Nucleus incertus Orexin2 receptors mediate alcohol seeking in rats

Kastman, Hanna E.; Błasiak, Anna; Siwiec, Marcin; Krstew, Elena; Gundlach, Andrew L.; Lawrence, Andrew J

doi:10.1016/j.neuropharm.2016.07.006

Cited by 41 publications

(63 citation statements)

References 81 publications

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“…Also, as described above, OxR1 signaling in BNST appears to play an important role in stress-induced drug seeking. More recently, stress-induced reinstatement of alcohol seeking was shown to be dependent on signaling at the OX 2 R in the nucleus incertus, a small pontine region [141]. In the cortex, infusions of SB-334867 into the prelimbic cortex attenuate cue-induced reinstatement of ethanol seeking [104], and local infusions of SB-334867 in the insular cortex reduce nicotine self-administration behavior [36].…”

Section: Interaction Between Orexin Neurons and Brain Reward Circuitrymentioning

confidence: 99%

“…Similarly, intra-VTA infusions of SB-334867 block cue-induced reinstatement of ethanol seeking [104], and infusions of the dual orexin receptor antagonist almorexant into the VTA reduce alcohol drinking [142]. Ethanol-seeking behaviors have been shown to be dependent on orexin signaling at other loci, including the prelimbic cortex (PL; [104]), nucleus accumbens (NAc; [51]), the anterior paraventricular thalamus (PVT; [128]), the bed nucleus of the stria terminalis [140], and the nucleus incertus (NI; [141]). Signaling at both the OX1R and OX2 in the NAc is important for stress-induced reinstatement of morphine conditioned place preference [69], and infusions of SB-334867 into the insular cortex (IC) reduce nicotine seeking behavior [36].…”

Section: Figmentioning

confidence: 99%

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A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

James

Mahler

Moorman

et al. 2016

Current Topics in Behavioral Neurosciences

152

112

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One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating “motivational activation” under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra®) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction.

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Section: Interaction Between Orexin Neurons and Brain Reward Circuitrymentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

James

Mahler

Moorman

et al. 2016

Current Topics in Behavioral Neurosciences

152

112

View full text Add to dashboard Cite

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“…Orexin neurons are directly activated by CRH and stress (Winsky-Sommerer et al, 2004) and play a key role in stress-induced overconsumption of food (Piccoli et al, 2012), and reinstatement of alcohol- and drug-seeking behavior (Kastman et al, 2016; Schmeichel et al, 2016). The functional link between the HPA-axis and orexin neurons is reciprocal, since orexins evoke an induction of c- fos mRNA in the PVN, and an increase in plasma ACTH and corticosterone (Kuru et al, 2000).…”

Section: Central Regulation Of Food Intake: the Interaction Of Orexigmentioning

confidence: 99%

“…Moreover, a majority of relaxin-3 neurons in NI and PAG express CRH 1 -receptors and are excited by CRH injections in vivo and in vitro (Tanaka et al, 2005; Blasiak et al, 2013; Ma et al, 2013). The relaxin-3/RXFP3 system plays a role in stress-induced binge eating (Lenglos et al, 2013; Calvez et al, 2016b) and stress-induced reinstatement of alcohol seeking (Ryan et al, 2013; Kastman et al, 2016; Walker et al, 2016). Relaxin-3/RXFP3 signaling may reciprocally influence stress responses since icv injections of relaxin-3 in male rats result in increased c- fos and CRH mRNA expression in PVN neurons and increased plasma ACTH and corticosterone levels (Watanabe et al, 2011; McGowan et al, 2014; Lenglos et al, 2015).…”

Section: Central Regulation Of Food Intake: the Interaction Of Orexigmentioning

confidence: 99%

Interactions of Circadian Rhythmicity, Stress and Orexigenic Neuropeptide Systems: Implications for Food Intake Control

et al. 2017

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Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the “control” of the “master biological clock” reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements.

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“…Male iP rats (250–300 g) were trained to self‐administer alcohol [10% (v./v)] under operant conditions using a fixed ratio of 3 (FR3) schedule during 20 min sessions as previously described in (Kastman, Blasiak, Walker, Siwiec & Krstew, ; Walker, Kastman, Krstew, et al., ). Two levers were available during the session, one that delivered a 100 μl alcohol reward (active lever) and the other that delivered 100 μl of water (water lever).…”

Section: Methodsmentioning

confidence: 99%

Pattern of neural activation following yohimbine‐induced reinstatement of alcohol seeking in rats

Kastman

Lawrence

2019

Eur J of Neuroscience

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Alcohol use disorders represent an extensive socioeconomic burden, yet effective treatment options are suboptimal. A major hurdle in treating alcohol use disorders is the high rate of relapse. Stress is a major factor that promotes relapse in abstinent drug users; therefore, understanding neural mechanisms that underpin the effects of stress on alcohol seeking is critical. In rodent models of stress‐induced relapse, the α2‐adrenoceptor antagonist, yohimbine, is a widely used chemical stressor to elicit reinstatement of drug/alcohol seeking. However, the exact mechanism how yohimbine precipitates reinstatement of alcohol seeking and the pattern of neural activation associated with yohimbine‐induced reinstatement is poorly understood. Therefore, we counted Fos‐protein positive nuclei across 42 brain regions in alcohol‐experienced alcohol preferring rats that received either yohimbine in the home‐cage (1 mg/kg i.p.) or following yohimbine‐induced reinstatement of alcohol seeking. The number of Fos‐protein positive nuclei was increased in the prefrontal cortex and extended amygdala after home‐cage yohimbine compared to naïve‐ and vehicle‐treated rats. Yohimbine‐induced reinstatement increased the number of Fos‐protein expressing nuclei in multiple other regions including the thalamus, hypothalamus and hippocampus. We then examined inter‐regional correlations in Fos‐protein expression for all 42 brain regions, which showed Fos expression was more strongly positively correlated following yohimbine‐induced reinstatement of alcohol seeking, compared to home‐cage yohimbine. These data suggest low‐dose yohimbine in a non‐drug‐associated context activates stress/impulsivity centres within the brain, whereas yohimbine in the drug‐associated context recruits additional brain regions to drive alcohol seeking.

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Nucleus incertus Orexin2 receptors mediate alcohol seeking in rats

Cited by 41 publications

References 81 publications

A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

Interactions of Circadian Rhythmicity, Stress and Orexigenic Neuropeptide Systems: Implications for Food Intake Control

Pattern of neural activation following yohimbine‐induced reinstatement of alcohol seeking in rats

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