Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Cryan, John F.; Kelly, Peter H.; Chaperon, Frédérique; Gentsch, C.; Mombereau, Cédric; Lingenhoehl, Kurt; Froestl, Wolfgang; Bettler, Bernhard; Kaupmann, Klemens; Spooren, Will

doi:10.1124/jpet.104.066753

Cited by 196 publications

(147 citation statements)

References 37 publications

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“…53,54 Furthermore, the novel positive GA-BA B R modulator, GS39783, proved to be anxiolytic in, among others, the light-dark box and the elevated plus maze. 55 Our findings agree nicely with these studies, given that the enhanced GABA B R responsiveness of dnActRIB mice was associated with decreased anxiety in the open-field and the lightdark exploration test. Thus it is well conceivable that activin influences anxiety-related behavior also through the modulation of GABA B R-dependent pathways.…”

Section: Discussionsupporting

confidence: 91%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Section: Discussionsupporting

confidence: 91%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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“…In fact, GS-39783 (novel GABA B receptor PAM) was shown to increase in vitro the GABA B receptor agonist affinity and potency, as well as the capacity of GABA to reduce cAMP production (Urwyler et al, 2005). In our hands, this compound exerted the same anxiolyticlike responses on the behavioral level as described elsewhere Cryan et al, 2004;Jacobson and Cryan, 2008). Importantly, we found that a subthreshold dose of GS-39783 (2 mg/kg) was able to counteract to a large extent the anxiogenic effects of CP-55,940 at high dose (Figures 4a-f).…”

Section: Discussionsupporting

confidence: 56%

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

Rey

Purrio

Viveros

et al. 2012

Neuropsychopharmacol

275

198

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Biphasic effects of cannabinoids have been shown in processes such as feeding behavior, motor activity, motivational processes and anxiety responses. Using two different tests for the characterization of anxiety-related behavior (elevated plus-maze and holeboard), we first identified in wild-type C57BL/6N mice, two doses of the synthetic CB1 cannabinoid receptor agonist CP-55,940 with anxiolytic (1 mg/kg) and anxiogenic properties (50 mg/kg), respectively. To clarify the role of CB1 receptors in this biphasic effect, both doses were applied to two different conditional CB1 receptor knockout (KO) mouse lines, GABA-CB1-KO (CB1 receptor inactivation in forebrain GABAergic neurons) and Glu-CB1-KO (CB1 receptor inactivation in cortical glutamatergic neurons). We found that the anxiolytic-like effects of the low dose of cannabinoids are mediated via the CB1 receptor on cortical glutamatergic terminals, because this anxiolytic-like response was abrogated only in Glu-CB1-KO mice. On the contrary, the CB1 receptor on the GABAergic terminals is required to induce an anxiogenic-like effect under a high-dose treatment because of the fact that this effect was abolished specifically in GABA-CB1-KO mice. These experiments were carried out in both sexes, and no differences occurred with the doses tested in the mutant mice. Interestingly, the positive allosteric modulation of GABA B receptor with GS-39783 was found to largely abrogate the anxiogenic-like effect of the high dose of CP-55,940. Our results shed new light in further understanding the biphasic effects of cannabinoids at the molecular level and, importantly, pave the way for the development of novel anxiolytic cannabinoid drugs, which may have favorable effect profiles targeting the CB1 receptor on glutamatergic terminals.

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“…Interestingly, GABA B receptorpositive allosteric modulator compounds, such as GS39783 and the more recently synthesized BHF177, are likely to have more subtle effects than GABA B receptor agonists, due to their modulatory, rather than full agonist, properties at the receptors (Guery et al 2007). Accordingly, such compounds do not impair performance in the rotarod test when administered alone (Cryan et al 2004). In a series of recent studies, we demonstrated that several GABA B receptor positive allosteric modulators decreased nicotine selfadministration, decreased break points for nicotine under a progressive ratio schedule of reinforcement and blocked the reward-enhancing effects of nicotine (Paterson et al in press).…”

Section: Neurosubstrates Of Nicotine Reward Dependence and Withdrawalmentioning

confidence: 99%

“…Nonetheless, GABA B receptor agonists have undesirable side effects, including disruption of performance on the rotarod test, a measure of locomotor impairment (Cryan et al 2004), and decreased responding for nondrug rewards, such as food and electrical brain stimulation (Macey et al 2001;Paterson et al 2005a;Slattery et al 2005). Interestingly, GABA B receptorpositive allosteric modulator compounds, such as GS39783 and the more recently synthesized BHF177, are likely to have more subtle effects than GABA B receptor agonists, due to their modulatory, rather than full agonist, properties at the receptors (Guery et al 2007).…”

Section: Neurosubstrates Of Nicotine Reward Dependence and Withdrawalmentioning

confidence: 99%

Neurobiology of nicotine dependence

Markou

2008

Phil. Trans. R. Soc. B

236

186

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Nicotine is a psychoactive ingredient in tobacco that significantly contributes to the harmful tobacco smoking habit. Nicotine dependence is more prevalent than dependence on any other substance. Preclinical research in animal models of the various aspects of nicotine dependence suggests a critical role of glutamate, g-aminobutyric acid (GABA), cholinergic and dopamine neurotransmitter interactions in the ventral tegmental area and possibly other brain sites, such as the central nucleus of the amygdala and the prefrontal cortex, in the effects of nicotine. Specifically, decreasing glutamate transmission or increasing GABA transmission with pharmacological manipulations decreased the rewarding effects of nicotine and cue-induced reinstatement of nicotine seeking. Furthermore, early nicotine withdrawal is characterized by decreased function of presynaptic inhibitory metabotropic glutamate 2/3 receptors and increased expression of postsynaptic glutamate receptor subunits in limbic and frontal brain sites, while protracted abstinence may be associated with increased glutamate response to stimuli associated with nicotine administration. Finally, adaptations in nicotinic acetylcholine receptor function are also involved in nicotine dependence. These neuroadaptations probably develop to counteract the decreased glutamate and cholinergic transmission that is hypothesized to characterize early nicotine withdrawal. In conclusion, glutamate, GABA and cholinergic transmission in limbic and frontal brain sites are critically involved in nicotine dependence.

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Behavioral Characterization of the Novel GABA_B Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Cited by 196 publications

References 37 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

Neurobiology of nicotine dependence

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