Biology subjects

McElligott, Z. A.

Publications and source records attributed to McElligott, Z. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Biased signaling via NtsR1 restrains food intake and weight gain in obese mice

Neurotensin receptor 1 (NTSR1) activation suppresses feeding and promotes weight loss but is limited by adverse effects associated with Gq signaling. SBI-553 is a {beta}-arrestin-biased allosteric modulator of NTSR1 that avoids these effects. We evaluated the effects of SBI-553 (5 or 12 mg/kg, i.p.) on food intake and body weight in lean and diet-induced obese mice. Neither dose altered metabolic parameters, locomotor activity, or wheel running. SBI-553 did not affect ad libitum feeding in lean mice; however, both doses acutely reduced high-fat diet intake in obese mice. While 5 mg/kg had no effect on hunger-induced feeding, 12 mg/kg suppressed refeeding in both chow- and high-fat-fed mice of both sexes and reduced weight regain in obese mice. These findings identify SBI-553 as a potential strategy for reducing food intake and supporting weight loss.

physiology↗

bioRxiv2026

Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice

Maladaptive consummatory behaviors can arise from dysregulated circuits, like those in the extended amygdala, governing motivation and feeding behaviors. Neurotensin (NTS), expressed throughout the central, peripheral, and enteric nervous systems, has well-established roles in energy balance and feeding. SBI-553, a biased allosteric modulator of NTSR1, recruits {beta}-arrestin while attenuating Gq-mediated signaling. We used SBI-553 to examine NTS modulation GABAergic signaling in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) and probed its effects on food consumption in mice. We found that NTS and SBI-553 differentially modulate GABAergic neurotransmission across extended amygdala subregions. In vivo, SBI-553 reduces palatable food consumption in both fed and food-deprived mice, with greater reductions under fasted conditions, altering activation across CeA subregions in a sex- and feeding-state-dependent manner. In the BNST, differences in SBI-553 altered cFos activity were observed between feeding states. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/722083v3_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1825c16org.highwire.dtl.DTLVardef@16be6acorg.highwire.dtl.DTLVardef@f5561eorg.highwire.dtl.DTLVardef@e8f82c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINTS enhances GABAergic transmission in the CeAL and the ovBNST C_LIO_LISBI-553 blocks NTS-induced increases in sIPSC frequency in the CeAL but not in the ovBNST C_LIO_LISBI-553 attenuates the feeding of a palatable high-carbohydrate food C_LIO_LIThe effect of SBI-553 on feeding is driven by energy deficit/motivation to feed C_LI

neuroscience↗

bioRxiv2026

Xylazine's k-opioid agonist activity is not shared with other FDA-approved alpha2-adrenergic agonists

Xylazine is a 2-adrenergic agonist typically used in as a sedative and analgesic in veterinary medicine. For some years, xylazine has been reported as an additive to fentanyl on the illicit drug market and has been associated with severe side-effects including severe ulcerations and potential amputations at the sites of injection along with an increased risk of respiratory depression and death. We recently reported that xylazine has modest {kappa} opioid agonist activity in vitro and in vivo and asked if other 2-adrenergic agonists had similar off-target activities. To test this hypothesis, we profiled US FDA-approved 2-adrenergic agonists at 320 G protein coupled receptors (GPCRs) to identify potentially deleterious and/or beneficial off-targets. Although all other tested 2-adrenergic agonists were devoid of {kappa} opioid agonist activity, each had a distinct pattern of activity at various GPCRs and differential patterns of signaling bias at 2-receptor subtypes. These findings suggest potential molecular targets for both side-effects and therapeutic activities among known 2-adrenergic agonists.

neuroscience↗

bioRxiv2025

Xylazine and fentanyl co-administration delays wound healing in mice

Xylazine, a veterinary sedative increasingly found in the unregulated drug supply, is associated with severe skin wounds in humans, particularly when co-used with fentanyl. Despite growing concern, the mechanisms underlying these wounds remain unclear. To investigate how xylazine and fentanyl affect wound healing, we administered subcutaneous injections of saline, xylazine (3.2 mg/kg), fentanyl (1.0 mg/kg), or their combination to female C57BL/6J mice for 28 days. After a standardized punch biopsy, wound closure was tracked for 14 days, with continued drug exposure. Mice receiving the xylazine-fentanyl combination exhibited significantly delayed wound healing compared to all other groups, as shown by slower closure rates and increased area under the healing curve. A follow-up study without chronic pretreatment showed that acute xylazine-fentanyl exposure still altered healing dynamics, although it did not significantly delay time to closure. Neither drug alone impaired healing at the tested doses. These findings suggest that prior exposure to xylazine and fentanyl contributes to impaired wound healing and support the hypothesis that xylazine-associated wounds may arise from delayed healing of pre-existing skin injuries rather than spontaneous formation. This is the first preclinical model of xylazine-related wound impairment and provides a foundation for future research into biological mechanisms and potential interventions for these emerging soft tissue injuries.

pharmacology and toxicology↗

bioRxiv2025

Glutamate delta-1 receptors regulate a novel tonic excitatory conductance in the mouse bed nucleus of the stria terminalis and influence neuronal function

The plasticity of ionotropic receptors (mainly AMPARs and NMDARs) within the glutamatergic system has long been investigated as a mechanism for physiological and pathological adaptive learning. The tetrameric delta glutamate receptors ({delta}GluRs, GluD1 and GluD2) are homologs of the AMPARs and NMDARs, however they are insensitive to glutamate. These proteins, especially GluD1, have been implicated in multiple psychiatric conditions and play a functional role in synapses assembly and stability, but recent evidence suggests they also may supply a tonic excitatory conductance, are sensitive to poly-amine blockade, and regulate synaptic plasticity. Here we use whole-cell patch clamp electrophysiology to functionally characterize these receptors in the dorsolateral bed nucleus of the stria terminalis (dlBNST) and investigate their modulation of both synaptic transmission and cell excitability. Our results suggest that {delta}GluRs, and in particular GluD1, carry a tonic conductance, modulate excitatory synapses, and regulate cell excitability in the dlBNST. These results imply that GluD1 functions to regulate the flow of information through the BNST and may play a role in affect, stress, and substance use disorders.

neuroscience↗

bioRxiv2025

Xylazine potentiates the interoceptive effects of fentanyl in male and female rats

RationaleXylazine, a sedative typically used in veterinary medicine, has been increasingly detected as an adulterant in the unregulated opioid supply and present in opioid overdose deaths. Therefore, xylazine-adulterated fentanyl is a growing public health concern. People who use drugs have reported that xylazine changes and prolongs the effects of fentanyl ObjectivesWe used standard operant drug discrimination procedures to better understand how xylazine impacts the discriminative stimulus/interoceptive effects of fentanyl. MethodsMale and female Long-Evans rats (n=23) were trained to discriminate fentanyl (0.032 mg/kg intraperitoneal) such that one lever was reinforced with sucrose on days when fentanyl was administered, and the other lever was reinforced when vehicle was administered. Once rats met testing criteria, we tested a dose range of fentanyl to confirm discriminative stimulus control, then we tested if xylazine alone produced fentanyl-like effects and if the addition of xylazine to fentanyl impacted fentanyl interoceptive effects. ResultsStimulus control was confirmed, as rats showed increased percent responses on the fentanyl-appropriate lever as well as decreased response rates for increasing doses of fentanyl. Xylazine alone did not substitute for the stimulus effects of fentanyl but produced similar response rate reductions as fentanyl alone. Xylazine co-administered with fentanyl potentiated the stimulus effects of lower doses of fentanyl in both males and females and potentiated response rate reductions. ConclusionsThese results indicate that xylazine enhances the interoceptive effects of fentanyl, which may inform clinical research about xylazine-adulterated fentanyl.

neuroscience↗

bioRxiv2025

Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice

Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimers disease and frontotemporal dementia. Phosphorylated tau accumulates in the LC and results in inflammation, synaptic loss, and eventually cell death as the disease progresses. Loss of LC neurons and noradrenergic innervation is thought to contribute to the symptoms of cognitive decline later in disease. While loss and degeneration of LC neurons has been well studied, less is known about changes in LC physiology at advanced stages of tau pathology that precedes neurodegeneration. In this study, we investigated the ex vivo electrophysiological properties of LC neurons in male and female mice from the P301S mouse model of tauopathy at 9 months of age, a time-point when significant tau accumulation, cell death, and cognitive impairments are observed. We found a reduction in excitatory inputs and changes in excitatory post-synaptic current kinetics in male and female P301S. There was also a decrease in spontaneous discharge of LC neurons and an increase in AP threshold in P301S mice of both sexes. Finally, we observed a decrease in excitability and increase in rheobase current in P301S mice. Despite the decrease in LC activity in slice, we did not identify differences in total tissue norepinephrine (NE) or NE metabolites in prefrontal cortex or hippocampus. Together these findings demonstrate reductions in the activity and excitability of LC neurons at late stages of tau accumulation. However, compensatory mechanisms may maintain normal NE levels in LC projection regions in vivo.

neuroscience↗

bioRxiv2024

Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors

The brainstem cell group, locus coeruleus (LC), is present across vertebrates and influences cardiorespiratory, metabolic, immune, and cognitive functions by activating in two putatively distinct firing patterns. Yet, the degree to which the LC firing rates and patterns are homogenous across species has never been assessed due to inherently limited sample sizes. To remedy this, we pooled cross-species data from 20 laboratories to show that firing rates differ across species and are modulated by sex, age, and type of in vitro or in vivo preparation. Contrary to the prevailing dual-mode firing pattern schema, we observed patterns spread across a low-dimensional manifold, with subregions enriched for specific biological factors and neurodegenerative disease models. Our findings show considerable diversity in an ancestral vertebrate neuromodulatory system.

neuroscience↗

bioRxiv2024

β-arrestin-biased Allosteric Modulator of Neurotensin Receptor 1 Reduces Ethanol Drinking and Responses to Ethanol Administration in Rodents

Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death1. Despite this, there are currently only 3 FDA approved pharmacological treatments for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant misuse. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces binge-like ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

neuroscience↗

bioRxiv2023

Oral Fentanyl Consumption Alters Sleep Rhythms, Promotes Avoidance Behaviors, and Impairs Fear Extinction Learning in Male and Female Mice

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 {micro}g/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having more withdrawal symptoms, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

neuroscience↗

bioRxiv2023

GABA Release From Central Amygdala Neurotensin Neurons Differentially Modulates Reward and Consummatory Behavior in Male and Female Mice

The central nucleus of the amygdala is known to play key roles in alcohol use and affect. Neurotensin neurons in the central nucleus of the amygdala have been shown to regulate alcohol drinking in male mice. However, little is known about which neurotransmitters released by these cells drive alcohol consumption or whether these cells drive alcohol consumption in female mice. Here we show that knockdown of GABA release from central amygdala neurotensin neurons using a Nts-cre-dependent vGAT-shRNA-based AAV strategy reduces alcohol drinking in male, but not female, mice. This manipulation did not impact avoidance behavior, except in a fasted novelty-suppressed feeding test, in which vGAT shRNA mice demonstrated increased latency to feed on a familiar high-value food reward, an effect driven by male mice. In contrast, vGAT shRNA female mice showed heightened sensitivity to thermal stimulation. These data show a role for GABA release from central amygdala neurotensin neurons in modulating consumption of rewarding substances in different motivational states.

neuroscience↗

bioRxiv2023

Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration

Xylazine has been found in the unregulated drug supply at increasing rates, usually in combination with fentanyl. It has become critical to understand its basic pharmacology, how it impacts behavior, and how it interacts with fentanyl in rodent models of opioid administration. Despite commentary from scientists, politicians, and public health officials, it is not known if xylazine impacts the efficacy of naloxone, the opioid receptor antagonist used to reverse opioid induced respiratory depression. Furthermore, few studies have examined the effects of xylazine alone, without co-administration of ketamine. Here, we examine the impact of xylazine alone and in combination with fentanyl on several key behaviors in male and female mice. We demonstrate differential locomotor responses by dose and sex to xylazine. Surprisingly, our results further indicate that naloxone precipitates withdrawal from xylazine and a fentanyl/xylazine combination, in both sexes, with enhanced sensitivity in females. Further, we show that xylazine is a full agonist at the kappa opioid receptor, a potential mechanism for its naloxone sensitivity. One-Sentence SummaryWe present surprising new insights into xylazine and fentanyl pharmacology with immediate implications for clinical practice and frontline public health.

neuroscience↗

bioRxiv2022

Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice

Alcohol use disorder is a major public health concern in the United States. Recent work has suggested a link between chronic alcohol consumption and the development of tauopathy disorders, such as Alzheimers Disease and Frontal-Temporal Dementia. However, relatively little work has investigated changes in neural circuitry involved in both tauopathy disorders and alcohol use disorder. The locus coeruleus (LC) is the major noradrenergic nuclei in the brain and is one of the earliest sites to be affected by tau lesions. The LC is also implicated in the rewarding effects of ethanol and alcohol withdrawal. In this study we assessed effects of long-term ethanol consumption and tauopathy on the physiology of LC neurons. Male and female P301S mice, a humanized transgenic mouse model of tauopathy, underwent 16 weeks of intermittent access to 20% ethanol from 3 to 7 months of age. We observed higher total alcohol consumption in female mice regardless of genotype. Male P301S mice consumed more ethanol and had a greater preference for ethanol than WT males. At the end of the drinking study, LC function was assessed using ex vivo whole cell electrophysiology. We found significant changes in excitatory inputs to the LC due to both ethanol and genotype., We found significantly increased excitability of the LC due to ethanol with greater effects in female P301S mice than WT. Our study identifies significant changes in the LC due to interactions between tauopathy and long-term ethanol use. These findings could have important implications regarding LC activity and changes in behavior due to both ethanol and tauopathy related dementia.

neuroscience↗

bioRxiv2022

Effects of Long-Term Alcohol Consumption on Behavior in the P301S (Line PS19) Tauopathy Mouse Model

Alcohol consumption and misuse remain prevalent public health issues with recent reports of increased heavy consumption in older populations in the United States. Several studies have identified alcohol consumption as a risk factor for developing multiple forms of dementia. The behavioral and psychological symptoms of dementia (BPSD), such as changes in affective behavior (e.g. anxiety), precede and coincide with cognitive decline. While many studies have characterized the intersection of alcohol use and affective behaviors, little is known regarding alcohol consumption and BPSD. This study characterizes the impact of long-term alcohol consumption on various behaviors in the P301S (line PS19) tauopathy mouse model. Male and female P301S and littermate control mice underwent two-bottle choice intermittent access to alcohol for sixteen weeks starting at 12 weeks of age. There were no significant differences in total ethanol consumption between wildtype and P301S mice of the same sex; however, drinking behavior differed among genotypes, and female mice of each genotype drank significantly more ethanol than males of each genotype. Following drinking studies, mice were run through a battery of behavioral tests during a period of forced abstinence, including approach/avoidance assays, social behavior tests, and memory and cognition tests. Across these tests we observed differences between groups due to genotype, alcohol history, and interactions between alcohol exposure and genotype. These differences were not always consistent between the sexes. In total, this study reveals significant alcohol-tauopathy interactions in subsequent behavior, which may have implications for understanding how alcohol may impact BPSD in conditions associated with tauopathy like Alzheimers disease and frontotemporal dementia.

neuroscience↗

bioRxiv2022

Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice

Opioid misuse has dramatically increased over the last few decades resulting in many people suffering from opioid use disorder (OUD). The prevalence of opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. Coinciding with increases in exposure to opioids, the United States has also observed increases in multiple Narcan (naloxone) administrations as life-saving measures for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is a main symptom of OUD and opioid withdrawal syndrome, and therefore, should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6J mice. We find that morphine administration and withdrawal dysregulate sleep, but not equally across morphine exposure paradigms. Furthermore, many environmental triggers promote relapse to drug-seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. Our data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid-induced sleep dysregulation and further validates the construct of this model for opioid dependence and OUD. HighlightsO_LIMorphine withdrawal differentially dysregulates the sleep of male and female mice C_LIO_LI3-day precipitated withdrawal results in larger changes than spontaneous withdrawal C_LIO_LIOpioid withdrawal affects responses to future sleep deprivation differently between sexes C_LI

neuroscience↗

bioRxiv2021

Examining opioid withdrawal scoring and adaptation of global scoring systems to male and female C57BL/6J mice

Opioid Use Disorder (OUD) is a chronic and relapsing psychiatric condition which is currently the leading cause of accidental death in the US. Symptoms of acute opioid withdrawal resemble a flu-like illness which is accompanied by a dysphoric state. Psychological comorbidities such as anxiety, depression, and disordered sleep can persist for months or years, well into the abstinence period. These symptoms are thought to drive further opioid intake in order to alleviate this unpleasant internal state. Many differences in OUD have been documented between male and female patients, with females at higher risk for relapse and overdose. This study sets out to characterize sex differences in symptoms and behavioral adaptations in mice during early withdrawal. Using our moderate dose, three-day precipitated withdrawal paradigm, we discovered significant effects of sex, time, and drug treatment on early withdrawal behaviors, locomotor activity, and gut motility in C57BL/6J mice. Here I will discuss previous methods of condensing behavioral phenotypes into one global withdrawal score, and propose a new methodology. This method increases the ability to detect nuanced effects and allows for more accurate translation across strain, sex, paradigm, and experimental context. Classification of opioid withdrawal-induced behavioral adaptations will allow for improved behavioral analysis of pharmacological manipulations, and investigations of brain circuitry involved in opioid withdrawal, as well as future screening of compounds with potential therapeutic benefit for the treatment of OUD.

neuroscience↗

bioRxiv2018

Male and female mice demonstrate divergent cellular responses in the bed nucleus of stria terminalis (BNST) following morphine withdrawal

The United States is experiencing an opioid epidemic of significant proportions, imposing enormous fiscal and societal costs. While prescription opioid analgesics are essential for treating pain, the cessation of these drugs can induce a withdrawal syndrome, and thus opioid use often persists to alleviate or avoid these symptoms. Therefore, it is essential to understand the neurobiology underlying this critical window of withdrawal from opioid analgesics to prevent continued usage. To model this, we administered a low dose of morphine, and precipitated withdrawal with naloxone to investigate the behavioral and cellular responses in C57BL/6J male and female mice. Following 3 days of administration, both male and female mice sensitized to the repeated bouts of withdrawal, as evidenced by their composite global withdrawal score. Female mice exhibited increased withdrawal symptoms on some individual measures, but did not show characteristic weight loss observed in male mice. Because of its role in mediating withdrawal-associated behaviors, we examined neuronal excitability and inhibitory synaptic transmission in the bed nucleus of the stria terminalis (BNST) 24 hours following the final precipitated withdrawal. In male mice, morphine withdrawal increased spontaneous GABAergic signaling compared to controls. In contrast, morphine withdrawal decreased spontaneous GABAergic signaling, and increased BNST projection neuron excitability in female mice. Intriguingly, these opposing GABAergic effects were dependent on within slice excitability. Our findings suggest that male and female mice manifest divergent cellular responses in the BNST following morphine withdrawal, and alterations in BNST inhibitory signaling may be a significant factor contributing to the expression of behaviors following opioid withdrawal.

neuroscience↗

bioRxiv2018

Stress-induced alterations of norepinephrine release in the bed nucleus of the stria terminalis of mice

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated noradrenergic release across multiple stimulation parameters, and reduced sensitivity to the 2-adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/335653_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@75ef4aorg.highwire.dtl.DTLVardef@b0fd27org.highwire.dtl.DTLVardef@1bc3afborg.highwire.dtl.DTLVardef@c469f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗