The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat

Abstract

Dual orexin receptor (OXR) antagonists emerge as a novel therapeutic class to treat insomnia that, based on anti-addictive effects of selective OXR type 1 antagonists in rats, might be associated with less abuse liability than commonly used γ-aminobutyric acid (GABA) receptor modulators. Here, we studied the effects of the sleep-enabling dual OXR antagonist almorexant on conditioned place preference (CPP) and locomotor sensitization in rats. First, we compared almorexant to the GABA metabolite γ-hydroxybutyrate (GHB), which is clinically used as a sleep-inducing drug and which is associated with mild abuse liability. Whereas conditioning with GHB induced significant place preference, conditioning with almorexant did not. Second, we tested the potential of almorexant to interfere with the conditioned rewarding or locomotor sensitizing effects related to psychostimulants or opiates. Almorexant attenuated the expression of CPP to high doses of cocaine (15 mg/kg) and d.l-amphetamine (2 mg/kg), but not to high dose of morphine (10 mg/kg). Conversely, almorexant interfered with the expression of locomotor sensitization to morphine, but not with that to cocaine and d.l-amphetamine. Third, we observed that chronic almorexant (12 d) treatment in morphine, cocaine or amphetamine pre-conditioned and locomotor-sensitized rats had no influence on the maintenance of CPP and locomotor sensitization when tested after almorexant washout. Our findings suggest that almorexant itself does not exert conditioned rewarding effects in the rat and that it may acutely interfere with the expression of CPP or locomotor sensitization in a drug-dependent manner (monoaminergic psychostimulants vs. opiates).

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

“…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]. Although humans with experience of non-therapeutic use of depressants do not generally experience euphoria when given Almorexant, they do report liking the drug and make some comparisons with benzodiazepines and opiates [63], suggesting some abuse potential.…”

“…Orexin antagonists currently under development are mainly targeted to the treatment of sleep disorders and so their pharmacology and kinetics may not be optimal for treating addiction but there are some promising signs. 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].…”

“…This models binge drinking during the animal's active phase a There is much agreement that extinction is not erasure [210], however there is also experimental evidence which suggests that extinction causes at least partial erasure of the original memories-see [211] for review of heroin in an extended access model with systemic administration of an OX 2 receptor antagonist suggesting that the OX 2 receptor, at least in part, may mediate the reinforcing properties of opiates [110]. Yet the DORA Almorexant does not prevent the expression of morphine CPP suggesting neither OX 1 nor OX 2 mediate the conditioned rewarding effects of opiates [111]. Almorexant does, however, reduce the expression of locomotor sensitization to morphine [111].…”

“…Yet the DORA Almorexant does not prevent the expression of morphine CPP suggesting neither OX 1 nor OX 2 mediate the conditioned rewarding effects of opiates [111]. Almorexant does, however, reduce the expression of locomotor sensitization to morphine [111]. Thus, the role of orexins in mediating the central effects of opiates is multi-faceted, covering many aspects of addictive behavior.…”

“…Repeated SB-334867 administration does not reduce self-administration, but when used as an adjunct to extinction it allows pretreatment to reduce cue-induced reinstatement, but only if administered prior to the reinstatement session [136]. If the orexin antagonist is administered chronically and allowed to washout prior to test, no effect is seen on CPP [111] and the magnitude of reinstatement is actually increased [136]. These findings suggest an important role for the OX 1 receptor in cocaine-seeking behavior.…”