Sex- and Genotype-Dependent Nicotine-Induced Behaviors in Adult Rats with a Human Polymorphism (rs2304297) in the 3'-UTR of the CHRNA6 Gene.

Introduction: The widespread use of nicotine across ages culminates in substantial consequences on individual health, public health, and broader socioeconomic strain. Concerningly, adolescence is a uniquely vulnerable stage in which exploratory drug exposure imposes detrimental effects on reward circuitry, cognitive function, and neurochemical processes. A single nucleotide polymorphism (SNP), rs2304297, in the 3'-untranslated region (UTR) of the CHRNA6 gene has been linked to increased nicotine use in humans.

"Unraveling the role of , the neuronal α6 nicotinic acetylcholine receptor subunit".

The increased prevalence of electronic cigarettes, particularly among adolescents, has escalated concerns about nicotine addiction. Nicotine, a potent psychostimulant found in tobacco products, exerts its effects by interacting with nicotinic acetylcholine receptors (nAChRs) in the brain. Recent findings in both pre-clinical and clinical studies have enhanced our understanding of nAChRs, overcoming limitations of pharmacological tools that previously hindered their investigation.

Neuroglia in substance use disorders.

Substance use disorders (SUD) remain a major public health concern in which individuals are unable to control their use of substances despite significant harm and negative consequences. Drugs of abuse dysregulate major brain and behavioral functions. Glial cells, primarily microglia and astrocytes, play a crucial role in these drug-induced molecular and behavioral changes.

Dynorphinergic lateral hypothalamus to posterior ventral tegmental area pathway matures after adolescence in male rats.

The highly plastic nature of the adolescent brain is well-known, and is thought to contribute to the unique susceptibility of adolescents to drugs of abuse. However, much investigation of adolescent plasticity has been focused on synaptic plasticity, as synapses are strengthened and pruned. Here, we show that dynorphin neurons in the lateral hypothalamus of adolescent male rats do not respond to low doses of intravenous combined nicotine + ethanol, while male adult lateral hypothalamus dynorphin neurons do.

Sub-chronic nicotine exposure influences methamphetamine self-administration and dopamine overflow in a sex-and genotype-dependent manner in humanized 6 3'-UTR SNP (rs2304297) adolescent rats.

The rewarding effects of drugs of abuse are associated with the dopaminergic system in the limbic circuitry. Nicotine exposure during adolescence is linked to increased use of drugs of abuse with nicotine and methamphetamine (METH) commonly used together. Nicotine acts on neuronal nicotinic acetylcholine receptor (nAChR) systems, critical for reward processing and drug reinforcement, while METH leads to a higher dopamine (DA) efflux in brain reward regions.

Hypersensitivity of the nicotinic acetylcholine receptor subunit (CHRNA2) in female adolescent mice produces deficits in nicotine-induced facilitation of hippocampal-dependent learning and memory.

Adolescence is characterized by a critical period of maturation and growth, during which regions of the brain are vulnerable to long-lasting cognitive disturbances. Adolescent exposure to nicotine can lead to deleterious neurological and psychological outcomes. Moreover, the nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain.

Nicotine on the developing brain.

Developmental periods such as gestation and adolescence have enhanced plasticity leaving the brain vulnerable to harmful effects from nicotine use. Proper brain maturation and circuit organization is critical for normal physiological and behavioral outcomes. Although cigarette smoking has declined in popularity, noncombustible nicotine products are readily used.

Sex- and genotype-dependent nicotine plus cue-primed reinstatement is enhanced in adolescent Sprague Dawley rats containing the human 6 3'-UTR polymorphism (rs2304297).

Rationale: Large-scale human candidate gene studies have indicated that a genetic variant (rs2304297) in the alpha(α)6 nicotinic acetylcholine receptor (nAChR) subunit, encoded by the 6 gene, may play a key role in adolescent nicotine addictive behavior. We hypothesized that the polymorphism selectively enhances nicotine + cue-primed reinstatement, but not nicotine- or cue-reinstatement in α6 (risk) vs. α6 (non-risk) allele carriers, without having baseline effects on natural rewards.

Antibiotic Knockdown of Gut Bacteria Sex-Dependently Enhances Intravenous Fentanyl Self-Administration in Adult Sprague Dawley Rats.

Communication between the brain and gut bacteria impacts drug- and addiction-related behaviors. To investigate the role of gut microbiota on fentanyl reinforcement and reward, we depleted gut bacteria in adult Sprague Dawley male and female rats using an oral, nonabsorbable antibiotic cocktail and allowed rats to intravenously self-administer fentanyl on an escalating schedule of reinforcement. We found that antibiotic treatment enhanced fentanyl self-administration in males, but not females, at the lowest schedule of reinforcement (i.

Male and Female Sprague Dawley Rats Exhibit Equivalent Natural Reward, Nicotine Self-Administration, Extinction, and Reinstatement During Adolescent-Initiated Behaviors.

Introduction: The initiation of nicotine and tobacco use peaks during adolescence. How adolescent males and females differ based on the acquisition of nicotine use and nicotine-seeking behavior is less understood. Our current studies develop a preclinical intravenous self-administration and reinstatement paradigm in male and female Sprague Dawley rats to evaluate how sex impacts the acquisition of nicotine self-administration and nicotine-seeking, when behavior is initiated during adolescence.

Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota.

Gut bacteria influence neural circuits in addiction-related behaviors. Given the association between opioid use, gastrointestinal distress, and microbial dysbiosis in humans and mice, we test the hypothesis that interactions between gut bacteria and the brain mediate the rewarding and reinforcing properties of fentanyl. We implant rats with intravenous catheters in preparation for fentanyl intravenous self-administration (IVSA) on an escalating schedule of reinforcement to determine factors that influence fentanyl intake, including sex, dose, and gut microbiota.

Sex- and Genotype-Dependent Nicotine-Induced Behaviors in Adolescent Rats with a Human Polymorphism (rs2304297) in the 3'-UTR of the 6 Gene.

In human adolescents, a single nucleotide polymorphism (SNP), rs2304297, in the 3'-UTR of the nicotinic receptor subunit gene, 6, has been associated with increased smoking. To study the effects of the human 3'-UTR SNP, our lab generated knock-in rodent lines with either C or G SNP alleles. The objective of this study was to determine if the 3'-UTR SNP is functional in the knock-in rat lines.

Unique effects of nicotine across the lifespan.

Smoking remains the leading cause of preventable death in the United States. Although combustible cigarettes are largely being replaced by tobacco-free products, nicotine use continues to increase in vulnerable populations, including youth, adolescents, and pregnant women. Nicotine exerts unique effects on specific brain regions during distinct developmental periods due to the dynamic expression of nicotinic acetylcholine receptors (nAChRs) throughout the lifespan.

Age- and Sex-Dependent Nicotine Pretreatment Effects on the Enhancement of Methamphetamine Self-administration in Sprague-Dawley Rats.

Introduction: Initiation of tobacco products typically occurs in adolescence. Adolescence is a critical period in development where the maturation of brain neurocircuitry is vulnerable to nicotine. Nicotine-containing products and psychostimulants, such as methamphetamine (METH), are often coabused.

Early adolescent subchronic low-dose nicotine exposure increases subsequent cocaine and fentanyl self-administration in Sprague-Dawley rats.

An exponential rise in nicotine-containing electronic-cigarette use has been observed during the period of adolescence. Preclinical studies have shown that nicotine exposure during early adolescence, but not adulthood, increases subsequent drug intake and reward. Although growing clinical trends highlight that stimulant use disorders are associated with the opioid epidemic, very few studies have assessed the effects of adolescent nicotine exposure on opioid intake.

The role of the gut microbiome in opioid use.

Although the gut and brain are separate organs, they communicate with each other via trillions of intestinal bacteria that collectively make up one's gut microbiome. Findings from both humans and animals support a critical role of gut microbes in regulating brain function, mood, and behavior. Gut bacteria influence neural circuits that are notably affected in addiction-related behaviors.

Specificity of a rodent alpha(α)6 nicotinic acetylcholine receptor subunit antibody.

Alpha(α)6-containing nicotinic acetylcholine receptors (nAChRs) have been implicated in nicotine reward and reinforcement. To date, a commercially available, validated α6 nAChR subunit antibody has not been reported. To evaluate a commercially available neuronal α6 nAChR subunit antibody we performed quantitative western blots on protein from the ventral tegmental area of wild type Sprague Dawley rats.

Prenatal nicotine sex-dependently alters adolescent dopamine system development.

Despite persistent public health initiatives, many women continue to smoke during pregnancy. Since maternal smoking has been linked to persisting sex-dependent neurobehavioral deficits in offspring, some consider nicotine to be a safer alternative to tobacco during pregnancy, and the use of electronic nicotine delivery systems is on the rise. We presently show, however, that sustained exposure to low doses of nicotine during fetal development, approximating plasma levels seen clinically with the nicotine patch, produces substantial changes in developing corticostriatal dopamine systems in adolescence.

Nicotine Gateway Effects on Adolescent Substance Use.

Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine's gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern.

Maternal nicotine exposure effects on adolescent learning and memory are abolished in alpha(α)2* nicotinic acetylcholine receptor-null mutant mice.

The objective of the current study is to test the hypothesis that the deletion of alpha(α)2* nicotinic acetylcholine receptors (nAChRs) (encoded by the Chrna2 gene) ablate maternal nicotine-induced learning and memory deficits in adolescent mice. We use a pre-exposure-dependent contextual fear conditioning behavioral paradigm that is highly hippocampus-dependent. Adolescent wild type and α2-null mutant offspring are exposed to vehicle or maternal nicotine exposure (200 μg/ml, expressed as base) in the drinking water throughout pregnancy until weaning.

Morphine hyposensitivity in streptozotocin-diabetic rats: Reversal by dietary l-arginine treatment.

Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post-STZ and maintained for 6 months post-STZ.

Optogenetic excitation of cholinergic inputs to hippocampus primes future contextual fear associations.

Learning about context is essential for appropriate behavioral strategies, but important contingencies may not arise during initial learning. A variant of contextual fear conditioning, context pre-exposure facilitation, allows us to directly test the relationship between novelty-induced acetylcholine release and later contextual associability. We demonstrate that optogenetically-enhanced acetylcholine during initial contextual exploration leads to stronger fear after subsequent pairing with shock, suggesting that novelty-induced acetylcholine release primes future contextual associations.

α2* Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice.

The absence of α2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of α2* nAChRs ( and ) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9'S) in the α2 subunit (encoded by the gene) to make a hypersensitive nAChR.