Understanding why the quit rate among smokers of menthol cigarettes is lower than non-menthol requires identifying neurons that are altered by nicotine, menthol, and acetylcholine. Dopaminergic (DA) in ventral tegmental area (VTA) mediate positive reinforcing effects nicotine. Using mouse models, we show enhances nicotine-induced changes nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number function more alone. also neuron...

Chronic exposure to nicotine up-regulates high sensitivity nicotinic acetylcholine receptors (nAChRs) in the brain. This up-regulation partially underlies addiction and may also contribute protection against Parkinson’s disease. nAChRs containing α6 subunit (α6* nAChRs) are expressed neurons several brain regions, but comparatively little is known about effect of chronic on these nAChRs. We report here that α6* mouse regions (substantia nigra pars compacta, ventral tegmental area, medial...

Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol smokers. We investigated the effect long-term alone on midbrain neurons containing nAChRs. In dopaminergic (DA) from mice fluorescent nAChR subunits, increased number α4 α6 but this upregulation did not occur GABAergic neurons. Thus, chronic produces a cell-type-selective...

Abstract Introduction Although the use of combustible cigarettes has decreased in many urban regions America, electronic nicotine delivery systems (ENDS) dramatically increased. ENDS, or (e-cigarettes), differ from given that there are no restrictions on flavorant additives e-liquids. With 95% ENDS users vaping flavored e-liquids, it is critical to understand how flavors alter vaping-related behaviors. We have previously shown menthol and green apple enhance reward-related behavior a mouse...

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurological and metabolic diseases. However, how the proteostasis network orchestrates folding assembly of multi-subunit membrane proteins poorly understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1 ), a heat shock protein in endoplasmic reticulum lumen, as most enriched interacting chaperone for gamma-aminobutyric acid type A (GABA ) receptors. Here, we show that enhances functional...

Glycosylphosphatidylinositol-anchored neurotoxin-like receptor binding proteins, such as lynx modulators, are topologically positioned to exert pharmacological effects by the extracellular portion of nAChRs. These actions generally thought proceed when both and nAChRs on plasma membrane. Here, we demonstrate that lynx1 also exerts α4β2 within endoplasmic reticulum. Lynx1 affects assembly nascent α4 β2 subunits alters stoichiometry population reaches Additionally, these data suggest shifts...

Retrospective epidemiological studies show an inverse correlation between susceptibility to Parkinson's disease and a person's history of tobacco use. Animal model suggest nicotine as neuroprotective agent nicotinic acetylcholine (ACh) receptors (nAChRs) targets for neuroprotection, but the underlying mechanism(s) are unknown. We cultured mouse ventral midbrain neurons 3 weeks. Ten 20% were dopaminergic (DA), revealed by tyrosine hydroxylase (TH) immunoreactivity. evoked mild endoplasmic...

While nicotine is the primary addictive component in tobacco products, additional flavors have become a concern with growing popularity of electronic delivery systems (ENDS). For this reason, we begun to investigate popular and ENDS flavors. Here, examined farnesol, chemical flavorant used green apple fruit e-liquids, for its ability produce reward-related behavior. Using male female 3-6 month old C57BL/6 J mice farnesol doses 0.1, 1, 10 mg/kg identified sex-dependent effect conditioned...

Electronic nicotine delivery systems (ENDS) are distinctly different from combustible cigarettes because of the availability flavor options. Subjective measures have been used to demonstrate that adults and adolescents prefer flavors for various reasons; (1) they pleasing (2) mask harshness nicotine. Despite this, there few investigations into molecular interactions connect chemical flavorants smoking or vaping-related behaviors. Here, we investigated effects three (hexyl acetate, ethyl...

Electronic nicotine delivery systems (ENDS) differ from combustible cigarettes given that nicotine-salt or nicotine-freebase may be used depending on the product. We have investigated how and freebase formulations alter e-Vape® self-administration (EVSA) behavior plasma cotinine levels in male female mice. Adult C57/BL6 J mice were EVSA assigned vaping e-liquids (50:50 PGVG, 6 mg/mL nicotine-freebase, nicotine-salt). Mice escalated a fixed ratio 1 (FR1) schedule daily 2 h sessions then...

The medial habenula (MHb) has been identified as the limiting factor for nicotine intake and facilitating withdrawal. However, few studies have assessed MHb neuronal excitability in response to nicotine, and, currently, a gap knowledge is present finding behavioral correlates region. Moreover, no study date evaluated sex or dosage factors of MHb. Here, we utilized an e-vape self-administration (EVSA) model determine differences between sexes with different dosages ± menthol. Following this...

The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in STN effectively alleviate symptoms movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about mechanisms modulation STN, we studied cellular circuit aspects nicotinic acetylcholine receptors (nAChRs) mouse STN. We discovered two largely divergent microcircuits STN; these are regulated part by either α4β2 or α7...

Abstract While combustible cigarette smoking has declined, the use of electronic nicotine delivery systems (ENDS) increased. ENDS are popular among adolescents, and chemical flavorants an increasing concern because growing zero-nicotine flavored e-liquids. Despite this, little is known regarding effects on vaping-related behavior. Following previous studies demonstrating green apple flavorant, farnesol, enhances reward exhibits rewarding properties without nicotine, this work focuses...

Abstract Introduction A wide variety of nicotine concentrations and formulations are available to users electronic delivery systems (ENDS). This is increasingly true when considering the many flavors with ENDS products. To date, there have been few preclinical investigations into impact doses, without flavors, on vaping-related behaviors. present study evaluated how relevant tank-based pod-based ENDS, reinforcement-related behavior in a mouse model. Aims Methods Adult male female C57/BL6J...

A number of mutations in α4β2-containing (α4β2*) nicotinic acetylcholine (ACh) receptors (nAChRs) are linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), including one the β2 subunit called β2V287L. Two α4β2* subtypes with different stoichiometries and ACh sensitivities co-exist brain, a high-sensitivity subtype (α4)2(β2)3 stoichiometry low-sensitivity (α4)3(β2)2 stoichiometry. The α5 also co-assembles α4β2 form α5α4β2 nAChR. Previous studies suggest that β2V287L mutation...

Abstract The regulation of synaptic connectivity in the brain is vital to proper functioning and development CNS. Formation neural networks CNS has been shown be heavily influenced by astrocytes, which secrete factors, including thrombospondin (TSP) family proteins, that promote synaptogenesis. However, whether this process different between males females not thoroughly investigated. In study, we found cortical neurons purified from newborn male rats showed a significantly more robust...

Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one the most promising approaches for therapeutics. We have previously reported on pharmacological activity several compounds that act as negative allosteric modulators (NAMs) nAChRs. In following studies, effects 30 NAMs from our small chemical library both human α4β2 (Hα4β2) and α3β4 (Hα3β4) nAChRs expressed in embryonic kidney ts201 cells were investigated. During calcium accumulation assays,...

Electronic nicotine delivery systems (ENDS) are unique from combustible cigarettes due to the availability of flavor options which make these devices popular among adolescents. However, there no preclinical investigations into impact vaporized on late-developing brain regions such as prefrontal cortex. Here, we investigated how neuronal function and drug self-administration differed between adult-exposed adolescent-exposed mice. Male female adolescent adult C57BL/6J mice were used in a...

Neuronal nicotinic receptors have been implicated in several diseases and disorders such as autism, Alzheimer's disease, Parkinson's epilepsy, various forms of addiction. To understand the role these conditions, it would be beneficial to selective molecules that target specific vitro vivo. Our laboratory has previously identified novel negative allosteric modulators human α4β2 (Hα4β2) α3β4 (Hα3β4) receptors. The effects sulfonylpiperazine analogues act on both Hα4β2 nAChRs Hα3β4 were...

Abstract Menthol contributes to poor cessation rates among smokers, in part because menthol enhances nicotine reward and reinforcement. Mentholated tobacco products contain (−)-menthol (+)-menthol, varying proportions. We examined these two stereoisomers for their ability upregulate α4β2 nAChRs alter dopamine neuron firing frequency using long-term, low-dose (≤500 n m ) exposure that is pharmacologically relevant smoking. found upregulates while (+)-menthol does not. also decreases baseline...