Hypocretin receptor 1 involvement in cocaine-associated behavior: Therapeutic potential and novel mechanistic insights

Brodnik, Zachary D.; Alonso, I. Pamela; Xu, Wei; Zhang, Yanan; Kortagere, Sandhya; España, Rodrigo A.

doi:10.1016/j.brainres.2018.07.027

Cited by 20 publications

(26 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Test days were separated by at least two regular sessions, and continued until Qo and α values were stable, i.e., within ± 25% of pre-treatment values (baseline); this allowed us to test and account for potential persistent effects of suvorexant on subsequent sessions [15,31].…”

Section: Experiments 1: Efficacy Of Systemic Suvorexant Administrationmentioning

confidence: 99%

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

O’Connor¹,

Fragale²,

James³

et al. 2020

Preprint

View full text Add to dashboard Cite

The orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD).Suvorexant (Belsomra TM ) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.

show abstract

Section: Experiments 1: Efficacy Of Systemic Suvorexant Administrationmentioning

confidence: 99%

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

O’Connor¹,

Fragale²,

James³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Treatment order was assigned pseudorandomly with all rats receiving 30 mg/kg on their final test. This was done to alleviate any concerns regarding a possible long duration of effects with 30 mg/kg SB (Brodnik et al, 2018).…”

Section: Within-session Behavioral Economics Proceduresmentioning

confidence: 99%

The Role of Orexin-1 Receptor Signaling in Demand for the Opioid Fentanyl

Fragale

Pantazis

James

et al. 2019

Preprint

View full text Add to dashboard Cite

The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand for all opioids, particularly ones with particularly high abuse liability. Here, we establish a behavioral economics (BE) procedure to assess the effects of OxR1 antagonism on demand for the highly abused opioid fentanyl. We also investigate the utility of our novel procedure in predicting OxR1 antagonism efficacy and relapse propensity. The OxR1 antagonist SB-334867 (SB) increased demand elasticity (a; decreased motivation) for fentanyl without affecting preferred consumption of fentanyl at null cost (Qo). Baseline a values predicted SB efficacy, such that SB was most effective at increasing demand elasticity in highly motivated rats. SB also attenuated cue-induced fentanyl seeking and baseline a values predicted the amount of reinstatement behavior. These results highlight the promise of the orexin system as a treatment target for opioid addiction and emphasize the usefulness of BE procedures in the study of opioid abuse. * * C.

show abstract

“…Orexin peptides A and B (also known as hypocretin 1 and 2) are produced by hypothalamic neurons Sakurai et al, 1998b) and are important for motivation for food and drugs of abuse (Barson, 2018;Borgland et al, 2009;Brodnik et al, 2018;Choi et al, 2010;Harris et al, 2005;Mahler et al, 2014a;Walker and Lawrence, 2017;Yeoh et al, 2018). Orexinergic fibers project widely throughout the brain (Baldo et al, 2003; to release orexin peptides A and B which act at two G-protein coupled receptors, orexin receptor 1 and 2 (Ox1R and Ox2R) Hervieu et al, 2001;Marcus et al, 2001;Sakurai et al, 1998a).…”

Section: Introductionmentioning

confidence: 99%

“…Orexinergic fibers project widely throughout the brain (Baldo et al, 2003; to release orexin peptides A and B which act at two G-protein coupled receptors, orexin receptor 1 and 2 (Ox1R and Ox2R) Hervieu et al, 2001;Marcus et al, 2001;Sakurai et al, 1998a). Studies generally support a dichotomy of function for Ox1R versus Ox2R signaling, whereby signaling at Ox1R is important for motivation and reward, and signaling at Ox2R is more involved in arousal processes (Brodnik et al, 2018). Accordingly, a significant body of literature shows that administration of Ox1R antagonists, either systemically or locally into reward regions, attenuates a broad range of drug-seeking behaviors (Bentzley and Aston-Jones, 2015;Espana et al, 2010;Harris et al, 2005;James et al, 2011;James et al, 2018a;Jupp et al, 2011;Mahler et al, 2013;Moorman et al, 2017;Porter-Stransky et al, 2017;Schmeichel et al, 2017;Smith and Aston-Jones, 2012).…”

Section: Introductionmentioning

confidence: 99%

Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast acting opioid remifentanil

Mohammadkhani

James

Aston‐Jones

2019

Preprint

View full text Add to dashboard Cite

For submission to the special issue: 'Orexin/hypocretin receptor antagonists for the treatment of addiction and related psychiatric disease: What are the steps from here?' (Eds. Aston-Jones and James). Abstract:The orexin (hypocretin) system is important for reward-seeking behavior. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of food and drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the shortacting opioid remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24h, but not on a third test at 48h. When injected locally into caudal ventral pallidum (cVP) the effects of SB were more persistent, with reduced motivation observed for up to 48h. We next made SB injections into cVP 24h prior to behavioral testing; this produced persistent effects that persisted for at least 72h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24h prior. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations might have important ramifications for the future clinical use of orexin receptor antagonists for the treatment of addiction.

show abstract

Hypocretin receptor 1 involvement in cocaine-associated behavior: Therapeutic potential and novel mechanistic insights

Cited by 20 publications

References 98 publications

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

The Role of Orexin-1 Receptor Signaling in Demand for the Opioid Fentanyl

Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast acting opioid remifentanil

Contact Info

Product

Resources

About