SR9883 is a novel small-molecule enhancer of α4β2* nicotinic acetylcholine receptor signaling that decreases intravenous nicotine self-administration in rats.

Background: Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents.

Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma.

Unlabelled: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and non-SHH group3 subtypes. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encode for mitochondrial import inner membrane translocase subunit and is responsible for translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines.

Cannabidiol as a potential cessation therapeutic: Effects on intravenous nicotine self-administration and withdrawal symptoms in mice.

Cigarette smoking remains a leading cause of preventable disease and death worldwide. Due to the devastating negative health effects of smoking, many users attempt to quit, but few are successful in the long-term. Thus, there is a critical need for novel therapeutic approaches.

Extracellular ATP Neurotransmission and Nicotine Sex-Specifically Modulate Habenular Neuronal Activity in Adolescence.

The recent increase in the use of nicotine products by teenagers has revealed an urgent need to better understand the impact of nicotine on the adolescent brain. Here, we sought to examine the actions of extracellular ATP as a neurotransmitter and to investigate whether ATP and nicotinic signaling interact during adolescence. With the GRAB (G-protein-coupled receptor activation-based ATP sensor), we first demonstrated that nicotine induces extracellular ATP release in the medial habenula, a brain region involved in nicotine aversion and withdrawal.

Beyond the label: current evidence and future directions for the interrelationship between electronic cigarettes and mental health.

Electronic cigarette use has dramatically increased over the last decade. With this recent technological development and wide range of constituents in various products, putative adverse effects on the brain and body have been largely unexplored. Here, we review current evidence linking electronic nicotine cigarette use with potential health consequences and provide evidence supporting an association between drug use and depression in humans.

Exomap1 mouse: a transgenic model for studies of exosome biology.

Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that have the same topology as the cell, are enriched in selected exosome cargo proteins, and play important roles in health and disease. To address large unanswered questions regarding exosome biology , we created the transgenic mouse model. In response to Cre recombinase, mice express HsCD81mNG, a fusion protein between human CD81, the most highly enriched exosome protein yet described, and the bright green fluorescent protein mNeonGreen.

Nasal accumulation and metabolism of Δ-tetrahydrocannabinol following aerosol ('vaping') administration in an adolescent rat model.

Passive aerosol exposure to Δ-tetrahydrocannabinol (THC) in laboratory animals results in faster onset of action and less extensive liver metabolism compared to most other administration routes and might thus provide an ecologically relevant model of human cannabis inhalation. Previous studies have, however, overlooked the possibility that rodents, as obligate nose breathers, may accumulate aerosolized THC in the nasal cavity, from where the drug might directly diffuse to the brain. To test this, we administered THC (ten 5-s puffs of 100 mg/mL of THC) to adolescent (31-day-old) Sprague-Dawley rats of both sexes.

Tobacco and nicotine use.

Tobacco smoking is a major determinant of preventable morbidity and mortality worldwide. More than a billion people smoke, and without major increases in cessation, at least half will die prematurely from tobacco-related complications. In addition, people who smoke have a significant reduction in their quality of life.

Effects of Prenatal Nicotine, THC, or Co-Exposure on Cognitive Behaviors in Adolescent Male and Female Rats.

Introduction: Although there has been a decrease in the prevalence of tobacco smoking, exposure to nicotine during pregnancy remains a substantial problem worldwide. Further, given the recent escalation in e-cigarette use and legalization of cannabis, it has become essential to understand the effects of nicotine and cannabinoid co-exposure during early developmental stages.

Aims And Methods: We systematically examined the effects of nicotine and/or THC prenatal exposure on cognitive behaviors in male and female offspring.

Disruption of VGLUT1 in Cholinergic Medial Habenula Projections Increases Nicotine Self-Administration.

Cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) have been studied for their complex contributions to nicotine addiction and have been implicated in nicotine reinforcement, aversion, and withdrawal. While it has been established that MHb cholinergic projections corelease glutamate, no direct evidence has demonstrated a role for this glutamate projection in nicotine consumption. In the present study, a novel floxed [vesicular glutamate transporter 1 (VGLUT1)] mouse was generated and used to create conditional knock-out (cKO) mice that lack VGLUT1 in MHb cholinergic neurons.

Differential Expression Patterns of Lynx Proteins and Involvement of Lynx1 in Prepulse Inhibition.

Negative allosteric modulators, such as lynx1 and lynx2, directly interact with nicotinic acetylcholine receptors (nAChRs). The nAChRs are integral to cholinergic signaling in the brain and have been shown to mediate different aspects of cognitive function. Given the interaction between lynx proteins and these receptors, we examined whether these endogenous negative allosteric modulators are involved in cognitive behaviors associated with cholinergic function.

Huntington's disease mice and human brain tissue exhibit increased G3BP1 granules and TDP43 mislocalization.

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology.

Potentiation of (α4)2(β2)3, but not (α4)3(β2)2, nicotinic acetylcholine receptors reduces nicotine self-administration and withdrawal symptoms.

The low sensitivity (α4)3(β2)2 (LS) and high sensitivity (α4)2(β2)3 (HS) nAChR isoforms may contribute to a variety of brain functions, pathophysiological processes, and pharmacological effects associated with nicotine use. In this study, we examined the contributions of the LS and HS α4β2 nAChR isoforms in nicotine self-administration, withdrawal symptoms, antinociceptive and hypothermic effects. We utilized two nAChR positive allosteric modulators (PAMs): desformylflustrabromine (dFBr), a PAM of both the LS and HS α4β2 nAChRs, and CMPI, a PAM selective for the LS nAChR.

E-cigarette vape and lung ACE2 expression: Implications for coronavirus vulnerability.

Evidence in humans suggests a correlation between nicotine smoking and severe respiratory symptoms with COVID-19 infection. In lung tissue, angiotensin-converting enzyme 2 (ACE2) appears to mechanistically underlie viral entry. Here, we investigated whether e-cigarette vapor inhalation alters ACE2 and nicotinic acetylcholine receptor (nAChR) expression in male and female mice.

Multidimensional Intersection of Nicotine, Gene Expression, and Behavior.

The cholinergic system plays a crucial role in nervous system function with important effects on developmental processes, cognition, attention, motivation, reward, learning, and memory. Nicotine, the reinforcing component of tobacco and e-cigarettes, directly acts on the cholinergic system by targeting nicotinic acetylcholine receptors (nAChRs) in the brain. Activation of nAChRs leads to a multitude of immediate and long-lasting effects in specific cellular populations, thereby affecting the addictive properties of the drug.

Method for Primary Epithelial Cell Culture from the Rat Choroid Plexus.

The choroid plexus consists of a network of secretory epithelial cells localized throughout the lateral, third and fourth ventricles of the brain. Cerebrospinal fluid (CSF) is generated by the choroid plexus and released into the ventricular environment. This biofluid contains an enriched source of proteins, ions, and other signaling molecules for extracellular support of neurons and glial cells within the central nervous system.

Nicotine e-cigarette vapor inhalation and self-administration in a rodent model: Sex- and nicotine delivery-specific effects on metabolism and behavior.

E-cigarettes, which deliver vaporized nicotine, have dramatically risen in popularity in recent years, despite many unanswered questions about safety, efficacy in reducing dependence, and overall impact on public health. Other factors, such as sex, also play an important role in determining behavioral and neurochemical responses to drugs of abuse. In these studies, we sought to develop a protocol for vaporized e-cigarette nicotine self-administration in rats, as a foundation to better understand the differing effects of nicotine exposure routes on behavior and physiological function.

α3* Nicotinic Acetylcholine Receptors in the Habenula-Interpeduncular Nucleus Circuit Regulate Nicotine Intake.

Allelic variation in , the gene encoding the α3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for α3-containing (α3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. α3* nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that hypomorphic mice, which express constitutively low levels of α3* nAChRs, self-administer greater quantities of nicotine (0.

The Interpeduncular-Ventral Hippocampus Pathway Mediates Active Stress Coping and Natural Reward.

Maladaptive stress-related behaviors are integral to multiple complex psychiatric disorders, and it has been well established that serotonergic signaling mediates various aspects of these maladaptive states. In these studies, we sought to uncover the function of a previously undefined serotonergic pathway, which projects from the interpeduncular nucleus (IPN) to the ventral hippocampus (vHipp). Intersectional retrograde and chemogenetic viral manipulation strategies were employed to manipulate the function of the IPN-vHipp pathway during a variety of behavioral measures in male mice.

Nicotinic Receptors Underlying Nicotine Dependence: Evidence from Transgenic Mouse Models.

Nicotine underlies the reinforcing properties of tobacco cigarettes and e-cigarettes. After inhalation and absorption, nicotine binds to various nicotinic acetylcholine receptor (nAChR) subtypes localized on the pre- and postsynaptic membranes of cells, which subsequently leads to the modulation of cellular function and neurotransmitter signaling. In this chapter, we begin by briefly reviewing the current understanding of nicotine's actions on nAChRs and highlight considerations regarding nAChR subtype localization and pharmacodynamics.