Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models

Anderson, Rachel I.; Becker, Howard C.; Adams, Benjamin L.; Jesudason, Cynthia D.; Rorick-Kehn, Linda

doi:10.3389/fnins.2014.00033

Cited by 78 publications

(132 citation statements)

References 31 publications

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“…By contrast, while antagonism of the OX 2 receptor by JNJ-10397049 reduces operant self-administration and acquisition, expression and reinstatement of CPP [116], TCS OX2 29 does not reduce cue-induced reinstatement of operant alcohol-seeking in male iP rats [118]. The OX 2 receptor antagonist LSN-2424100 does, however, reduce breakpoint on a progressive ratio in female iP rats [115] and ligands of both OX 1 and OX 2 as well as the DORA Almorexant have also recently been shown to reduce 'binge drinking' in C57BL/6J mice [115].…”

Section: Orexin and Alcoholmentioning

confidence: 56%

“…It makes little theoretical sense using a DORA to treat a patient with cocaine addiction, given that systemic administration of TCS OX2 29 has not been shown to affect cocaine selfadministration or cue-induced reinstatement while SB-334867 reduces reinstatement [124]. A patient with alcoholism, on the other hand, may benefit from a DORA because three separate preclinical studies, each from a different lab using a different OX 2 receptor antagonist, have all implicated the OX 2 receptor in alcohol consumption [115,116,118]. However, pharmaceutical companies may have insufficient incentive to develop an OX 1 receptor antagonist specifically for addictions where only OX 1 receptors are implicated when the DORAs for insomnia are on the verge of FDA and PMDA approval.…”

Section: Target Selection: Sora or Dora?mentioning

confidence: 95%

“…Systemic SB-334867 administration reduces operant responding for both alcohol and 0.5-0.7 % sucrose (w/v) under FR3, yet reduces the break-point for alcohol but not sucrose in male iP rats [171], though see [115] for conflicting data in female iP rats. SB-334867 reduces reinstatement of alcohol-seeking but not SuperSac (3 % glucose/0.125 % saccharin (w/v)) [172].…”

Section: Natural and Synthetic Reward Discriminationmentioning

confidence: 96%

“…Almorexant, a DORA first reported in the literature in 2007 [57], was shown to reduce cocaine and amphetamine CPP yet not morphine CPP [111]. Almorexant also reduces alcohol consumption in rat two-bottle free-choice and progressive ratio paradigms and the mouse drinking-in-thedark paradigm [115]. Moreover, rats do not learn CPP for Almorexant-paired contexts which suggests orexin antagonism itself is not rewarding [111].…”

Section: Drug Developmentmentioning

confidence: 96%

“…The OX 1 receptor is important for operant self-administration, home-cage alcohol consumption as well as cue-induced and stress-induced reinstatement of alcohol-seeking using SB-334867 in both outbred and inbred alcohol-preferring (iP) rats [112][113][114][115], however see [116] regarding null effects of SB-408124. Moreover, this effect of SB-334867 on cue-induced alcohol-seeking is observed both immediately after extinction as well as after a protracted period of abstinence [117].…”

Section: Orexin and Alcoholmentioning

confidence: 96%

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Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Khoo

Brown

2014

CNS Drugs

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Addiction is a chronic relapsing disorder which presents a significant global health burden and unmet medical need. The orexin/hypocretin system is an attractive potential therapeutic target as demonstrated by the successful clinical trials of antagonist medications like Suvorexant for insomnia. It is composed of two neuropeptides, orexin-A and orexin-B and two excitatory and promiscuous G-protein coupled receptors, OX1 and OX2. Orexins are known to have a variety of functions, most notably in regulating arousal, appetite and reward. The orexins have been shown to have a role in mediating the effects of several drugs of abuse, such as cocaine, morphine and alcohol via projections to key brain regions such as the ventral tegmental area, nucleus accumbens and prefrontal cortex. However, it has not yet been demonstrated whether the dual orexin receptor antagonists (DORAs) under development for insomnia are ideal drugs for the treatment of addiction. The question of whether to use a DORA or single orexin receptor antagonist (SORA) for the treatment of addiction is a key question that will need to be answered in order to maximize the clinical utility of orexin receptor antagonists. This review will examine the role of the orexin/hypocretin system in addiction, orexin-based pharmacotherapies under development and factors affecting the selection of one or both orexin receptors as drug targets for the treatment of addiction.

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Section: Orexin and Alcoholmentioning

confidence: 56%

Section: Target Selection: Sora or Dora?mentioning

confidence: 95%

Section: Natural and Synthetic Reward Discriminationmentioning

confidence: 96%

Section: Drug Developmentmentioning

confidence: 96%

Section: Orexin and Alcoholmentioning

confidence: 96%

See 3 more Smart Citations

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Khoo

Brown

2014

CNS Drugs

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Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol

Anderson

Moorman

Becker

2018

The Neuropharmacology of Alcohol

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Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders. These systems are also closely interrelated with one another - dynorphin/kappa opioid receptors and orexin/hypocretin receptors are found in similar regions and hypocretin/orexin neurons also express dynorphin - suggesting that these two systems may work together in the regulation of alcohol seeking and may be mutually disrupted in alcohol use disorders. This chapter reviews studies demonstrating a role for each of these systems in motivated behavior, with a focus on their roles in regulating alcohol-seeking and self-administration behaviors. Consideration is also given to evidence indicating that these neuropeptide systems may be viable targets for the development of potential treatments for alcohol use disorders.

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Orexin OX2 Receptor Antagonists as Sleep Aids

Jacobson

Chen

Mir

et al. 2016

Current Topics in Behavioral Neurosciences

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The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX and OX receptors (OXRs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OXR antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OXR antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OXR is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OXR antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OXR antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.

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Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models

Cited by 78 publications

References 31 publications

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol

Orexin OX2 Receptor Antagonists as Sleep Aids

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