Elsevier

Neuropharmacology

Volume 54, Issue 5, April 2008, Pages 854-862
Neuropharmacology

Evaluation of the anxiolytic-like profile of the GABAB receptor positive modulator CGP7930 in rodents

https://doi.org/10.1016/j.neuropharm.2008.01.004Get rights and content

Abstract

There is a growing body of data to support the notion that GABAB receptors may be a therapeutic target for anxiety disorders. However, the application of GABAB receptor agonists in anxiety research and psychiatry is hampered by side effects that include motor in-coordination and hypothermia. Recently the GABAB receptor positive modulator GS39783 was shown to be anxiolytic in rodent models, but was devoid of accompanying side effects characteristic of full agonists. However, it is important to test whether such anxiolytic effects generalise to another chemical class of GABAB receptor positive modulators. We therefore aimed to investigate the anxiolytic and side-effect profile of CGP7930, the first-reported GABAB receptor positive modulator, in rodent models of anxiety, motor coordination and hypothermia. CGP7930 (3–300 mg/kg) showed a modest, compared to the benzodiazepine chlordiazepoxide (10 mg/kg), dose-dependent anxiolytic profile in the mouse stress-induced hyperthermia (100 mg/kg), staircase (100 and 300 mg/kg) and elevated zero maze tests (3–100 mg/kg), but did not have any anxiolytic effects in the rat elevated plus maze. Similar to GS39783, CGP7930 also demonstrated a greatly reduced side-effect profile in comparison to the GABAB receptor full agonist baclofen in the mouse rotarod and traction wire tests and did not induce hypothermia. Although the effects of CGP7930 were modest, these results represent a second, structurally distinct, class of GABAB positive modulators showing anxiolytic activity. As such, these data support the premise that GABAB receptor positive modulation represents a novel therapeutic strategy for the development of anxiolytic drugs with a superior side-effect profile. The generation of more potent compounds is now warranted.

Introduction

The GABAB receptor is a G-protein coupled receptor consisting of a heterodimer made up of two subunits, GABAB(1) and GABAB(2), both of which are necessary for GABAB receptors to be functionally active (Calver et al., 2002). Clinical and preclinical evidence strongly implicates GABAergic dysfunction in anxiety (Millan, 2003). In particular, the ionotropic GABAA receptors have been a key target for anxiolytic drug development (Mohler et al., 2002) propelled largely by the clinical success of benzodiazepines, positive modulators of this receptor. Over the past number of years a growing body of research has accumulated, supporting a role for the GABAB receptor in anxiety (see Cryan and Kaupmann, 2005, Pilc and Nowak, 2005). Mice deficient in either the GABAB(1) or GABAB(2) receptor subunits show a highly anxious phenotype in exploratory anxiety paradigms (Mombereau et al., 2004a, Mombereau et al., 2004b, Mombereau et al., 2005). Furthermore, the prototypical GABAB receptor agonist baclofen, has shown anxiolytic actions in a number of clinical and preclinical investigations (Cryan and Kaupmann, 2005, Jacobson et al., 2007). Baclofen, however, is well known for its hypothermic, sedative and muscle-relaxant profile in a wide range of different species (Bettler et al., 2004, Cryan and Kaupmann, 2005, Jacobson and Cryan, 2005) which limit the applicability of baclofen as a tool for behavioural research and as a therapeutic agent in psychiatry.

The pharmacological strategy of using positive modulators has been hypothesised to reduce the side-effect profile relative to full agonists by enhancing endogenous, physiological signalling, rather than indiscriminate activation of receptors independently of synaptic activity (Christopoulos, 2002, Soudijn et al., 2004). Recently, positive modulators of the GABAB receptor have been developed. 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analogue CGP13501 were the first GABAB receptor positive modulators to be characterised in vitro (Urwyler et al., 2001). A subsequent, structurally distinct chemical series which includes the more efficacious N,N′- dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) were published shortly thereafter (Urwyler et al., 2003). These compounds enhance both the potency and the maximal efficacy of GABA at GABAB receptors in vitro, via interactions with the 7-transmembrane domain of the GABAB(2) subunit, although they have little to no intrinsic action by themselves (Binet et al., 2004, Dupuis et al., 2006, Urwyler et al., 2001, Urwyler et al., 2003, Urwyler et al., 2005). Both CGP7930 and GS39783 have also demonstrated GABAB receptor positive modulation properties in vivo. CGP7930 potentiated the loss of righting effects of the GABAB receptor agonists baclofen and gamma-hydroxybutyrate (GHB) (Carai et al., 2004), while in a microdialysis study, GS39783 potentiated the inhibitory effects of baclofen on forskolin-induced cAMP production in the rat striatum (Gjoni et al., 2006).

Of particular note, GS39783 has demonstrated a broad anxiolytic profile in rodents (Cryan et al., 2004, Mombereau et al., 2004b). Specifically, acute GS39783 induced anxiolytic responses in the mouse elevated zero maze (Cryan et al., 2004, Mombereau et al., 2004b), and stress-induced hyperthermia (Cryan et al., 2004) tests, and in the rat elevated zero and plus mazes (Cryan et al., 2004). Acute and chronic dosing of GS39783 was also efficacious in reducing indicators of anxiety in mice in the light–dark box (Mombereau et al., 2004b). Importantly, in these studies, GS39783 did not show motor impairing (Cryan et al., 2004, Mombereau et al., 2004b), hypothermic or cognitive impairing actions (Cryan et al., 2004) that are characteristic of full GABAB receptor agonists. Together these findings indicated that positive modulation of the GABAB receptor may be an interesting potential target for the development of novel anxiolytics (Cryan and Kaupmann, 2005). However, this premise is based solely on data derived from just one compound from one chemical class. Therefore, it is important to assess if such effects generalise to another positive modulator from a different chemical class.

Although CGP7930 has been characterised in vitro, its actions in vivo have not been well defined. CGP7930 attenuates cocaine and ethanol self administration (Liang et al., 2006, Smith et al., 2004, Orru et al., 2005). However, its effects in animal tests of motor impairment, hypothermia and anxiety have yet to be reported. The aim of the present study, therefore, was to examine the anxiolytic and side-effect profile of CGP7930 in a test battery with rodents.

Section snippets

Animals and experimental conditions

Male mice (OF1 strain) and rats (WI (AF/Han)) were obtained from Charles River (L'Abresle, France) and were tested within 2 weeks of arrival at the laboratory. Animals were group-housed on wood shavings in macrolon cages. Mice received one Mouse House (Nalgene) per home cage and tissue paper nesting materials. In the rotarod, temperature and traction-wire study, mice were group-housed 20 mice per 55 × 3 × 19 cm home cage. Twenty-four hours before the start of the experiment, mice were randomly

Rotarod, temperature and traction wire test

Rotarod endurance was influenced by drug treatments and time (Treatment: F5,239 = 9.81, P < 0.001; Time: F3,239 = 16.55, P < 0.001; Interaction: F15,239 = 5.49, P < 0.001). Post hoc analysis showed baclofen-treated mice had a reduced mean rotarod endurance 1 and 2 h after drug application relative to vehicle-treated mice (Fig. 1), but had returned to levels not different from vehicle-treated mice, or their own pre-drug baseline, within 4 h of treatment (P > 0.05, respectively). CGP7930 at 300 mg/kg only, also

Discussion

In this study we evaluated the side-effect profile and anxiolytic actions of the GABAB receptor positive modulator CGP7930. To this end, we employed a test battery approach in mice and rats. The data demonstrated that CGP7930 was largely devoid of classical GABAB receptor-mediated ataxic or hypothermic effects, with the exception of transient, minor influences on rotarod endurance at a very high dose (300 mg/kg). No influences on locomotor activity, however, were detected in the mouse elevated

Acknowledgements

This work was supported by the National Institutes of Mental Health/National Institute on Drug Abuse grant U01 MH69062. The authors gratefully thank Dr Klemens Kaupmann for critical reading of the manuscript, and Christine Hunn, Stefan Imobersteg and Hugo Bürki for expert technical assistance.

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