Stimulus mediation, specificity and impact of menthol in rats trained to discriminate puffs of nicotine e-cigarette aerosol from nicotine-free aerosol.

Rationale: It is unclear if e-cigarettes have reduced abuse liability relative to traditional cigarettes, especially when considering advanced devices which deliver nicotine more efficiently. Translatable and predictive animal models are needed to addresses this question.

Objectives: Our goal was to explore the subjective stimulus effects of e-cigarettes by training rats to discriminate puffs of nicotine aerosol from vehicle aerosol using an aerosol delivery system designed to model e-cigarette use patterns in humans.

Comparison of three DREADD agonists acting on Gq-DREADDs in the ventral tegmental area to alter locomotor activity in tyrosine hydroxylase:Cre male and female rats.

Rationale: Despite the increasingly pervasive use of chemogenetic tools in preclinical neuroscience research, the in vivo pharmacology of DREADD agonists remains poorly understood. The pharmacological effects of any ligand acting at receptors, engineered or endogenous, are influenced by numerous factors including potency, time course, and receptor selectivity. Thus, rigorous comparison of the potency and time course of available DREADD ligands may provide an empirical foundation for ligand selection.

Assessment of Abuse-Related Discriminative Stimulus Effects of Nicotine Aerosol in Rodents.

The rapid increase in e-cigarette use highlights the importance of developing relevant, predictive animal models exploring their potential health implications. The goal of the present study was to examine the abuse-related effects of brief, repeated e-cigarette aerosol exposures in rodents modeling human e-cigarette user behavior. We evaluated the discriminative stimulus effects of brief, repeated puffs of inhaled nicotine in rats that had been trained to discriminate injected nicotine from saline.

Reinforcing effects of fentanyl and sufentanil aerosol puffs in rats.

Rationale: Rapidly evolving e-cigarette technology developed for self-administering nicotine aerosol has the potential to be utilized to self-administer other aerosolized drugs of abuse. Rodent models which mirror characteristics of human e-cigarette use are necessary to explore the degree to which this may be a public health concern.

Objectives: Our goal was to develop a highly translational model of discrete nose-only aerosol puff drug delivery to explore the reinforcing effects of fentanyl and sufentanil aerosols in rats.

Convergent Evidence From Humans and Drosophila melanogaster Implicates the Transcription Factor MEF2B/Mef2 in Alcohol Sensitivity.

Background: Self-Rating of the Effects of Alcohol (SRE) measures level of response to ethanol (EtOH) in humans. Interestingly, there is a positive relationship between the SRE and risk for abusing alcohol, suggesting mechanistic connections between SRE and alcohol abuse.

Methods: To identify candidate genes with a role in SRE and alcohol-related behavior more generally, we coupled human genetic analyses with studies in Drosophila melanogaster.

Dietary yeast influences ethanol sedation in Drosophila via serotonergic neuron function.

Abuse of alcohol is a major clinical problem with far-reaching health consequences. Understanding the environmental and genetic factors that contribute to alcohol-related behaviors is a potential gateway for developing novel therapeutic approaches for patients that abuse the drug. To this end, we have used Drosophila melanogaster as a model to investigate the effect of diet, an environmental factor, on ethanol sedation.

Discriminative Stimulus Effects of Abused Inhalants.

Inhalants are a loosely organized category of abused compounds defined entirely by their common route of administration. Inhalants include volatile solvents, fuels, volatile anesthetics, gasses, and liquefied refrigerants, among others. They are ubiquitous in modern society as ingredients in a wide variety of household, commercial, and medical products.

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice.

Rationale: There is an emerging body of evidence that implicates a crucial role of γ-aminobutyric acid subtype A (GABAA) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABAA receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics.

Objectives: We tested the hypothesis that the GABAA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice.

Oral operant ethanol self-administration in the absence of explicit cues, food restriction, water restriction and ethanol fading in C57BL/6J mice.

Rationale: Mouse models of ethanol (EtOH) self-administration are useful to identify genetic and biological underpinnings of alcohol use disorder.

Objectives: These experiments developed a novel method of oral operant EtOH self-administration in mice without explicitly paired cues, food/water restriction, or EtOH fading.

Methods: Following magazine and lever training for 0.

N-methyl-D-aspartate receptor channel blocker-like discriminative stimulus effects of nitrous oxide gas.

Nitrous oxide (N2O) gas is a widely used anesthetic adjunct in dentistry and medicine that is also commonly abused. Studies have shown that N2O alters the function of the N-methyl-d-aspartate (NMDA), GABAA, opioid, and serotonin receptors among others. However, the receptors systems underlying the abuse-related central nervous system effects of N2O are unclear.

Pharmacological classification of the abuse-related discriminative stimulus effects of trichloroethylene vapor.

Inhalants are distinguished as a class primarily based upon a shared route of administration. Grouping inhalants according to their abuse-related pharmacological effects using the drug discrimination procedure has the potential to provide a more relevant classification scheme to the research and treatment community. Mice were trained to differentiate the introceptive effects of the trichloroethylene vapor from air using an operant procedure.

Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence.

Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration.

Benzodiazepine-like discriminative stimulus effects of toluene vapor.

In vitro studies show that the abused inhalant toluene affects a number of ligand-gated ion channels.The two most consistently implicated of these are γ-aminobutyric acid type A(GABAA) receptors which are positively modulated by toluene and N-methyl-D-aspartate(NMDA) receptors which are negatively modulated by toluene. Behavioral studies also suggest an interaction of toluene with GABAA and/or NMDA receptors but it is unclear if these receptors underlie the abuse-related intoxicating effects of toluene.

Discriminative stimulus effects of nitrous oxide in mice: comparison with volatile hydrocarbons and vapor anesthetics.

The abuse-related behavioral effects produced by nitrous oxide (N₂O) gas have been suggested as being unique compared with other abused inhalants. The drug discrimination paradigm in animals can be used to study subjective effects of drugs in humans and to test this hypothesis. The goals of the present experiment were to establish N₂O discrimination in mice and to compare its discriminative stimulus effects with those of abused volatile vapors and vapor anesthetics.

Assessment of reinforcement enhancing effects of toluene vapor and nitrous oxide in intracranial self-stimulation.

Rationale: Despite widespread abuse, there are few validated methods to study the rewarding effects of inhalants. One model that may have utility for this purpose is intracranial self-stimulation (ICSS).

Objectives: This study aims to compare and contrast the ICSS reward-facilitating effects of abused inhalants to other classes of abused drugs.

Efficacy of buspirone for attenuating cocaine and methamphetamine reinstatement in rats.

Background: There are no approved pharmacotherapies for preventing psychomotor stimulant relapse. The operant reinstatement model has been suggested as a screen for identifying candidate medications. The present study examined if the anxiolytic buspirone could attenuate reinstatement of extinguished responding in Long-Evans rats that previously self-administered intravenous cocaine or methamphetamine.

Prime-, stress-, and cue-induced reinstatement of extinguished drug-reinforced responding in rats: cocaine as the prototypical drug of abuse.

This unit describes the testing of rats in prime-, footshock-, and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock-induced), or by stimuli previously associated with drug administration (cue-induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior.

Role of adrenal glucocorticoid signaling in prefrontal cortex gene expression and acute behavioral responses to ethanol.

Background: Glucocorticoid hormones modulate acute and chronic behavioral and molecular responses to drugs of abuse including psychostimulants and opioids. There is growing evidence that glucocorticoids might also modulate behavioral responses to ethanol ( EtOH ). Acute EtOH activates the hypothalamic-pituitary-adrenal axis, causing the release of adrenal glucocorticoid hormones.

Ethanol metabolism and osmolarity modify behavioral responses to ethanol in C. elegans.

Background: Ethanol (EtOH) is metabolized by a 2-step process in which alcohol dehydrogenase (ADH) oxidizes EtOH to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase (ALDH). Although variation in EtOH metabolism in humans strongly influences the propensity to chronically abuse alcohol, few data exist on the behavioral effects of altered EtOH metabolism. Here, we used the nematode Caenorhabditis elegans to directly examine how changes in EtOH metabolism alter behavioral responses to alcohol during an acute exposure.

Different genes influence toluene- and ethanol-induced locomotor impairment in C. elegans.

Background: The abused volatile solvent toluene shares many behavioral effects with classic central nervous system depressants such as ethanol. Similarities between toluene and ethanol have also been demonstrated using in vitro electrophysiology. Together, these studies suggest that toluene and ethanol may be acting, at least in part, via common mechanisms.

GABAA-positive modulator selective discriminative stimulus effects of 1,1,1-trichloroethane vapor.

Background: The abuse-related behavioral effects of inhalant vapors are poorly understood but probably involve multiple neurotransmitter receptor mechanisms. The present study examined the receptor systems responsible for transducing the discriminative stimulus of the abused chlorinated hydrocarbon 1,1,1-trichloroethane (TCE) in mice.

Methods: Thirty mice were trained to discriminate 10 min of 12,000 ppm TCE vapor exposure from air using an operant procedure.

Genomic analysis of individual differences in ethanol drinking: evidence for non-genetic factors in C57BL/6 mice.

Genetic analysis of factors affecting risk to develop excessive ethanol drinking has been extensively studied in humans and animal models for over 20 years. However, little progress has been made in determining molecular mechanisms underlying environmental or non-genetic events contributing to variation in ethanol drinking. Here, we identify persistent and substantial variation in ethanol drinking behavior within an inbred mouse strain and utilize this model to identify gene networks influencing such "non-genetic" variation in ethanol intake.

GABA(A) positive modulator and NMDA antagonist-like discriminative stimulus effects of isoflurane vapor in mice.

Rationale: Several neurotransmitter systems have been hypothesized to be involved in the in vivo effects of volatile anesthetics. Drug discrimination may represent a novel procedure to explore the neurochemical systems underlying the sub-anesthetic behavioral effects of these compounds.

Objectives: The purpose of the present study was to examine the contribution of GABA(A) and NMDA receptors to the discriminative stimulus effects of a behaviorally active sub-anesthetic concentration of isoflurane vapor.

The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse.

Stress and renewed contact with drug (a "slip") have been linked to persisting relapse of methamphetamine abuse. Human brain microglial activation has been linked with methamphetamine abuse, and inhibitors of glial cell activation, certain phosphodiesterase (PDE) inhibitors, and glial cell derived neurotrophic factor (GDNF) have been reported to modulate drug abuse effects. Our objective was to determine whether the glial cell attenuator, 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine (AV411, ibudilast), a non-selective PDE inhibitor and promoter of GDNF, could reduce stress- and methamphetamine prime-induced reinstatement of methamphetamine-seeking behavior.

Pharmacological characterization of the discriminative stimulus of inhaled 1,1,1-trichloroethane.

The present study examined the involvement of the GABAA, N-methyl-D-aspartate (NMDA), nicotinic acetylcholine, and mu-opioid receptor systems in the transduction of the discriminative stimulus effects of the abused inhalant 1,1,1-trichloroethane (TCE). Sixteen B6SJLF1/J mice were trained to discriminate 10 min of exposure to 12,000-ppm inhaled TCE vapor from air. Substitution and antagonism tests and TCE blood concentration analysis were subsequently conducted.