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

Prasad, Asheeta A.; McNally, Gavan P.

doi:10.1371/journal.pone.0110385

Cited by 16 publications

(14 citation statements)

References 54 publications

(67 reference statements)

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“…Evidence supporting a role for endogenous MCH in stimulating alcohol intake comes from a study showing peripheral administration of an MCHR1 antagonist to suppress alcohol self-administration and cue-induced reinstatement of alcohol-seeking (Cippitelli et al, 2010). Moreover, a recent study using antisense vivo morpholinos that reduce MCH and OX protein levels reported that this reduced the renewal of extinguished alcohol seeking (Prasad and McNally, 2014), lending further support to the idea that MCH does endogenously promote alcohol intake.…”

Section: Neuropeptides With Complex Relationships To Alcoholmentioning

confidence: 76%

“…While OX on its own is not necessary for renewal of alcohol seeking, it may work in concert with other neuropeptides to induce this behavior (Prasad and McNally, 2014). Specifically, an OX antisense vivo morpholino microinjected into the LH diminished renewal of alcohol seeking when injected at a level that reduced both OX and MCH protein but not at a level that reduced only OX protein (Prasad and McNally, 2014). While hypothalamic OX is therefore capable of promoting alcohol drinking, it may not be sufficient for the execution of this behavior.…”

Section: Neuropeptides With a Positive Feedback Relationship To Almentioning

confidence: 99%

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Hypothalamic neuropeptide signaling in alcohol addiction

Barson

Leibowitz

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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The hypothalamus is now known to regulate alcohol intake in addition to its established role in food intake, in part through neuromodulatory neurochemicals termed neuropeptides. Certain orexigenic neuropeptides act in the hypothalamus to promote alcohol drinking, although they affect different aspects of the drinking response. These neuropeptides, which include galanin, the endogenous opioid enkephalin, and orexin/hypocretin, appear to stimulate alcohol intake not only through mechanisms that promote food intake but also by enhancing reward and reinforcement from alcohol. Moreover, these neuropeptides participate in a positive feedback relationship with alcohol, whereby they are upregulated by alcohol intake to promote even further consumption. They contrast with other orexigenic neuropeptides, such as melanin-concentrating hormone and neuropeptide Y, which promote alcohol intake under limited circumstances, are not consistently stimulated by alcohol, and do not enhance reward. They also contrast with neuropeptides that can be anorexigenic, including the endogenous opioid dynorphin, corticotropin-releasing factor, and melanocortins, which act in the hypothalamus to inhibit alcohol drinking as well as reward and therefore counter the ingestive drive promoted by orexigenic neuropeptides. Thus, while multiple hypothalamic neuropeptides may work together to regulate different aspects of the alcohol drinking response, excessive signaling from orexigenic neuropeptides or inadequate signaling from anorexigenic neuropeptides can therefore allow alcohol drinking to become dysregulated.

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Section: Neuropeptides With Complex Relationships To Alcoholmentioning

confidence: 76%

Section: Neuropeptides With a Positive Feedback Relationship To Almentioning

confidence: 99%

Hypothalamic neuropeptide signaling in alcohol addiction

Barson

Leibowitz

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…The impacts of direct manipulation of the orexin system generally agree with these findings. Consistent with the robust recruitment of lateral orexin neurons during context‐induced reinstatement of cocaine seeking, this reinstatement is prevented by pretreatment with SB‐334867 (0–30 mg/kg) (Smith et al ), whereas selective knockdown of orexin protein expression does not prevent context‐induced reinstatement of alcohol seeking (Prasad & McNally ).…”

Section: Hypothalamusmentioning

confidence: 77%

How contexts promote and prevent relapse to drug seeking

Khoo

Gibson

Prasad

et al. 2016

Genes Brain and Behavior

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The contexts where drugs are self-administered play an important role in regulating persistent drug taking and in relapse to such taking after periods of abstinence. Here, we review the behavioral and brain mechanisms enabling contexts to promote and prevent relapse to drug seeking. We review the key brain structures, their neuropharmacology and their connectivity. We discuss the similarities and differences between the mechanisms for context-induced reinstatement of drug seeking vs. other forms of relapse to drug seeking in animal models and we highlight the numerous deficits in our understanding. We emphasize that current understanding, although significant, defies explanations in terms of models at the level of brain structures and their connectivity. Rather, we show that there is significant functional compartmentalization and segregation within these structures during reinstatement and extinction of drug seeking that parallels their anatomical segregation into circuits and channels. A key challenge is to recognize this complexity, understand how these circuits and channels are organized, as well as understand how different modes of activity of ensembles of neurons within them promote abstinence or relapse to drug seeking.Keywords: Accumbens, addiction, amygdala, circuits, context-induced reinstatement, learning, orexin, prefrontal cortex, reinstatement, relapse, renewal Received 15 June 2016, revised 13 August 2016 and 30 August 2016, accepted for publication 31 August 2016Drug addiction remains a chronic condition imposing significant burdens on individuals, their families and communities. It is associated with increased rates of physical health problems including cardiovascular and liver disease; mental health problems including depression and anxiety; reduced levels of productivity, as well as higher utilization of health and social services (Lim et al. 2012;Nutt et al. 2010;Rehm et al. 2009). Considerable progress has been made in understanding the mechanisms of drug addiction including those contributing to the reinforcing effects of drugs of abuse and the escalation as well as loss of control over drug intake rendering it compulsive. A fundamental problem is relapse to drug taking after a period of abstinence. Rates of relapse are high and largely unchanged over a long period of time ( Basic work in neuroscience has provided significant information on the behavioral and brain mechanisms that initiate and sustain behavioral change. The relevance and importance of this work to the clinical problem of relapse is rightly judged on its clinical impact (Connor et al. 2016;Hall et al. 2014). There have been some successes, but much of this basic work is yet to achieve translational success (Heilig et al. 2016). There are many reasons for this but one theme that we explore here is that the mechanisms for behavioral change during extinction and reinstatement are significantly more nuanced than most current models of relapse to drug seeking allow. Here, we review current knowledge on how contexts promote and pr...

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“…Another prominent subpopulation of LH neurons expresses MCH, which are distinct from OX neurons. Prasad et al [67] examined the involvement of OX and MCH on ABA renewal of alcohol seeking. [67].…”

Section: Ox Loci-specific Targetingmentioning

confidence: 99%

“…Prasad et al [67] examined the involvement of OX and MCH on ABA renewal of alcohol seeking. [67]. Long-Evans rats were injected with an antisense morpholino (0.6 nM), which knocked down 50 % of OX protein expression in the LH, without affecting MCH protein expression.…”

Section: Ox Loci-specific Targetingmentioning

confidence: 99%

Role of Lateral Hypothalamic Orexin (Hypocretin) Neurons in Alcohol Use and Abuse: Recent Advances

Ch’ng

Lawrence

2016

Curr Pharmacol Rep

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Purpose of Review Alcohol use disorders (AUDs) are chronic relapsing disorders with the modest efficacy of current medications. The US Food and Drug Administration (FDA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) approval of the dual orexin (OX) receptor antagonist, suvorexant for the treatment of insomnia, may enable repurposing of this drug for the treatment of other diseases. Here, we summarize and reflect on the most recent research on the role of OX neurons in alcohol use and abuse. Recent Findings OX neurons regulate alcohol intake and seeking, although their involvement in different aspects of alcohol consumption/seeking, specific loci of action and interactions with other transmitter systems are still being clarified. Summary Recent studies have identified anatomic loci of action and interactions between OX and other neuropeptides that drive alcohol seeking. Future studies are required to fully elucidate these behaviors, in which optogenetic and chemogenetic approaches may prove useful.

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

Cited by 16 publications

References 54 publications

Hypothalamic neuropeptide signaling in alcohol addiction

Hypothalamic neuropeptide signaling in alcohol addiction

How contexts promote and prevent relapse to drug seeking

Role of Lateral Hypothalamic Orexin (Hypocretin) Neurons in Alcohol Use and Abuse: Recent Advances

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