scholarly journals Acute Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Prevents Drug-Induced Heroin Seeking in Rats

2021 ◽  
Author(s):  
Joaquin E Douton ◽  
Nikhil K Acharya ◽  
Brooke Stoltzful ◽  
Dongxiao Sun ◽  
Patricia S. Grigson ◽  
...  
Keyword(s):  
Drugs Of Abuse ◽  
Opioid Use Disorder ◽  
Opioid Use ◽  
Self Administration ◽  
Drug Induced ◽  
Locomotor Impairment ◽  
Pretreatment Time ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Substance use disorder is a difficult disease to treat due to its relapsing nature. In the last decade, opioid use disorder has been a threat to public health, being declared an epidemic by the Centers for Disease Control and Prevention. This is a tragic situation, considering there are currently effective, yet not ideal, treatments to prevent relapse. Recent research has shown that hormones that modulate hunger and satiety also can modulate motivated behavior for drugs of abuse. For example, the short-acting analog of glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates homeostatic feeding, has been shown to reduce responding for rewarding stimuli such as food, cocaine, heroin and nicotine. Here, we tested the acute effects of the long-acting GLP-1 analog, liraglutide, on heroin seeking. We found that, in rats with heroin self-administration experience, subcutaneous (sc) administration of an acute dose of 0.3 mg/kg liraglutide was effective in preventing relapse after exposure to three major precipitators: drug-associated cues, stress, and the drug itself. However, the effects of the drug were contingent upon the pretreatment time, with the drug being fully effective when administered using a 6 h, rather than a 4 h pretreatment time. Finally, we confirmed that the reduction in drug seeking is not due to a locomotor impairment, as liraglutide did not significantly alter performance in a rotarod test. As such, this acute non-opioid treatment may serve as a new and effective bridge to treatment.

scholarly journals The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

2020 ◽  
Author(s):  
Shayna L. O’Connor ◽  
Jennifer E. Fragale ◽  
Morgan H James ◽  
Gary Aston-Jones
Keyword(s):  
Drugs Of Abuse ◽  
Therapeutic Potential ◽  
Opioid Use Disorder ◽  
Opioid Use ◽  
Self Administration ◽  
Drug Experience ◽  
Reward Seeking ◽  
Intermittent Access ◽  
General Locomotor Activity ◽  
Target Effects

AbstractThe orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD). Suvorexant (Belsomra™) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.

scholarly journals Glucagon-like peptide-1 receptor agonist, exendin-4, reduces reinstatement of heroin seeking behavior in rats

2019 ◽  
Author(s):  
Joaquin E. Douton ◽  
Corinne Augusto ◽  
Brooke A Stultzfus ◽  
Nurgul Carkaci-Salli ◽  
Kent E. Vrana ◽  
...  
Keyword(s):  
Phase 1 ◽  
Phase 2 ◽  
Sprague Dawley ◽  
Nucleus Accumbens Shell ◽  
Self Administration ◽  
Phase 3 ◽  
Drug Induced ◽  
Seeking Behavior ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

AbstractBackgroundStudies have shown that ‘satiety’ agents such as exendin-4 (a glucagon-like peptide-1 analog) reduce responding for addictive drugs (e.g., cocaine, nicotine, alcohol). In this study we tested the effect of exendin-4 on cue-induced and drug-induced reinstatement of heroin seeking behavior in rats.MethodsThis study consisted of three phases: In Phase 1, 55 male Sprague-Dawley rats had 15 daily pairings of saccharin with heroin self-administration. In Phase 2, rats experienced a 16-day home cage abstinence period and daily treatment with vehicle or exendin-4. On day 17, an extinction/reinstatement test was performed to assess drug seeking. In Phase 3, rats experienced 9 days of extinction followed by a reinstatement only test. Finally, expression of mRNA for various receptors in the nucleus accumbens shell (NAcS) was measured using RTqPCR.ResultsIn Phase 1, rats that avoided intake of the heroin-paired saccharin cue exhibited shorter latency to obtain the first infusion. In Phase 2, treatment with exendin-4 decreased cue-induced, but not drug-induced heroin seeking. In Phase 3, saccharin avoiders previously treated with exendin-4 increased acceptance of saccharin, and 1-hour pretreatment with Exendin-4 abolished drug-induced heroin seeking. Finally, exendin-4 treatment increased expression of mRNA for the Orexin 1 receptor (OX1) in the NAcS, but did not affect expression of dopamine D2 receptors, GLP-1 receptors, or leptin receptors in this same structure.ConclusionExendin-4 reduced cue- and drug-induced heroin seeking and increased acceptance of the drug-associated saccharin cue. These changes in behavior were accompanied by an increase in the expression of the OX1 receptor in the NAcS.

Hippocampal-Dependent Inhibitory Learning and Memory Processes in the Control of Eating and Drug Taking

2020 ◽  
Vol 26 (20) ◽  
pp. 2334-2352 ◽  
Author(s):  
Matthew M. Clasen ◽  
Anthony L. Riley ◽  
Terry L. Davidson
Keyword(s):  
Learning And Memory ◽  
Behavioral Inhibition ◽  
Drugs Of Abuse ◽  
Self Administration ◽  
Drug Induced ◽  
Main Hypothesis ◽  
Memory Mechanism ◽  
Glucagon Like Peptide 1 ◽  
Inhibitory Power ◽  
Inhibitory Learning

As manifestations of excessive and uncontrolled intake, obesity and drug addiction have generated much research aimed at identifying common neuroadaptations that could underlie both disorders. Much work has focused on changes in brain reward and motivational circuitry that can overexcite eating and drug-taking behaviors. We suggest that the regulation of both behaviors depends on balancing excitation produced by stimuli associated with food and drug rewards with the behavioral inhibition produced by physiological “satiety” and other stimuli that signal when those rewards are unavailable. Our main hypothesis is that dysregulated eating and drug use are consequences of diet- and drug-induced degradations in this inhibitory power. We first outline a learning and memory mechanism that could underlie the inhibition of both food and drug-intake, and we describe data that identifies the hippocampus as a brain substrate for this mechanism. We then present evidence that obesitypromoting western diets (WD) impair the operation of this process and generate pathophysiologies that disrupt hippocampal functioning. Next, we present parallel evidence that drugs of abuse also impair this same learning and memory process and generate similar hippocampal pathophysiologies. We also describe recent findings that prior WD intake elevates drug self-administration, and the implications of using drugs (i.e., glucagon-like peptide- 1 agonists) that enhance hippocampal functioning to treat both obesity and addiction are also considered. We conclude with a description of how both WD and drugs of abuse could initiate a “vicious-cycle” of hippocampal pathophysiology and impaired hippocampal-dependent behavioral inhibition.

scholarly journals Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice

2018 ◽  
Vol 315 (4) ◽  
pp. R595-R608 ◽  
Author(s):  
Jacob D. Brown ◽  
Danielle McAnally ◽  
Jennifer E. Ayala ◽  
Melissa A. Burmeister ◽  
Camilo Morfa ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Expenditure ◽  
Receptor Agonist ◽  
Day Treatment ◽  
Mtor Pathway ◽  
Obese Mice ◽  
Promote Weight Loss ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

scholarly journals Buprenorphine exposure alters the development and migration of interneurons in the cortex

2020 ◽  
Author(s):  
Vanesa Nieto-Estévez ◽  
Jennifer J. Donegan ◽  
Courtney McMahon ◽  
Hannah B. Elam ◽  
Teresa A. Chavera ◽  
...  
Keyword(s):  
Human Brain ◽  
Fetal Brain ◽  
Opioid Use Disorder ◽  
Prescription Opioid ◽  
Opioid Use ◽  
Child Bearing ◽  
Increased Risk ◽  
Adverse Neonatal Outcomes ◽  
And Migration ◽  
Long Acting

ABSTRACTThe misuse of opioids has reached epidemic proportions over the last decade, with over 2.1 million people in the U.S. suffering from substance use disorders related to prescription opioid pain relievers. This increase in opioid misuse affects all demographics of society, including women of child-bearing age, which has led to a rise in opioid use during pregnancy. Opioid use during pregnancy has been associated with increased risk of obstetric complications and adverse neonatal outcomes, including neonatal abstinence syndrome. Currently, opioid use disorder in pregnant women is treated with long-acting opioid agonists, including buprenorphine. Although buprenorphine reduces illicit opioid use during pregnancy and improves infant outcomes at birth, few long-term studies of the neurodevelopmental consequences have been conducted. The goal of the current experiments was to examine the effects of buprenorphine on the development of the cortex using fetal brain tissue, 3D brain cultures, and rodent models. First, we demonstrated that we can grow cortical and subpallial spheroids, which model the cellular diversity, connectivity, and activity of the developing human brain. Next, we show that cells in the developing human cortex express the nociceptin opioid (NOP) receptor and that buprenorphine can signal through this receptor in cortical spheroids. Using subpallial spheroids to grow inhibitory interneurons, we show that buprenorphine can alter interneuron development and migration into the cortex. Finally, using a rodent model of prenatal buprenorphine exposure, we demonstrate that alterations in interneuron distribution can persist into adulthood. Together, these results suggest that more research is needed into the long-lasting consequences of buprenorphine exposure on the developing human brain.

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