RT Journal Article
SR Electronic
T1 Behavioral Characterization of the Novel GABA<sub>B</sub> Receptor-Positive Modulator GS39783 (<em>N</em>,<em>N</em>′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 952
OP 963
DO 10.1124/jpet.104.066753
VO 310
IS 3
A1 Cryan, John F.
A1 Kelly, Peter H.
A1 Chaperon, Frederique
A1 Gentsch, Conrad
A1 Mombereau, Cedric
A1 Lingenhoehl, Kurt
A1 Froestl, Wolfgang
A1 Bettler, Bernhard
A1 Kaupmann, Klemens
A1 Spooren, Will P. J. M.
YR 2004
UL http://jpet.aspetjournals.org/content/310/3/952.abstract
AB The role of GABAB receptors in various behavioral processes has been largely defined using the prototypical GABAB receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioral paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety, the role of GABAB receptors in these disorders is largely unclear. We recently identified GS39783 (N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) as a selective allosteric positive modulator at GABAB receptors. The aim of the present study was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition, and anxiety. The following tests were included: locomotor activity in rats and mice, rotarod and traction tests (including determinations of core temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital- and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature, or narcosis. Most interestingly, GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABAB receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side effect profile to both baclofen and benzodiazepines. The American Society for Pharmacology and Experimental Therapeutics