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

Abstract

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.

Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice

“…In addition, alcohol-quinine drinking was not reduced by an OX2R antagonist, suggesting that OX regulated compulsive-like drinking in a receptor-specific manner. Together, our results indicate that compulsive-like drinking, compared to alcohol-only intake, was selectively and more sensitively regulated by OX1Rs, and that OX1Rs may represent a potentially effective and immediately available therapy (Khoo and Brown, 2014; Li et al, 2016) to address compulsive aspects of human AUDs.…”

“…OX and OX1R signaling could represent an important and interesting mechanism that promotes compulsive-like alcohol drinking, with possible utility for clinical and therapeutic settings (Khoo and Brown, 2014; Li et al, 2016). …”

Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking

“…Since OX1Rs play a predominant role in driving motivated intake (see above), and excessive drinking in humans is driven by pathological drives for alcohol, our results suggest that the mNAsh is a key region where OX1Rs can promote excessive alcohol intake. Thus, OX1R inhibitors might represent a viable therapeutic intervention to suppress alcohol drinking in humans (Khoo and Brown, 2014; Li et al, 2016). …”

“…For example, OX1Rs mediate greater alcohol preference and intake in rats (Moorman and Aston-Jones, 2009) and increased alcohol drinking in dependent mice (Lopez et al, 2016). Thus, OX1R signaling could represent an important and novel clinical and therapeutic target for intervention for AUDs (Khoo and Brown, 2014; Li et al, 2016). …”

Orexins and fear: implications for the treatment of anxiety disorders

“…Accordingly, direct injections of orexin A in the ventral tegmental area increase dopamine levels in the nucleus accumbens [86,87]. Although most of the research on the involvement of orexins in drug addiction has focused on elucidating the function of OX1R [84,88], recent studies point to a role for OX2R in reward regulation. Thus, antagonism of OX2R reduces heroin [89] and ethanol-self administration [90], as well as cue-induced reinstatement of nicotine-seeking behavior [91].…”