Orexin‐1 receptor signaling increases motivation for cocaine‐associated cues

Abstract

The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at orexin-1 receptors (OX1R), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light+tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then asked if cocaine demand is linked to cued-reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high demand animals, i.e., animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not for cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.

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

“…Indeed, the ORX system also plays a major role in motivation for other drugs of abuse. Of note with respect to our findings, is the fact that, whereas OX1R antagonism had no effect on steady maintenance of FR1 cocaine self-administration (Smith et al, 2009), blockade at these receptors significantly reduced enhanced motivation for cocaine seen in studies using higher ratios (Hollander et al, 2012), progressive ratios (Espana et al, 2010), and behavioral economic-type threshold procedures (Bentzley and Aston-Jones, 2015; Espana et al, 2010). A similar inhibitory influence of OX1R antagonism has been seen for seeking of heroin (Smith and Aston-Jones, 2012), cannabinoids (Flores et al, 2014), nicotine (Hollander et al, 2008; Plaza-Zabala et al, 2013), and highly palatable food rewards (Borgland et al, 2009; Cason and Aston-Jones, 2013b; Cason and Aston-Jones, 2014; Choi et al, 2010; Kay et al, 2014; Sharf et al, 2010).…”

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats

“…Further, a number of previous studies have shown that the ORX system is particularly involved in elevated motivation for drugs of abuse and natural rewards. OX1R antagonism does not decrease FR1 cocaine self-administration (Smith et al, 2009), but does decrease cocaine seeking in FR5 testing (Hollander et al, 2012), progressive ratio (Espana et al, 2010), and behavioral economic-type measures of enhanced motivation for cocaine (Bentzley and Aston-Jones, 2015; Espana et al, 2010). With respect to natural rewards, the ORX system has been shown to be more involved in the enhanced motivation for highly-palatable rewards, such as chocolate, as compared to lower motivation associated with less-preferable rewards such as rodent chow (Borgland et al, 2009).…”

“…The OX1R-selective antagonist SB-334867 (SB) decreases seeking of multiple drugs of abuse (Bentzley and Aston-Jones, 2015; James et al, 2012; Mahler et al, 2012; Plaza-Zabala et al, 2012; Porter-Stransky et al, 2015). There is a particularly (though not exclusively) (Anderson et al, 2014; Barson et al, 2015; Brown et al, 2013b; Shoblock et al, 2011) strong relationship between the OX1R vs OX2R and alcohol seeking.…”

Role of hypocretin/orexin receptor blockade on drug-taking and ultrasonic vocalizations (USVs) associated with low-effort self-administration of cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV) in rats

“…A series of prior research reports demonstrated that hcrt/ox functionally contributes to motivational effects of psychostimulant drugs. Hcrt/ox antagonists reduce drug-taking predominantly in tasks requiring more effort to receive intravenous drug infusions (e.g., Bentzley and Aston-Jones 2015; Brodnik et al 2015). In the present report, suvorexant failed to significantly suppress drug-taking (Figure 2A).…”

“…In 2005, Aston-Jones and colleagues provided evidence that neurons producing hcrt/ox express the neuronal activity marker c-Fos after exposure to a chamber paired with palatable food or morphine, and that intra-VTA hcrt/ox receptor blockade reduces reinstatement of place preference for a morphine-paired context (Harris et al 2005). Research teams have since demonstrated that blocking OX 1 R transmission by systemic or intra-VTA injection reduces motivated responding and reinstated reward-seeking behavior for palatable reinforcers including self-administered cocaine (Bentzley and Aston-Jones 2015; Borgland et al 2009; Boutrel et al 2005; James et al 2011; Muschamp et al 2014; Smith et al 2010). Reward suppression following hcrt/ox receptor antagonism may be driven in part by reductions in psychostimulant-evoked dopamine efflux within ventral striatum as has been supported using in vivo fast-scan cyclic voltammetry (España et al 2011; España et al 2010).…”