Biology subjects

LeSage, M. G.

Publications and source records attributed to LeSage, M. G..

5 recordsLinked to original sources

bioRxiv2026

The collective effect of non-nicotine constituents on the reinforcing and neuropharmacological effects of comprehensive cigarette smoke and electronic nicotine delivery system (ENDS) aerosol extracts in rats.

Tobacco product extracts containing nicotine and non-nicotine constituents are useful for understanding the collective role of these constituents in tobacco use disorder (TUD). However, few studies have used extracts with both water-soluble and non-water-soluble constituents with accompanying chemical analysis, or compared behavioral and neuropharmacological effects across product types. To address these limitations, we compared the relative abuse liability of cigarette smoke (CS) and electronic nicotine delivery system (ENDS) aerosol (EA) extracts to nicotine alone using intravenous self-administration in rats, and examined effects on nucleus accumbens (NAc) dopamine (DA) release and binding/function at nicotinic acetylcholine receptors (nAChRs) and other addiction-related receptors in vitro. CS extract contained higher levels of several behaviorally active non-nicotine constituents than EA extract. Both extracts produced a downward/leftward shift in the descending limb of the unit dose-response curve relative to nicotine alone, while only CS extract produced greater compensatory increases in responding compared to nicotine alone. Demand intensity (Q0) was lower for CS but not EA extract, relative to nicotine alone, whereas demand elasticity for both extracts was similar to nicotine alone. Stress-induced reinstatement was comparable between CS extract and nicotine alone but attenuated for EA extract. CS extract, but not EA extract, showed greater potency for 4{beta}2 nAChR activation and substantial binding across numerous non-nAChRs (DA, serotonergic, opioid) relative to nicotine alone at a high screening concentration. CS extract, but not nicotine alone, also inhibited cyclooxygenase (COX)-1 and -2 at smoking-relevant concentrations. There was no difference in NAc DA release between formulations. These findings indicate non-nicotine constituents contribute to certain reinforcing and neuropharmacological effects of CS, and to a lesser extent EA. Our finding of COX inhibition by CS extract warrants further investigation as a potential mechanism contributing to the effects of CS and TUD.

pharmacology and toxicology↗

bioRxiv2026

6-Methylnicotine is a strong agonist at α4β2 and α3β4 nicotinic cholinergic receptors

(-)6-Methylnicotine (6-MN), is a structural analog of (-)nicotine that has been added to some e-cigarette/vape solutions and to nicotine oral pouches. 6-MN binds with high affinity to nicotinic cholinergic receptors (nAChRs) in brain, but its receptor subtype selectivity and its potency to activate and desensitize these receptors is unknown. Also unknown is whether chronic administration of 6-MN increases (upregulates) nAChRs in brain as does nicotine. Currently, 6-MN is unregulated in the U.S. by the FDA. Here we compared 6-MN and nicotine at 4{beta}2 and 3{beta}4 nAChRs, which are two major nAChR subtypes that mediate important functions in the brain and autonomic nervous system. Specifically, we quantitatively compared (-)6-MN and (-)nicotine with respect to receptor binding affinity and functional potency to activate 4{beta}2 and 3{beta}4 nAChRs, as well as its potency to desensitize these receptors, which is one of the key effects of nicotine. In addition, because chronic administration of nicotine upregulates the number of 4{beta}2 nAChRs in rat, mouse and human brain, we measured whether 6-MN also increases these receptors. Our results indicate that 6-MN is a more potent agonist than nicotine at both the 4{beta}2 and 3{beta}4 nAChRs, and it also upregulates nAChRs in brain.

pharmacology and toxicology↗

bioRxiv2024

Differential gene expression and chromatin accessibility in the rat medial prefrontal cortex mediating individual variability in vulnerability to opioid use

We characterized gene transcriptional activity in the medial prefrontal cortex of rats associated with individual differences in vulnerability to three distinct phases of opioid use disorder (OUD). Resilient rats showed many more changes in canonical pathway activity than Vulnerable rats in models of both early and advanced OUD, involving passive opioid exposure and opioid self-administration (SA), respectively. The Resilient/Vulnerable phenotype was also associated across phases with functionally specific gene networks, including those mediating epigenetic, neuroimmune, and neuroplasticity function. In contrast, we identified two phase-specific effects. First, differential activity of a myelination-related gene network was associated with Resilience/Vulnerability measured after passive morphine exposure. Second, expression of the calmodulin-inhibitor Pcp4, a gene recently implicated in a rat opioid SA GWAS analysis, was associated with Resilience/Vulnerability measured after SA but not after passive morphine exposure. Thus, we have identified both general and phase-specific transcriptional signatures involved in OUD vulnerability across its trajectory. TeaserAdaptations in the brain transcriptome are associated with resilience and vulnerability to opioid use disorder.

neuroscience↗

bioRxiv2019

Flavor-specific enhancement of electronic cigarette liquid consumption and preference in mice

BackgroundThe use of electronic cigarettes has increased over the past decade. To determine how the abuse liability of electronic cigarette liquids (e-liquids) differs from nicotine alone, and to determine the impact of flavor, we compared nicotine-containing fruit- and tobacco-flavored e-liquids, and their nicotine-free versions, to nicotine alone in mouse models of oral consumption, reward and aversion. MethodsAdult male C57BL/6J mice voluntarily consumed oral nicotine, equivalent nicotine concentrations of fruit- and tobacco-flavored e-liquid, and equivalent dilutions of the nicotine-free versions in 2-bottle choice tests. Conditioned place preference and place aversion were assessed with peripherally administered e-liquids or nicotine. Serum nicotine and cotinine levels were measured after subcutaneous injections of e-liquid or nicotine. ResultsMice showed higher consumption and preference for the fruit-flavored e-liquid compared with nicotine alone. This increase was not due to the flavor itself as consumption of the nicotine-free fruit-flavored e-liquid was not elevated until the highest concentration tested. The increased consumption and preference were not observed with the tobacco-flavored e-liquid. The conditioned place preference, place aversion and nicotine pharmacokinetics of the fruit-flavored e-liquid were not significantly different from nicotine alone. ConclusionsOur data suggest that fruit, but not tobacco flavor, increased the oral consumption of e-liquid compared with nicotine alone. Moreover, this enhancement was not due to increased consumption of the flavor itself, altered rewarding or aversive properties after peripheral administration, or altered pharmacokinetics. This flavor-specific enhancement suggests that some flavors may lead to higher nicotine intake and increased use of e-liquids compared with nicotine alone. HighlightsO_LIFruit flavor, but not tobacco flavor, enhances e-liquid consumption and preference C_LIO_LIThe nicotine-free flavored e-liquid is not preferred over nicotine alone C_LIO_LIConditioning rewarding and aversive effects are equal between nicotine and e-liquid C_LI

pharmacology and toxicology↗

bioRxiv2019

Higher anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid self-administration in rats.

Understanding factors contributing to individual differences in vulnerability to opioid addiction is essential for developing more effective preventions and treatments, yet few reliable behavioral predictors of subsequent opioid self-administration have been identified in rodents. Sensitivity to the acute effects of initial drug exposure predicts later addiction vulnerability in both humans and animals, but the relationship of sensitivity to withdrawal from initial drug exposure and later drug use vulnerability is unclear. The goal of the current study was to evaluate whether the degree of anhedonia experienced during withdrawal from early opioid exposure predicts subsequent vulnerability to opioid addiction. Rats were first tested for withdrawal sensitivity following acute injections of morphine (i.e., "acute dependence"), measured as elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during naloxone-precipitated and spontaneous withdrawal. Rats were then tested for addiction vulnerability using various measures of i.v. morphine self-administration (MSA) including acquisition, demand, extinction, and reinstatement induced by morphine, stress, and/or drug-associated cues. Greater naloxone-precipitated withdrawal across repeated morphine injections and greater peak spontaneous withdrawal severity following a single morphine injection were associated with lower addiction vulnerability on multiple MSA measures. Withdrawal-induced anhedonia predicted a wider range of MSA measures than did any individual measure of MSA itself. These data suggest that high anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid addiction vulnerability in rodents, thereby establishing one of the first behavioral measures to predict individual differences in opioid SA. This model promises to be useful for furthering our understanding of behavioral and neurobiological mechanisms underlying vulnerability to opioid addiction.

animal behavior and cognition↗