Hypocretin/orexin knock‐out mice display disrupted behavioral and dopamine responses to cocaine

Shaw, Jessica K.; Ferris, Mark J.; Locke, Jason L.; Brodnik, Zachary D.; España, Rodrigo A.

doi:10.1111/adb.12432

Cited by 34 publications

(25 citation statements)

References 49 publications

(77 reference statements)

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“…Though, Hcrt KO mice have been shown to display disrupted dopamine signaling and attenuated dopamine responses to cocaine (Espana et al, 2010;Shaw et al, 2016), which contrasts with our findings. However, dopamine is not critical for developing cocaine-induced CPP since dopamine deficient mice display normal CPP possibly through serotonin signaling (Hnasko et al, 2007).…”

Section: Discussioncontrasting

confidence: 99%

Hypocretin/orexin deficiency decreases cocaine abuse liability

et al. 2018

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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.

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Section: Discussioncontrasting

confidence: 99%

Hypocretin/orexin deficiency decreases cocaine abuse liability

et al. 2018

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“…Cyclic voltammograms were recorded at the carbon fiber electrode every 100 ms with a scan rate of 400 V/s using a voltammeter/amperometer (Chem-Clamp; Dagan Corporation, Minneapolis, MN). Carbon fiber and stimulating electrode positions were maximized until a 1 s, 60 Hz monophasic (4 ms; 500–750 μA) stimulation train elicited a robust DA signal as previously described (España et al 2011; España et al 2010; Prince et al 2015; Shaw et al 2016). After collecting stable baselines (< 10% variation) in the NAc core at 5 min intervals, rats received an i.p.…”

Section: Methodsmentioning

confidence: 99%

“…HCRT signaling has been implicated in arousal and sleep/wake transitions, stress, homeostatic regulation, cognition, and motivation (Berridge et al 2010; Mahler et al 2014), and accumulating evidence indicates that HCRT signaling influences cocaine reward-related behavior (España et al 2011; España et al 2010; Mahler et al 2012; Shaw et al 2016). This modulation of cocaine taking appears to be predominately associated with actions at HCRTr1 versus HCRT receptor 2 (Prince et al 2015; Smith et al 2009), and extensive investigation into these effects has shown that HCRTr1 blockade reduces distinct features of cocaine self-administration (Bentzley and Aston-Jones 2015; Borgland et al 2009; Brodnik et al 2015; Calipari and España 2012; Mahler et al 2012).…”

Section: Introductionmentioning

confidence: 99%

“…These excitatory effects are likely driven by actions at HCRTr1 (Borgland et al 2009; Tung et al 2016), as blockade of HCRTr1 reduces VTA DA neuron activity (Moorman and Aston-Jones 2010). In consideration of this evidence, it has been posited that the effects of HCRTr1 inhibition on cocaine self-administration are mediated through modulation of mesolimbic DA activity (Baimel et al 2012; Borgland et al 2009; Borgland et al 2006; Calipari and España 2012; España 2012; España et al 2011; España et al 2010; Moorman and Aston-Jones 2010; Prince et al 2015; Shaw et al 2016). Indeed, blockade of HCRTr1 attenuates cocaine-induced increases in DA tone and reduces cocaine-induced DA uptake inhibition following stimulated DA release (España et al 2010; Prince et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

et al. 2017

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Rationale Cocaine addiction is a chronic psychiatric disorder characterized by pathological motivation to obtain cocaine and behavioral and neurochemical hypersensitivity to cocaine-associated cues. These features of cocaine addiction are thought to be driven by aberrant phasic dopamine signaling. We previously demonstrated that blockade of the hypocretin receptor 1 (HCRTr1) attenuates cocaine self-administration and reduces cocaine-induced enhancement of dopamine signaling. Despite this evidence, the effects of HCRTr1 blockade on endogenous phasic dopamine release are unknown. Objective In the current studies we assessed whether blockade of HCRTr1 alters spontaneous and cue-evoked dopamine release in the nucleus accumbens core of freely moving rats. Methods We first validated the behavioral and neurochemical effects of the novel, highly selective, HCRTr1 antagonist RTIOX-276 using cocaine self-administration and fast-scan cyclic voltammetry (FSCV) in anesthetized rats. We then used FSCV in freely moving rats to examine whether RTIOX-276 impacts spontaneous and cue-evoked dopamine release. Finally, we used ex vivo slice FSCV to determine whether the effects of RTIOX-276 on dopamine signaling involve dopamine terminal adaptations. Results Doses of RTIOX-276 that attenuate the motivation for cocaine reduce spontaneous dopamine transient amplitude and cue-evoked dopamine release. Further, these doses attenuated cocaine-induced dopamine uptake inhibition at the level of DA terminals. Conclusion Our results provide support for the standing hypothesis that HCRTr1 blockade suppresses endogenous phasic dopamine signals, likely via actions at dopamine cell bodies. These results also elucidate a second process through which HCRTr1 blockade attenuates the effects of cocaine by reducing cocaine sensitivity at dopamine terminals.

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“…In a conditioned place preference paradigm in which animals are conditioned to associate a distinct chamber with experimenter-administered cocaine, the dual OX receptor antagonist almorexant is found to reduce the expression of this place preference (Steiner, Lecourt, & Jenck, 2013), similar to the effect produced by knockout of the OX gene (Shaw et al, 2016). Conversely, direct injection of OX-A into the ventral tegmental area is sufficient to reinstate an extinguished place preference (Tung et al, 2016).…”

Section: Role Of Orexin/hypocretin In Non-homeostatic Intakementioning

confidence: 99%

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

Barson

Leibowitz

2017

International Review of Neurobiology

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The neuropeptide orexin/hypocretin (OX), while largely transcribed within the hypothalamus, is released throughout the brain to affect complex behaviors. Primarily through the hypothalamus itself, OX homeostatically regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, through extra-hypothalamic limbic brain regions, OX promotes seeking and intake of rewarding substances of abuse, like palatable food, alcohol, nicotine, and cocaine. This neuropeptide, in turn, is stimulated by the intake of or early life exposure to these substances, forming a non-homeostatic, positive feedback loop. The OX receptor involved in these behaviors, adaptive behavior or substance seeking and intake, is dependent on the particular brain region that contributes to them. Thus, we propose that, while the primary function of OX is to maintain arousal for the performance of adaptive behaviors, this neuropeptide system is readily coopted by rewarding substances that involve positive feedback, ultimately promoting their abuse.

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Hypocretin/orexin knock‐out mice display disrupted behavioral and dopamine responses to cocaine

Cited by 34 publications

References 49 publications

Hypocretin/orexin deficiency decreases cocaine abuse liability

Hypocretin/orexin deficiency decreases cocaine abuse liability

Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

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