. GHB is a registered drug for the treatment of narcolepsy and alcoholism, but is also known for its illicit use under pseudonyms such as Fantasy, liquid ecstasy and ‘the date rape drug’. At high doses, or mixed with alcohol, GHB causes deep sedation, coma and death, and several cases of intoxication and death have been attributed to GHB intake. As no antidote for GHB intoxication currently exists, it is important to investigate the neurobiological effects of GHB to address this unmet clinical need.

Many of the reported effects of exogenously administered GHB appear to be mediated through GABA_B receptors, but the clinical use of GHB in sleep disorders and its reported euphoric effects cannot be mimicked by GABA_B agonists. There is general agreement that separate GHB and GABA_B binding sites exist in the brain, but despite substantial recent research, the “putative GHB receptor” remains an elusive protein with elusive physiological importance.

Objectives
The objectives of the current project are 1) to provide insight into the GHB  system and the identity of the GHB receptor in the mammalian brain and 2) to address the unmet clinical need for an efficient GHB antidote to treat GHB intoxication.

Approach
We have recently identified a novel receptor for GHB different from the GABA_B receptor, which may be equivalent to the GHB high-affinity binding site. This will be tested in in vitro binding studies at recombinant receptors expressed in oocytes using a radiolabeled selective GHB receptor ligand. Additionally, the affinity of GHB and selected ligands will be characterized in brain tissue from receptor subunit knock-out mice relative to wild-type mice, in membrane preparations and by autoradiography.

A novel selective GHB receptor ligand has shown to produce sedation in vivo, and its neuropharmacological potential will be investigated in behavioural models for sedation, sleep, anxiety and general activity. The effects of selected GHB and GABA receptor ligands as well as different readily available clinical drugs on GHB intoxication will be investigated in similar behavioural models to evaluate their potential as GHB antidotes.

Main advisor

• Petrine Wellendorph, Associate Professor, Department of Medicinal Chemistry

Co-advisors

• Gitte Moos Knudsen, Professor, Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet
• Hans Bräuner-Osborne, Professor, Department of Medicinal Chemistry
• Anders Bue Klein, Post Doc., Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet

Rikke Rie Hansen; Christian K Nielsen; Arafat Nasser; Stine M Thomsen; Laura F Eghorn; Yen Pham; Celia Schulenburg; Susanne Syberg; Ming Ding; Stanko S Stojilkovic; Niklas R Jørgensen; Anne-Marie Heegaard. P2X7 receptor-deficient mice are susceptible to bone cancer pain (accepted March 21^st 2011 by Pain).