Targeting the Orexin System for Prescription Opioid Use Disorder

Matzeu, Alessandra; Martin‐Fardon, Rémi

doi:10.3390/brainsci10040226

Cited by 17 publications

(14 citation statements)

References 133 publications

(210 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several recent reviews have comprehensively summarized the literature on the role of the paraventricular nucleus of the thalamus (PVT) in reward-seeking (James and Dayas, 2013 ; Kirouac, 2015 ; Do-Monte and Kirouac, 2017 ; Millan et al, 2017 ; Zhou and Zhu, 2019 ; Matzeu and Martin-Fardon, 2020 ). Based on a growing body of evidence, a consensus is emerging that PVT is part of a network that mediates appetitive/approach and aversive/avoidance behaviors, particularly during motivational conflicts (Choi and McNally, 2017 ; Choi et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity in the Paraventricular Thalamus: The Traffic Light of Motivated Behaviors

McGinty

Otis

2020

Front. Behav. Neurosci.

View full text Add to dashboard Cite

The paraventricular thalamic nucleus (PVT) is highly interconnected with brain areas that control reward-seeking behavior. Despite this known connectivity, broad manipulations of PVT often lead to mixed, and even opposing, behavioral effects, clouding our understanding of how PVT precisely contributes to reward processing. Although the function of PVT in influencing reward-seeking is poorly understood, recent studies show that forebrain and hypothalamic inputs to, and nucleus accumbens (NAc) and amygdalar outputs from, PVT are strongly implicated in PVT responses to conditioned and appetitive or aversive stimuli that determine whether an animal will approach or avoid specific rewards. These studies, which have used an array of chemogenetic, optogenetic, and calcium imaging technologies, have shown that activity in PVT input and output circuits is highly heterogeneous, with mixed activity patterns that contribute to behavior in highly distinct manners. Thus, it is important to perform experiments in precisely defined cell types to elucidate how the PVT network contributes to reward-seeking behaviors. In this review, we describe the complex heterogeneity within PVT circuitry that appears to influence the decision to seek or avoid a reward and point out gaps in our understanding that should be investigated in future studies.

show abstract

Section: Introductionmentioning

confidence: 99%

Heterogeneity in the Paraventricular Thalamus: The Traffic Light of Motivated Behaviors

McGinty

Otis

2020

Front. Behav. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The role of orexin in promoting arousal and waking from sleep has been well documented, with evidence showing that orexin plays a critical role in the regulation of sleep-to-wake transitions [ 3 , 17 ]. Additionally, an orexin deficiency is observed in narcolepsy, a disorder characterized by excessive sleepiness, sleep paralysis, and in some cases, episodes of cataplexy [ 3 , 17 ].…”

Section: Overview Of Physiological Roles Of the Orexin Systemmentioning

confidence: 99%

“…Neuropeptides orexin A and orexin B were first described in the late 1990s and were initially shown to regulate feeding behaviour [ 1 , 2 ]. Since their discovery, it has been shown that orexins are involved in diverse functions that range from the modulation of autonomic functions (i.e., food intake, sleep regulation, and cardiovascular function), and promotion of physical activity, as well as reward-seeking behaviour and higher cognitive functions, including attention, cognition, and mood [ 3 , 4 ]. While the roles of orexin in the regulation of food intake, sleep/wake cycles, and addictive behaviours have been extensively studied and reviewed [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ], the role of these peptides in the modulation of mood and affect has not been as thoroughly explored.…”

Section: Introductionmentioning

confidence: 99%

Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone

Katzman

2022

Brain Sciences

View full text Add to dashboard Cite

Orexin peptides comprise two neuropeptides, orexin A and orexin B, that bind two G-protein coupled receptors (GPCRs), orexin receptor 1 (OXR1) and orexin receptor 2 (OXR2). Although cell bodies that produce orexin peptides are localized in a small area comprising the lateral hypothalamus and adjacent regions, orexin-containing fibres project throughout the neuraxis. Although orexins were initially described as peptides that regulate feeding behaviour, research has shown that orexins are involved in diverse functions that range from the modulation of autonomic functions to higher cognitive functions, including reward-seeking, behaviour, attention, cognition, and mood. Furthermore, disruption in orexin signalling has been shown in mood disorders that are associated with low hedonic tone or anhedonia, including depression, anxiety, attention deficit hyperactivity disorder, and addiction. Notably, projections of orexin neurons overlap circuits involved in the modulation of hedonic tone. Evidence shows that orexins may potentiate hedonic behaviours by increasing the feeling of pleasure or reward to various signalling, whereas dysregulation of orexin signalling may underlie low hedonic tone or anhedonia. Further, orexin appears to play a key role in regulating behaviours in motivationally charged situations, such as food-seeking during hunger, or drug-seeking during withdrawal. Therefore, it would be expected that dysregulation of orexin expression or signalling is associated with changes in hedonic tone. Further studies investigating this association are warranted.

show abstract

“…In 2005, our lab provided the first evidence that the orexin system mediates drug seeking behavior, reporting that the expression of conditioned place preference for cocaine (and morphine) is associated with Fos recruitment in LH orexin neurons (Harris et al, 2005). In the ~15 years since, a role for the orexin system has been extended beyond cocaine and morphine to all drugs of abuse tested, including alcohol (Brodnik et al, 2018;Hopf, 2020;James et al, 2017b;Matzeu and Martin-Fardon, 2020;Moorman, 2018;Walker and Lawrence, 2017). Fos activation of orexin neurons has been reported following alcohol sensitization in mice (Macedo et al, 2013) and in response to discriminative stimuli predictive of ethanol and cocaine availability (Dayas et al, 2008;Martin-Fardon et al, 2018).…”

Section: Orexin As a Mediator Of Cocaine And Alcohol Behaviorsmentioning

confidence: 99%

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse

et al. 2021

View full text Add to dashboard Cite

An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report co-abusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators. Here, we seek to describe studies demonstrating efficacy of orexin receptor antagonists in reducing cocaine, alcohol-and stress-related behaviors, but note that these studies have largely focused on each of these phenomena in isolation. For orexin-based compounds to be viable in the clinical setting, we argue that it is imperative that their efficacy be tested in animal models that account for polysubstance use patterns. To begin to examine this, we present new data showing that rats' preferred level of cocaine intake is significantly increased following chronic homecage access to alcohol. We also report that cocaine intake and motivation are reduced by a selective orexin-1 receptor antagonist when rats have a history of cocaine + alcohol, but not a limited history of cocaine alone. In light of these proof-of-principle data, we outline what we believe to be the key priorities going forward with respect to further examining the orexin system in models of polysubstance use.

show abstract

Targeting the Orexin System for Prescription Opioid Use Disorder

Cited by 17 publications

References 133 publications

Heterogeneity in the Paraventricular Thalamus: The Traffic Light of Motivated Behaviors

Heterogeneity in the Paraventricular Thalamus: The Traffic Light of Motivated Behaviors

Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse

Contact Info

Product

Resources

About