A novel dual agonist of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors attenuates fentanyl taking and seeking in male rats

Zhang, Yafang; Rahematpura, Suditi; Ragnini, Kael; Moreno, Amanda; Stecyk, Kamryn; Kahng, Michelle W; Milliken, Brandon T.; Hayes, Matthew R.; Doyle, Robert P.; Schmidt, Heath D.

doi:10.1016/j.neuropharm.2021.108599

Cited by 19 publications

(7 citation statements)

References 91 publications

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“…Rats escalated their daily intake of morphine over the 10-day self-administration phase (Fig. 1D), similar to published studies from our lab and others investigating voluntary opioid taking in rats [22,23,[38][39][40]. Rats self-administered almost double the amount of morphine on day 10 versus day 1 of the selfadministration phase, and the total morphine infused was similar to previous rat morphine self-administration studies that used a threehour daily access paradigm (Fig.…”

Section: Volitional Morphine Takingsupporting

confidence: 85%

“…A separate group of Brown Norway rats was implanted with indwelling jugular catheters as described in our previous intravenous drug selfadministration studies (Fig. 1B) [22][23][24]. Briefly, rats were handled daily and allowed two weeks to acclimate to their home cages upon arrival and grow to the desired weight needed for surgery.…”

Section: Morphine Self-administrationmentioning

confidence: 99%

“…in rats [22,23]. The unit dose of morphine was based on our pilot studies as well as previous studies of morphine self-administration in rats [25][26][27].…”

Section: Morphine Self-administrationmentioning

confidence: 99%

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Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake

et al. 2022

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Opioid exposure is known to cause transcriptomic changes in the nucleus accumbens (NAc). However, no studies to date have investigated cell type-specific transcriptomic changes associated with volitional opioid taking. Here, we use single nucleus RNA sequencing (snRNAseq) to comprehensively characterize cell type-specific alterations of the NAc transcriptome in rats self-administering morphine. One cohort of male Brown Norway rats was injected with acute morphine (10 mg/kg, i.p.) or saline. A second cohort of rats was allowed to self-administer intravenous morphine (1.0 mg/kg/infusion) for 10 consecutive days. Each morphine-experienced rat was paired with a yoked saline control rat. snRNAseq libraries were generated from NAc punches and used to identify cell type-specific gene expression changes associated with volitional morphine taking. We identified 1106 differentially expressed genes (DEGs) in the acute morphine group, compared to 2453 DEGs in the morphine self-administration group, across 27 distinct cell clusters. Importantly, we identified 1329 DEGs that were specific to morphine self-administration. DEGs were identified in novel clusters of astrocytes, oligodendrocytes, and D1R- and D2R-expressing medium spiny neurons in the NAc. Cell type-specific DEGs included Rgs9, Celf5, Oprm1, and Pde10a. Upregulation of Rgs9 and Celf5 in D2R-expressing neurons was validated by RNAscope. Approximately 85% of all oligodendrocyte DEGs, nearly all of which were associated with morphine taking, were identified in two subtypes. Bioinformatic analyses identified cell type-specific upstream regulatory mechanisms of the observed transcriptome alterations and downstream signaling pathways, including both novel and previously identified molecular pathways. These findings show that volitional morphine taking is associated with distinct cell type-specific transcriptomic changes in the rat NAc and highlight specific striatal cell populations and novel molecular substrates that could be targeted to reduce compulsive opioid taking.

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Section: Volitional Morphine Takingsupporting

confidence: 85%

Section: Morphine Self-administrationmentioning

confidence: 99%

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Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake

et al. 2022

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“…In a rat model of relapse, the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 reduces fentanyl self-administration in rats but causes malaise-like behavior. A novel dual agonist of GLP-1Rs and neuropeptide Y 2 receptors, GEP44, reduces fentanyl self-administration with fewer adverse effects compared with exendin-4 [ 101 , 102 ]. The growth hormone secretagogue receptor antagonist JMV2959 reduces fentanyl-induced conditioned place preference and fentanyl self-administration [ 64 ].…”

Section: Pharmacological Interventions To Prevent Fentanyl-seekingmentioning

confidence: 99%

Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse

et al. 2022

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Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties. It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere, consequently imposing devastating social, economic, and health burdens worldwide. However, the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown, and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce. This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action, including neural circuit dysfunction and neuroinflammation. We discuss recent progress in the development of pharmacological interventions, anti-fentanyl vaccines, anti-fentanyl/heroin conjugate vaccines, and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression. However, translational studies and clinical trials are still lacking. Considering the present opioid crisis, the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.

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“…However, its short half-life (Parkes et al , 2001) will require patients to receive multiple injections throughout the day for continuous prophylactic protection, leading to poor compliance. In addition, Ex-4, at doses that reduce responding for drug, also causes gastrointestinal (GI) malaise (Zhang et al , 2021). On the other hand, less research has focused on the effects of GLP-1R agonist formulations with longer half-lives such as liraglutide [~12 h (Degn et al , 2004)] or semaglutide [~165 h (Kapitza et al , 2015)] on drug-seeking behavior.…”

Section: Introductionmentioning

confidence: 99%

Acute glucagon-like peptide-1 receptor agonist liraglutide prevents cue-, stress-, and drug-induced heroin-seeking in rats

Douton

Acharya

Stoltzfus

et al. 2022

Behavioural Pharmacology

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Substance use disorder is challenging 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 currently are only three effective, yet not ideal, treatments to prevent relapse to opioids. 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 when administered over several days or weeks. This may serve as an effective adjuvant during treatment; however, whether it would be effective when used acutely to bridge a patient between cessation of use and onset of medication for the treatment of an opioid addiction is unknown. Here, we tested the acute effects of the longer acting GLP-1 analog, liraglutide, on heroinseeking. In rats with heroin self-administration experience, we found that subcutaneous administration of an acute dose of 0.3-mg/kg liraglutide was effective in preventing drug-seeking after exposure to three major precipitators: drug-associated cues, stress (yohimbine-induced), and the drug itself. 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, acute use of GLP-1 analogs may serve as a new and effective nonopioid bridge to treatment. Behavioural Pharmacology 33: 364-376

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A novel dual agonist of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors attenuates fentanyl taking and seeking in male rats

Cited by 19 publications

References 91 publications

Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake

Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake

Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse

Acute glucagon-like peptide-1 receptor agonist liraglutide prevents cue-, stress-, and drug-induced heroin-seeking in rats

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