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      Effects of Vivo Morpholino Knockdown of Lateral Hypothalamus Orexin/Hypocretin on Renewal of Alcohol Seeking

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      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Two experiments used vivo morpholinos to assess the role of orexin/hypocretin in ABA renewal of extinguished alcohol seeking. Rats were trained to respond for alcoholic beer in a distinctive context, A, and then extinguished in a second distinctive context, B. When rats were tested in the extinction context, ABB, responding was low but when they were tested in the training context, ABA, responding was significantly higher. Microinjection of an orexin/hypocretin antisense vivo morpholino into LH significantly reduced orexin/hypocretin protein expression but had no effect on the ABA renewal of alcohol seeking (Experiment 1). Microinjection of a higher dose of the antisense vivo morpholino into LH also significantly reduced orexin/hypocretin protein expression but this was not selective and yielded significant reduction in melanin -concentrating hormone (MCH) protein expression. This non-selective knockdown did significantly reduce ABA renewal as well as reduce the reacquisition of alcohol seeking. Taken together, these findings show an important role for LH in the ABA renewal of alcohol seeking but that orexin/hypocretin is not necessary for this renewal.

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          Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.

          T Sakurai, A Amemiya, M Ishii … (1998)
          The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.
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            The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness.

            Takeshi Sakurai (2007)
            Sleep and wakefulness are regulated to occur at appropriate times that are in accordance with our internal and external environments. Avoiding danger and finding food, which are life-essential activities that are regulated by emotion, reward and energy balance, require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.
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              The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats.

              Martin R. Fuchs, LAUREN PARKER, Adele Evans … (2005)
              The present study tested the hypothesis that separate neural substrates mediate cocaine relapse elicited by drug-associated contextual stimuli vs explicit conditioned stimuli (CSs) and cocaine. Specifically, we investigated the involvement of the dorsal hippocampus (DH), basolateral amygdala (BLA), and dorsomedial prefrontal cortex (dmPFC) in contextual reinstatement of cocaine-seeking behavior and the involvement of the DH in explicit CS- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine in a distinct context or in the presence of CSs paired explicitly with cocaine infusions. Responding of context-trained rats was then extinguished in the previously cocaine-paired or an alternate context, whereas responding of explicit CS-trained rats was extinguished in the absence of the CSs. Subsequently, the target brain regions or anatomical control regions were functionally inactivated using tetrodotoxin (0 or 5 ng/side), and cocaine-seeking behavior (ie, nonreinforced responses) was assessed in the cocaine-paired context, in the alternate context, in the presence of the explicit CSs, or following cocaine priming (10 mg/kg, i.p.). DH inactivation abolished contextual, but failed to alter explicit CS- or cocaine-induced, reinstatement of cocaine-seeking behavior. BLA or dmPFC inactivation also abolished contextual reinstatement. Conversely, inactivation of the control brain regions failed to alter contextual reinstatement. In conclusion, the DH, BLA, and dmPFC play critical roles in contextual reinstatement. Previous findings suggest that the BLA is critical for explicit CS-induced, but not cocaine-primed, reinstatement and the dmPFC is critical for both explicit CS-induced and cocaine-primed reinstatement. Thus, distinct but partially overlapping neural substrates mediate context-induced, explicit CS-induced, and cocaine-primed reinstatement of extinguished cocaine-seeking behavior.
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                Author and article information

                Contributors
                Vinod K. Yaragudri: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 17 October 2014
                Volume: 9
                Issue: 10
                Electronic Location Identifier: e110385
                Affiliations
                [1]School of Psychology, UNSW Australia, Sydney, New South Wales, Australia
                Nathan Kline Institute for Psychiatric Research and New York School of Medicine, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AP GM. Performed the experiments: AP. Analyzed the data: AP GM. Contributed reagents/materials/analysis tools: AP GM. Contributed to the writing of the manuscript: AP GM.

                Article
                Publisher ID: PONE-D-14-27888
                DOI: 10.1371/journal.pone.0110385
                PMC ID: 4201541
                PubMed ID: 25329297
                SO-VID: 05299ad9-117a-482c-a423-9eebcdb7c1ed
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 23 June 2014
                Date accepted : 17 September 2014
                Page count
                Pages: 9
                Funding
                This work was supported by the National Health and Medical Research Council #1047899 ( www.nhmrc.gov.au) and the Australian Research Council #FT120100250 ( www.arc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Behavioral Neuroscience
                Subject: Psychology
                Subject: Addiction
                Subject: Behavior
                Custom metadata
                Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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