Biology subjects

Slosky, L. M.

Publications and source records attributed to Slosky, L. M..

6 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↗

bioRxiv2024

Design of allosteric modulators that change GPCR G protein subtype selectivity

G protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of G proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we find that small molecules binding the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling rational drug design. We demonstrate that the compound SBI-553 switches NTSR1 G protein preference by acting both as a molecular bumper and a molecular glue. Structurally, SBI-553 occludes G protein binding determinants on NTSR1, promoting association with select G protein subtypes for which an alternative, shallow-binding conformation is energetically favorable. Minor modifications to the SBI-553 scaffold produce allosteric modulators with distinct G protein subtype selectivity profiles. Selectivity profiles are probe-independent, conserved across species, and translate to differences in in vivo activity. These studies demonstrate that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the receptor-transducer interface and, as this pocket is broadly conserved, present a strategy for pathway-selective drug discovery applicable to the diverse GPCR superfamily.

pharmacology and toxicology↗

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↗

bioRxiv2022

Neurotensin receptor allosterism revealed in complex with a biased allosteric modulator

The NTSR1 neurotensin receptor (NTSR1) is a G protein coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward {beta}-Arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and Go with and without the brain penetrant small molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are G subunit selective and positive allosteric modulation and agonism for {beta}-Arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1. These insights promise to both accelerate the structure-guided design of more effective NTSR1 therapeutics and provide insights into the complexities of GPCR allosteric modulation.

biophysics↗

bioRxiv2020

Establishment of Multi-stage Models of Drug Taking and Seeking in Mice

A genetically tractable animal model would provide a needed strategy to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling cocaine and opioid addiction in animals, but technical limitations have precluded the widespread use of IVSA in mice. Here, we describe the first IVSA paradigms for mice that capture the multi-stage nature of the disease and permit predictive modeling. Mice with long-standing indwelling jugular catheters engaged in cocaine or opioid-associated lever responding that was fixed ratio- and dose-dependent, extinguished by the withholding of drug, and reinstated by the presentation of paired cues. Machine learning revealed that vulnerability to drug seeking and relapse were predicted by a mouses a priori response to novelty, sensitivity to drug-induced locomotion, and drug-taking behavior. Application of this behavioral and analysis approach to genetically-engineered mice will facilitate the identification of the neural circuits driving addiction susceptibility and relapse and focused therapeutic development.

neuroscience↗