Hypocretin/orexin deficiency decreases cocaine abuse liability

Abstract

Compelling evidence indicates that hypocretin/orexin signaling regulates arousal, stress and reward-seeking behaviors. However, most studies on drug reward-related processes have so far described the effects of pharmacological blockers disrupting hypocretin/orexin transmission. We report here an extensive study on cocaine-related behaviors in hypocretin/orexin-deficient mice (KO) and their heterozygous (HET) and wildtype (WT) littermates. We evaluated behavioral sensitization following repeated administrations and preference for an environment repeatedly paired with cocaine injections (15 mg/kg). Mice were also trained to self-administer cocaine (0.5-1.5 mg/kg/infusion). Our observations show that whereas all mice exhibited quite similar responses to acute administration of cocaine, only Hcrt KO mice exhibited reduced cocaine-seeking behaviors following a period of abstinence or extinction, and reduced cocaine incubation craving. Further, if the present findings confirm that Hcrt deficient mice may display a hypoactive phenotype, possibly linked to a reduced alertness concomitant to a decreased exploration of their environment, hypocretin/orexin defiency did not cause any attentional deficit. We thus report that innate disruption of hypocretin/orexin signaling moderately alters cocaine reward but significantly reduces long-term affective dependence that may explain the lack of relapse for cocaine seeking seen in Hcrt KO mice. Overall, with blunted cocaine intake at the highest concentration and reduced responsiveness to cocaine cues after prolonged abstinence, our findings suggest that hypocretin deficient mice may display signs of resilience to cocaine addiction.

Activation of lateral hypothalamic group III mGluRs suppresses drug-seeking following abstinence and cocaine-associated increases in excitatory drive to orexin/hypocretin cells

“…indicates that this behavioral effect was mediated by a suppression of orexin cell activity elicited by the drug-context. This finding aligns well with previous studies that have reported reduced stimulus-driven cocaine-seeking following abstinence or extinction in orexin knockout mice (Steiner et al, 2018) or following either systemic or local pretreatment with an orexin-1 receptor antagonist (Smith et al, 2010;James et al, 2011;Mahler et al, 2013).…”

“…Therefore, some caution should be taken when considering how our electrophysiological findings relate to the reported behavioral data, and vice versa. However, we note that all published literature to date points to a large degree of overlap in the orexin system between rat and mouse in terms of topography (de Lecea et al, 1998;Sakurai et al, 1998;Sakurai et al, 1999;Stricker-Krongrad et al, 2002), projections and receptor distribution (Peyron et al, 1998;Chen et al, 1999;Marcus et al, 2001;Lin et al, 2002;Puskás et al, 2010;Ch'ng & Lawrence, 2015), electrophysiological properties (Yeoh et al, 2012) and role in reward-seeking behaviors (James et al, 2017b;Schmeichel et al, 2018;Steiner et al, 2018). Moreover, we have previously reported that plasticity at orexin cells occurs similarly between rats that self-administer cocaine and mice that receive experimenter-administered cocaine (as was the case here) on d1 of withdrawal (Yeoh et al, 2012).…”

The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

“…Thus, higher expression and/or activation of these cells may attach greater motivational significance to cocaine‐associated stimuli and result in greater motivation (demand) for cocaine. A recent study in hypocretin/orexin knockout mice demonstrated that animals lacking the neuropeptide have reduced incubation of cocaine craving and do not reinstate drug‐seeking in response to cocaine‐paired cues . Greater numbers of cells promoting cue reactivity in high motivation animals may also explain our previous finding that animals with low α measured in BE have greater cue‐induced reinstatement of cocaine seeking .…”

The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

“…We proposed that orexin signaling translates motivational drive into behavioral output (Mahler, Moorman, Smith et al, 2014), particularly in response to drug-associated cues and (Steiner, Rossetti, Sakurai et al, 2018). Greater numbers of cells promoting cue reactivity in high motivation animals may also explain our previous finding that animals with low α measured in BE have greater cue-induced reinstatement of cocaine seeking (Bentzley, Jhou & Aston-Jones, 2014).…”