Table 3.
Summary of recent findings on orexin receptor antagonists for the treatment of drug addiction.
| Addictive drug | Manipulation | Target | Subjects | Findings | References |
|---|---|---|---|---|---|
| Cocaine | Suvorexant | dual OX1/2R | Rats | Attenuated acute cocaine-induced impulsivity when administered systemically or directly into the ventral tegmental area. | Gentile et al. [113] |
| Suvorexant | dual OX1/2R | Rats | Attenuated motivational and hedonic properties of cocaine. | Gentile et al. [114] | |
| SB-334867 | OX1R | Rats | Reduced the acquisition and expression of cocaine self-administration and expression of amphetamine-induced conditioned place preference. | Hutcheson et al. [108] | |
| SB-334867 | OX1R | Rats | Systemic administration decreased cocaine intake specifically in prolonged-access rats; microinjections into the central nucleus of the amygdala reduced cocaine intake in prolonged-access rats and attenuated yohimbine-induced reinstatement of cocaine seeking. | Schmeichel et al. [111] | |
| SB-334867 | OX1R | Mice | Intra-ventral tegmental area microinjections of orexin-A reinstated extinguished cocaine-induced conditioned place preference in wildtype mice, which was blocked by SORA1 SB-334867. | Tung et al. [85] | |
| SB-334867 | OX1R | Mice | Intra-ventral tegmental area injections decreased cocaine self-administration, lateral hypothalamus self-stimulation, and impulsive-like behavior, which were reversed by dynorphin antagonism. | Muschamp et al. [104] | |
| SB-334867 | OX1R | Rats | Reduced the motivation for cocaine and attenuated the addiction phenotype. | James et al. [106] | |
| SB-334867 | OX1R | Female rhesus monkeys | Decreased cocaine self-administration. | Foltin et al. [107] | |
| SB-334867 | OX1R | Rats | Reduced cocaine demand in the presence of cocaine-associated cues and blocked cue-induced reinstatement. | Bentzley et al. [109] | |
| SB-334867 | OX1R | Rats | SB-334867 but not the SORA2 4PT attenuated the cocaine-induced inhibition of dopamine uptake and reduced cocaine self-administration. | Prince et al. [110] | |
| Almorexant | dual OX1/2R | Rats | Attenuated the cocaine-induced inhibition of dopamine uptake and reduced cocaine self-administration. | Prince et al. [110] | |
| RTIOX-276 | OX1R | Rats | Systemic administration decreased high-effort responding for cocaine and reduced the inhibition of cocaine-induced dopamine uptake. | Levy et al. [112] | |
| Alcohol | Suvorexant | dual OX1/2R | Rats | Dose-dependently decreased the latency to REM sleep and SWS onset and produced REM sleep and SWS fragmentation in rats exposed to chronic intermittent alcohol and protracted withdrawal. | Sanchez-Alavez et al. [138] |
| Almorexant | dual OX1/2R | Healthy humans | Did not potentiate impairing effects of alcohol. | Hoch et al. [137] | |
| Almorexant | dual OX1/2R | Rats | Systemic or intra-ventral tegmental area administration decreased alcohol self-administration. | Srinivasan et al. [135] | |
| Almorexant | dual OX1/2R | Rats | Did not interfere with forced motor performance or grip strength in rats and did not further increase the sedative effects of alcohol. | Steiner et al. [136] | |
| SB-334867 | OX1R | Rats | Intra-nucleus accumbens infusions decreased alcohol intake and preference. | Mayannavar et al. [118] | |
| SB-334867 | OX1R | Rats | Reduced alcohol relapse drinking. | Dhaher et al. [120] | |
| SB-334867 | OX1R | Rats | Attenuated alcohol self-administration and the cue-induced reinstatement of alcohol-seeking in highly motivated rats. | Moorman et al. [121] | |
| GSK1059865 | OX1R | Mice | Reduced alcohol drinking in alcohol-dependent mice but had no effect on sucrose intake. | Lopez et al. [119] | |
| TCS-OX2-29 | OX2R | Rats | Microinjections of TCS-OX2-29 but not SB-334867 into the anterior paraventricular nucleus of the thalamus decreased intermittent-access alcohol drinking. | Barson et al. [132] | |
| Opioids | SB-334867 | OX1R | Mice | Inhibited the acquisition of morphine-induced locomotor sensitization. | Łupina et al. [123] |
| SB-334867 | OX1R | Rats | Intra-locus coeruleus microinjections significantly attenuated somatic signs of naloxone-induced morphine withdrawal, which was blocked by the GABAA receptor antagonist bicuculline. | Davoudi et al. [127] | |
| SB-334867 | OX1R | Rats | Intra-locus coeruleus microinjections attenuated the expression of glutamate-induced morphine withdrawal during the active phase. | Hooshmand et al. [128] | |
| SB-334867 | OX1R | Mice | Systemic administration significantly attenuated naloxone-induced morphine withdrawal symptoms. | Sharf et al. [126] | |
| SB-334867 | OX1R | Mice | Significantly attenuated morphine-induced conditioned place preference but not morphine-induced hyperactivity or sensitization. | Sharf [144] | |
| SB-334867 | OX1R | Rats | Intra-ventral tegmental area microinjections significantly attenuated the acquisition and expression of morphine-induced conditioned place preference. | Farahimanesh et al. [129] | |
| SB-334867 | OX1R | Rats | Intra-dentate gyrus administration dose-dependently attenuated morphine priming-induced reinstatement. | Ebrahimian et al. [130] | |
| SB-334867 | OX1R | Rats | Reduced motivation and the cue-induced reinstatement of remifentanil-seeking in low takers. | Porter-Stransky et al. [125] | |
| NBI-80713 | OX2R | Rats | Systemic administration dose-dependently decreased heroin self-administration in prolonged-access rats and had no effect on food pellet self-administration. | Schmeichel et al. [133] | |
| TCS-OX2-29 | OX2R | Rats | Intra-ventral tegmental area microinjections significantly attenuated the acquisition and expression of morphine-induced conditioned place preference. | Farahimanesh et al. [129] | |
| TCS-OX2-29 | OX2R | Rats | Intra-dentate gyrus administration dose-dependently attenuated morphine priming-induced reinstatement. | Ebrahimian et al. [130] | |
| Amphetamine | Almorexant | dual OX1/2R | Rats | Attenuated the expression of cocaine- and amphetamine-induced conditioned place preference but not morphine-induced conditioned place preference; interfered with the expression of morphine-induced locomotor sensitization but not cocaine- or amphetamine-induced locomotor sensitization. | Steiner et al. [134] |
| SB-334867 | OX1R | Rats | Reduced amphetamine-induced dopamine outflow in the nucleus accumbens shell and decreased the expression of amphetamine sensitization. | Quarta et al. [122] | |
| Cannabis | SB334867 | OX1R | Mice | Systemic SB334867 administration but not the SORA2 TCSOX229 reduced the reinforcing and motivational properties of the synthetic cannabinoid agonist WIN55,212-2. | Flores et al. [145] |
| Nicotine | TCS 1102 | dual OX1/2R | Rats | No effect on the reinstatement of nicotine seeking. | Khoo et al. [143] |
| SB334867 | OX1R | Mice | SB334867 but not the SORA2 TCS-OX2-29 attenuated somatic signs of nicotine withdrawal. | Plaza-Zabala et al. [140] |
OX1R, orexin type 1 receptor; OX2R, orexin type 2 receptor; REM, rapid-eye-movement; SWS, slow-wave sleep; SORA1, selective orexin receptor 1 antagonist; SORA2, selective orexin receptor 2 antagonist; DORA, dual orexin receptor 1/2 antagonist.