GSK1059865

The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice

The orexin/hypocretin (ORX) system plays a major role in motivation for natural and drug rewards. In particular, a number of studies have shown that ORX signaling through the orexin 1 receptor (OX1R) regulates alcohol seeking and consumption. Despite the association between ORX signaling and motivation for alcohol, no study to date has investigated what role the ORX system plays in alcohol dependence, an understanding of which would have significant clinical relevance. This study was designed to evaluate the effect of the highly selective OX1R antagonist GSK1059865 on voluntary ethanol intake in ethanol-dependent and control non-dependent mice. Mice were subjected to a protocol in which they were evaluated for baseline ethanol intake and then exposed to intermittent ethanol or air exposure in inhalation chambers. Each cycle of chronic intermittent ethanol (CIE), or air, exposure was followed by a test of ethanol intake. Once the expected effect of increased voluntary ethanol intake was obtained in ethanol dependent mice, mice were tested for the effect of GSK1059865 on ethanol and sucrose intake. Treatment with GSK1059865 significantly decreased ethanol drinking in a dose-dependent manner in CIE-exposed mice. In contrast GSK1059865 decreased drinking in air-exposed mice only at the highest dose used. There was no effect of GSK1059865 on sucrose intake. Thus, ORX signaling through the OX1R, using a highly-selective antagonist, has a profound influence on high levels of alcohol drinking induced in a dependence paradigm, but limited or no influence on moderate alcohol drinking or sucrose drinking. These results indicate that the ORX system may be an important target system for treating disorders of compulsive reward seeking such as alcoholism and other addictions in which motivation is strongly elevated.

Orexin 1 receptor antagonists in compulsive behavior and anxiety: possible therapeutic use

Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were initially associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA) suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders. In this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1) antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioral and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.

Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists

Orexins are neuro-modulatory peptides involved in the control of diverse physiological functions through interaction with two receptors, orexin-1 (OX1R) and orexin-2 (OX2R). Recent evidence in pre-clinical models points toward a putative dichotomic role of the two receptors, with OX2R predominantly involved in the regulation of the sleep/wake cycle and arousal, and the OX1R being more specifically involved in reward processing and motivated behaviour. However, the specific neural substrates underlying these distinct processes in the rat brain remain to be elucidated. Here we used functional magnetic resonance imaging (fMRI) in the rat to map the modulatory effect of selective OXR blockade on the functional response produced by D-amphetamine, a psychostimulant and arousing drug that stimulates orexigenic activity. OXR blockade was produced by GSK1059865 and JNJ1037049, two novel OX1R and OX2R antagonists with unprecedented selectivity at the counter receptor type. Both drugs inhibited the functional response to D-amphetamine albeit with distinct neuroanatomical patterns: GSK1059865 focally modulated functional responses in striatal terminals, whereas JNJ1037049 induced a widespread pattern of attenuation characterised by a prominent cortical involvement. At the same doses tested in the fMRI study, JNJ1037049 exhibited robust hypnotic properties, while GSK1059865 failed to display significant sleep-promoting effects, but significantly reduced drug-seeking behaviour in cocaine-induced conditioned place preference. Collectively, these findings highlight an essential contribution of the OX2R in modulating cortical activity and arousal, an effect that is consistent with the robust hypnotic effect exhibited by JNJ1037049. The subcortical and striatal pattern observed with GSK1059865 represent a possible neurofunctional correlate for the modulatory role of OX1R in controlling reward-processing and goal-oriented behaviours in the rat.

Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats

Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine), a selective OX(1)R antagonist, JNJ-10397049 (N-(2,4-dibromophenyl)-N'-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea), a selective OX(2)R antagonist, and SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide), a dual OX(1)/OX(2)R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX(1)R mechanisms in BE, suggesting that selective antagonism at OX(1)R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.

Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine

Translational approaches to study the neural substrates of stress and assess the mechanistic efficacy of novel anti-anxiety agents necessitate the use of stressors with a similar degree of saliency across species. The alpha-2 adrenoreceptor antagonist yohimbine represents an attractive experimental tool owing to its well-documented stress-inducing properties in humans and laboratory species. We investigated the neural substrates engaged by yohimbine in the rat brain by using functional magnetic resonance imaging and mapped their modulation by neurotransmitter systems involved in stress responses. Yohimbine elicited a composite pattern of brain activation, highlighting the recruitment of cortico-striato-thalamic regions and extra-hypothalamic stress neurocircuits. This effect was strongly attenuated by the α-2-adrenoceptor agonist medetomidine and by the dopamine (DA) D1 receptor antagonist SCH23390, thus revealing a primary contribution of both norepinephrine and DA on the neurofunctional cascade elicited by the drug. Pretreatment with the corticotrophin-releasing factor type-1 receptor (CRF1R) antagonist CP154,526 produced a region-dependent inhibition of yohimbine-induced activation in the amygdala, striatum, and cingulate cortex, while the orexin type-1 receptor (OX1R) antagonists GSK1059865 robustly inhibited the response in fronto-hippocampal regions as well as in several key components of the extended amygdala. CP154,526 and GSK1059865 did not prevent yohimbine-induced plasma corticosterone release, a finding that corroborates a central origin of the effects mapped. Our findings provide novel insight into the brain substrates and neurochemical mediators engaged by the stress-inducing agent yohimbine. The differential pattern of inhibition produced by CRF1R and OX1R antagonists suggests that these two neuropeptide systems can modulate the functional response to stress via distinct central neural pathways.