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

Yeoh, Jiann Wei; James, Morgan H.; Adams, Cameron D.; Bains, Jaideep S.; Sakurai, Takeshi; Aston‐Jones, Gary; Graham, Brett A.; Dayas, Christopher V.

doi:10.1016/j.neuropharm.2018.09.033

Cited by 15 publications

(12 citation statements)

References 72 publications

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“…It may be interesting to investigate this given that OxR1 antagonists have been shown to block cocaine-induced increases in impulsivity in the 5-CSRTT (Gentile et al, 2017;Muschamp et al, 2014). Recent evidence from our lab and others also demonstrated that drug exposure or a history of high fat food intake can increase the number and excitability of orexin-expressing neurons (James et al, 2018b;Lawrence et al, 2006;Park et al, 2004;Thannickal et al, 2018;Yeoh et al, 2012;Yeoh et al, 2018). Thus, it cannot be ruled out that the role of orexin signaling in executive functions such as response inhibition changes following exposure to drugs of abuse or following a period of overconsumption of palatable food.…”

Section: Orexin Signaling and Inhibitory Controlmentioning

confidence: 98%

“…First, Ox1R signaling has been implicated in several psychiatric disorders that are commonly associated with deficient impulse control. Most notably, addiction is associated with higher numbers, activity and excitability of orexin cells (James et al, 2018b;Lawrence et al, 2006;Moorman et al, 2016;Pantazis et al, 2019;Thannickal et al, 2018;Yeoh et al, 2012Yeoh et al, , 2018, and SB is highly effective at reducing several addiction-related behaviors in rodents (Brodnik et al, 2018;Campbell et al, 2018;James et al, 2017James et al, , 2018aMartin-Fardon and Weiss, 2014a,b;Moorman et al, 2017;Perrey and Zhang, 2018;Schmeichel et al, 2017). Secondly, orexin neurons are interconnected with a variety of brain regions (e.g.…”

Section: Orexin Signaling and Inhibitory Controlmentioning

confidence: 99%

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The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

2020

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There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this receptor affects cognitive functioning. Response inhibition-the ability to cancel ongoing behavior-is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop-signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards, consistent with other recent findings. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug-seeking behavior are not related to effects on response inhibition.

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Section: Orexin Signaling and Inhibitory Controlmentioning

confidence: 98%

Section: Orexin Signaling and Inhibitory Controlmentioning

confidence: 99%

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

2020

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“…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%

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

Mohammadkhani

James

Aston‐Jones

2019

Preprint

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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.

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“…It may be interesting to investigate this given that OxR1 antagonists have been shown to block cocaine-induced increases in impulsivity in the 5-CSRTT (Gentile et al, 2017;Muschamp et al, 2014). Recent evidence from our lab and others also demonstrated that drug exposure or a history of high fat food intake can increase the number and excitability of orexinexpressing neurons (James et al, 2018b;Lawrence et al, 2006;Park et al, 2004;Thannickal et al, 2018;Yeoh et al, 2012;Yeoh et al, 2018). Thus, it cannot be ruled out that the role of orexin signaling in executive functions such as response inhibition changes following exposure to drugs of abuse or following a period of overconsumption of palatable food.…”

Section: Orexin Signaling and Inhibitory Controlmentioning

confidence: 97%

“…First, Ox1R signaling has been implicated in several psychiatric disorders that are commonly associated with deficient impulse control. Most notably, addiction is associated with higher numbers, activity and excitability of orexin cells (James et al, 2018b;Lawrence et al, 2006;Moorman et al, 2016;Thannickal et al, 2018;Yeoh et al, 2012;Yeoh et al, 2018), and SB is highly effective at reducing several addictionrelated behaviors in rodents (Brodnik et al, 2018;Campbell et al, 2018;James et al, 2017;James et al, 2018a;Martin-Fardon and Weiss, 2014a;Martin-Fardon and Weiss, 2014b;Moorman et al, 2017;Perrey and Zhang, 2018;Schmeichel et al, 2017). Secondly, orexin neurons are interconnected with a variety of brain regions (e.g.…”

Section: Orexin Signaling and Inhibitory Controlmentioning

confidence: 99%

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

Wiskerke

James

Aston‐Jones

2018

Preprint

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Authors contributed equallyHighlights  Orexin-1 receptor antagonists hold great promise for treatment of drug addiction  These compounds are thought to reduce motivation for drug seeking  Less is known about effects of orexin-1 receptor blockade on cognitive functioning  We tested the orexin-1 receptor antagonist SB-334867 in a rat stop signal task  SB-334867 reduced task motivation but had little effect on executive control as measured with response inhibition AbstractThere is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this receptor affects cognitive functioning. Response inhibition -the ability to cancel ongoing behavior -is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug seeking behavior are not related to effects on response inhibition. Abbreviations 5-CSRTT = five choice serial reaction time task DMH/PF = dorsomedial hypothalamus and perifornical area GoRT = Go trial reaction time ICV = intra-individual coefficient of variation LH = lateral hypothalamus MT = movement time OxR1 and OxR2 = orexin-1 and orexin-2 receptors SB = SB-334867, orexin-1 receptor antagonist SSD = stop signal delay SSRT = stop signal reaction time SST = stop signal task WT = stop trial wait time

show abstract

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

Cited by 15 publications

References 72 publications

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

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

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

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