The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship

Kim, Andrezza Kyunmi; Brown, Robyn M.; Lawrence, Andrew J

doi:10.3389/fnbeh.2012.00078

Cited by 28 publications

(19 citation statements)

References 110 publications

(154 reference statements)

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“…Pharmacological studies demonstrate that central injection of MCH increases ethanol intake (Duncan et al, 2005, Morganstern et al, 2010b) while an MCH antagonist reduces it (Cippitelli et al, 2010), and endogenous expression of MCH is greater in rats prone to consuming excess ethanol (Morganstern et al, 2010b). Clinical studies also provide support for a role of MCH in mediating the rewarding properties of ethanol (DiLeone et al, 2003, Duncan et al, 2005, Kim et al, 2012). In addition, there is evidence that the CCL2/CCR2 signaling pathway itself has a role in controlling ethanol consumption, with studies showing a deletion of the CCR2 gene in males and CCL2 gene in females to reduce the drinking of ethanol (Blednov et al, 2005).…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, in a recent report (Chang et al, 2012), we demonstrated that exposure to ethanol during gestation, at low-to-moderate doses (1 or 3 g/kg/day) that elevate blood ethanol concentration (BEC) to <100 mg/dL, markedly stimulates neurogenesis and increases the density and long-term expression of the orexigenic peptides, OX in the LH as well as galanin and enkephalin in the hypothalamic paraventricular nucleus (Chang et al, 2012). Although yet to be investigated, recent studies of MCH showing its role in mediating the rewarding and motivating properties of ethanol (DiLeone et al, 2003, Duncan et al, 2005, Kim et al, 2012) suggest that neurons expressing this peptide are likely to be similarly affected by gestational ethanol and, in turn, to contribute significantly to the phenomenon of excess alcohol drinking.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring

2015

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Clinical and animal studies indicate that maternal consumption of ethanol during pregnancy increases alcohol drinking in the offspring. Possible underlying mechanisms may involve orexigenic peptides, which are stimulated by prenatal ethanol exposure and themselves promote drinking. Building on evidence that ethanol stimulates neuroimmune factors such as the chemokine CCL2 that in adult rats is shown to colocalize with the orexigenic peptide, melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH), the present study sought to investigate the possibility that CCL2 or its receptor CCR2 in LH are stimulated by prenatal ethanol exposure, perhaps specifically within MCH neurons. Our paradigm of intraoral administration of ethanol to pregnant rats, at low-to-moderate doses (1 or 3 g/kg/day) during peak hypothalamic neurogenesis, caused in adolescent male offspring two-fold increase in drinking of and preference for ethanol and reinstatement of ethanol drinking in a two-bottle choice paradigm under an intermittent access schedule. This effect of prenatal ethanol exposure was associated with an increased expression of MCH and density of MCH+ neurons in LH of preadolescent offspring. Whereas CCL2+ cells at this age were low in density and unaffected by ethanol, CCR2+ cells were dense in LH and increased by prenatal ethanol, with a large percentage (83–87%) identified as neurons and found to colocalize MCH. Prenatal ethanol also stimulated the genesis of CCR2+ and MCH+ neurons in the embryo, which co-labeled the proliferation marker, BrdU. Ethanol also increased the genesis and density of neurons that co-expressed CCR2 and MCH in LH, with triple-labeled CCR2+/MCH+/BrdU+ neurons that were absent in control rats accounting for 35% of newly generated neurons in ethanol-exposed rats. With both the chemokine and MCH systems believed to promote ethanol consumption, this greater density of CCR2+/MCH+ neurons in the LH of preadolescent rats suggests that these systems function together in promoting alcohol drinking during adolescence.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring

2015

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“…Orexin has also been implicated in nonfood rewards such as addictive drugs (Harris et al, 2005;Harris and Aston-Jones, 2006;Aston-Jones et al, 2010;Smith et al, 2010b;Kim et al, 2012;Mahler et al, 2012). Involvement in drug rewards raises the possibility that the VP orexin hotspot identified here might also have a role in generating intense drug pleasures, and possibly of other non-ingestive sensory rewards.…”

Section: Circuit and Clinical Implicationsmentioning

confidence: 81%

An Orexin Hotspot in Ventral Pallidum Amplifies Hedonic ‘Liking’ for Sweetness

Berridge

2013

Neuropsychopharmacol

149

101

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Orexin (hypocretin) is implicated in stimulating appetite as well as arousal, and in both food reward and drug reward. The ventral pallidum (VP) receives orexin projections from lateral hypothalamus neurons (LH), and orexin terminals are especially dense in the posterior half of VP, which is also the location of an opioid hedonic hotspot. The VP hotspot is a roughly cubic-millimeter site where mu opioid stimulation can amplify the hedonic impact of sweetness, expressed as an increase in 'liking' reactions to sucrose taste. The anatomical overlap in posterior VP between opioid hotspot and orexin inputs raises the possibility that the hedonic hotspot might allow orexin to amplify 'liking' too. We examined whether microinjections of orexin-A into the VP hotspot enhance the hedonic impact of sucrose, as assessed via affective taste reactivity measures of 'liking' reactions, and additionally compared effects at nearby sites in adjacent LH and extended amygdala. Taste reactivity results indicated that orexin stimulation specifically in the VP hotspot nearly doubled the magnitude of positive 'liking' reactions elicited by the taste of sucrose. Mapping results for localization of function, aided by Fos plume measures of the local spread of orexin impact, suggested that hedonic enhancement was generated by essentially the same cubicmillimeter of posterior VP previously identified as the opioid hotspot. By contrast, microinjection sites in the anterior half of VP, or in LH or extended amygdala, generally failed to produce any hedonic enhancement. We conclude that an orexin hedonic hotspot exists in posterior VP, with similar boundaries to the opioid hotspot. An orexin hedonic hotspot may permit regulatory hypothalamic circuitry to make foods more 'liked' during hunger by acting through VP. Dysfunction in a VP orexin hotspot in addiction or mood disorders might also contribute to some types of affective psychopathology.

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“…The mechanisms of these disruptions may include alterations to the expression of tyrosine hydroxylase and dopamine firing in the VTA (Coque et al, 2011; McClung et al, 2005), or altered dopamine levels and D1 to D2 receptor ratio in the nucleus accumbens (Hampp & Albrecht, 2008). Animal models have uncovered that orexin, a neuropeptide involved in the homeostatic regulation of sleep, serves to modulate both circadian gene function and mesolimbic pathways (Belle et al, 2014; Kim, Brown, & Lawrence, 2012). Furthermore, circadian gene mutants often demonstrate altered reward behavior, such as increased preference for alcohol or hypersensitization to cocaine (McClung et al, 2005; Spanagel et al, 2005).…”

Section: Reward As a Mechanismmentioning

confidence: 99%

Sleep and circadian contributions to adolescent alcohol use disorder

Hasler

Soehner

Clark

2015

Alcohol

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Adolescence is a time of marked changes across sleep, circadian rhythms, brain function, and alcohol use. Starting at puberty, adolescents’ endogenous circadian rhythms and preferred sleep times shift later, often leading to a mismatch with the schedules imposed by secondary education. This mismatch induces circadian misalignment and sleep loss, which have been associated with affect dysregulation, increased drug and alcohol use, and other risk-taking behaviors in adolescents and adults. In parallel to developmental changes in sleep, adolescent brains are undergoing structural and functional changes in the circuits subserving the pursuit and processing of rewards. These developmental changes in reward processing likely contribute to the initiation of alcohol use during adolescence. Abundant evidence indicates that sleep and circadian rhythms modulate reward function, suggesting that adolescent sleep and circadian disturbance may contribute to altered reward function, and in turn, alcohol involvement. In this review, we summarize the relevant evidence and propose that these parallel developmental changes in sleep, circadian rhythms, and neural processing of reward interact to increase risk for alcohol use disorder (AUD).

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The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship

Cited by 28 publications

References 110 publications

Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring

Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring

An Orexin Hotspot in Ventral Pallidum Amplifies Hedonic ‘Liking’ for Sweetness

Sleep and circadian contributions to adolescent alcohol use disorder

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