Behavioral characterization of the novel GABA(B) receptor-positive modulator GS39783 (N,N '-dicyclopentyl-2methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-like activity without side effects associated with baclofen or benzodiazepines

Psychiatry Program, Neuroscience Research, The Novartis Institutes for BioMedical Research WSJ 386.344, Novartis Pharma AG, Basel CH-4002, Switzerland.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 10/2004; 310(3):952-63. DOI: 10.1124/jpet.104.066753
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature.
    Alcohol 12/2014; 49(1). DOI:10.1016/j.alcohol.2014.11.005 · 2.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Stressful life events, especially those in early life, can exert long-lasting changes in the brain, increasing vulnerability to mental illness especially in females. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a critical role in the development and function of the central nervous system (CNS). Thus, we investigated the influence of an eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (80% EPA, 20% DHA) n-3 PUFAs mixture on stress-related behavioural and neurobiological responses. Sprague-Dawley female rats were subjected to an early-life stress, maternal separation (MS) procedure from postnatal days 2 to 12. Non-separated (NS) and MS rats were administered saline, EPA/DHA 0.4g/kg/day or EPA/DHA 1g/kg/day, respectively. In adulthood, EPA/DHA treated animals had a dose dependent reduction in anxiety in NS rats. Furthermore, cognitive performance in the novel object recognition task (NOR) was improved by EPA/DHA treatment in NS animals only. EPA/DHA 1g/kg/day decreased behavioural despair in the forced swim test. Notably, EPA/DHA high dose increased the translocation of GRs into the nucleus of NS rat hippocampus. However, the levels of mBDNF remained unchanged in all the experimental groups. The corticosterone response to an acute stress was blunted in MS rats and this was further attenuated by pre-treatment with EPA/DHA. Immune response and monoamine neurotransmission were significantly altered by early-life stress. In conclusion, our study supports the view that n-3 PUFAs are beneficial in neurodevelopmentally normal animals but have little positive benefit in animals exposed to early life stress. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 04/2015; 58:79-90. DOI:10.1016/j.psyneuen.2015.04.015 · 5.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diverse preclinical studies exploiting the modulation of the GABAergic and/or glutamatergic system in brain via metabotropic receptors suggest their potential therapeutic utility. GS39783 and CDPPB, a positive allosteric modulators of GABAB and mGlu5 receptors, were previously shown to reverse behavioral phenotypes in animal models thought to mimic selected (predominantly positive) symptoms of schizophrenia. In the present study we investigated the activity of selected GABAB (GS39783 and CGP7930) and mGlu5 (CDPPB) positive allosteric modulators. We focused mainly on the aspects of their efficacy in the models of negative and cognitive symptoms of schizophrenia. We used modified swim test, social interactions (models of negative symptoms) and novel object recognition (model of cognitive disturbances). The activity of the compounds was also tested in haloperidol-induced catalepsy test. The mutual interaction between GABAB/mGlu5 ligands was investigated as well. In the second part of the study, DHPG-induced PI hydrolysis in the presence of GABAB receptor antagonist (SKF97541), and SKF97541-induced inhibition of cAMP formationin the presence of DHPG, were performed. Both mGlu5 and GABAB receptor modulators effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783, induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches. The concomitant administration of group I mGlu and GABAB agonists did not displayed any synergistic effects in vitro. Summing up, an activation of both types of receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious towards positive, negative and cognitive symptoms. Copyright © 2015. Published by Elsevier Ltd.
    Neurochemistry International 04/2015; DOI:10.1016/j.neuint.2015.03.010 · 2.65 Impact Factor