Molecular mechanisms underlying sex and treatment-dependent differences in an animal model of cue-exposure therapy for cocaine relapse prevention.

Environmental enrichment combined with the glycine transporter-1 inhibitor Org24598 (EE+ORG) during cocaine-cue extinction (EXT) inhibited reacquisition of 1.0 mg/kg cocaine self-administration in male but not female rats in a previous investigation. In this investigation, we determined if this treatment benefit in males required EXT training and ascertained the molecular basis for the observed sex difference in treatment efficacy.

Assessment of Binge-Like Eating of Unsweetened vs. Sweetened Chow Pellets in BALB/c Substrains.

Binge eating disorder (BED) is defined as chronic episodes of consuming large amounts of food in less than 2 h. Binge eating disorder poses a serious public health problem, as it increases the risk of obesity, type II diabetes, and heart disease. Binge eating is a highly heritable trait; however, its genetic basis remains largely unexplored.

Role of preexisting inhibitory control deficits vs. drug use history in mediating insensitivity to aversive consequences in a rat model of polysubstance use.

Rationale: The nature and predictors of insensitivity to aversive consequences of heroin + cocaine polysubstance use are not well characterized.

Objectives: Translational methods incorporating a tightly controlled animal model of drug self-administration and measures of inhibitory control and avoidance behavior might be helpful for clarifying this issue.

Methods: The key approach for distinguishing potential contributions of pre-existing inhibitory control deficits vs.

Rodent models of attention-deficit hyperactivity disorder: An updated framework for model validation and therapeutic drug discovery.

There are over twenty rodent models of Attention-Deficit Hyperactivity Disorder (ADHD), with most reflecting a recognized ADHD subtype. Of these, only five rat models (Neonatal 6-Hydroxydopamine, Spontaneously Hypertensive Rat, Prenatal Alcohol Exposure, Prenatal Nicotine Exposure, and Lphn3 Knockout) and three mouse models (Dopamine Transporter Knockout, Neurokinin-1 Receptor Knockout, and Prenatal Nicotine Exposure) have a sufficient number of publications to explore their suitability for modelling ADHD with respect to core features, executive dysfunction, and medication effects. An updated view is advanced specifying that an informative model encompasses elevated drug use risk as a means to assess ADHD/Substance Use Disorder (SUD) comorbidity, a common co-occurrence among patients.

Spontaneously Hypertensive Rat substrains show differences in model traits for addiction risk and cocaine self-administration: Implications for a novel rat reduced complexity cross.

Forward genetic mapping of F2 crosses between closely related substrains of inbred rodents - referred to as a reduced complexity cross (RCC) - is a relatively new strategy for accelerating the pace of gene discovery for complex traits, such as drug addiction. RCCs to date were generated in mice, but rats are thought to be optimal for addiction genetic studies. Based on past literature, one inbred Spontaneously Hypertensive Rat substrain, SHR/NCrl, is predicted to exhibit a distinct behavioral profile as it relates to cocaine self-administration traits relative to another substrain, SHR/NHsd.

Integrating data science into the translational science research spectrum: A substance use disorder case study.

The availability of large healthcare datasets offers the opportunity for researchers to navigate the traditional clinical and translational science research stages in a nonlinear manner. In particular, data scientists can harness the power of large healthcare datasets to bridge from preclinical discoveries (T0) directly to assessing population-level health impact (T4). A successful bridge from T0 to T4 does not bypass the other stages entirely; rather, effective team science makes a direct progression from T0 to T4 impactful by incorporating the perspectives of researchers from every stage of the clinical and translational science research spectrum.

Aging-induced microbleeds of the mouse thalamus compared to sensorimotor and memory defects.

The aim of this study is to investigate the relationship between aging and brain vasculature health. Three groups of mice, 3, 17-18, and 24 months, comparable to young adult, middle age, and old human were studied. Prussian blue histology and fast imaging with steady precession T2∗-weighted magnetic resonance imaging were used to quantify structural changes in the brain across age groups.

Sex differences in the effects of a combined behavioral and pharmacological treatment strategy for cocaine relapse prevention in an animal model of cue exposure therapy.

Brief interventions of environmental enrichment (EE) or the glycine transporter-1 inhibitor Org24598 administered with cocaine-cue extinction training were shown previously to inhibit reacquisition of cocaine self-administration in male rats trained to self-administer a moderate 0.3 mg/kg dose of cocaine. Determining how EE and Org24598 synergize in combination in an animal model of cue exposure therapy is novel.

Adolescent-onset vs. adult-onset cocaine use: Impact on cognitive functioning in animal models and opportunities for translation.

Animal models are poised to make key contributions to the study of cognitive deficits associated with chronic cocaine use in people. Advantages of animal models include use of a longitudinal experimental design that can control for drug use history and onset-age, sex, drug consumption, and abstinence duration. Twenty-two studies were reviewed (13 in adult male rats, 5 in adolescent vs.

Cocaine reward and memory after chemogenetic inhibition of distinct serotonin neuron subtypes in mice.

Rationale: We probed serotonin neurons, those denoted by their developmental gene expression as r2Hoxa2-Pet1 (experiment 1) and Drd1a-Pet1 (experiment 2), for differential modulation of cocaine reward and memory as revealed by the expression and development of conditioned place preference (CPP) in transgenic mice.

Objectives: To query roles in CPP, we inhibited neurons cell autonomously in vivo by activating the transgenically expressed, synthetic DREADD receptor hMDi (Di) with the exogenous ligand clozapine-N-oxide (CNO).

Methods: To examine CPP expression, mice were conditioned using behaviorally active doses of cocaine (10.

Facilitating Complex Trait Analysis via Reduced Complexity Crosses.

Genetically diverse inbred strains are frequently used in quantitative trait mapping to identify sequence variants underlying trait variation. Poor locus resolution and high genetic complexity impede variant discovery. As a solution, we explore reduced complexity crosses (RCCs) between phenotypically divergent, yet genetically similar, rodent substrains.

Facilitative effects of environmental enrichment for cocaine relapse prevention are dependent on extinction training context and involve increased TrkB signaling in dorsal hippocampus and ventromedial prefrontal cortex.

Cocaine-cue extinction training combined with brief interventions of environmental enrichment (EE) was shown previously to facilitate extinction and attenuate reacquisition of cocaine self-administration in rats. It is unknown whether or not the usefulness of this approach would be undermined if extinction training took place in a novel rather than familiar context. Drawing on previous studies involving pharmacological interventions, we hypothesized that the facilitative effects of EE for cocaine relapse prevention would be independent of the context used for extinction training.

Predicting substance use disorder using long-term attention deficit hyperactivity disorder medication records in Truven.

About 20% of individuals with attention deficit hyperactivity disorder are first diagnosed during adolescence. While preclinical experiments suggest that adolescent-onset exposure to attention deficit hyperactivity disorder medication is an important factor in the development of substance use disorder phenotypes in adulthood, the long-term impact of attention deficit hyperactivity disorder medication initiated during adolescence has been largely unexplored in humans. Our analysis of 11,624 adolescent enrollees with attention deficit hyperactivity disorder in the Truven database indicates that temporal medication features, rather than stationary features, are the most important factors on the health consequences related to substance use disorder and attention deficit hyperactivity disorder medication initiation during adolescence.

Predicting Substance Use Disorder in ADHD Patients using Long-Short Term Memory Model.

About 20% of individuals with attention deficit hyperactivity disorder (ADHD) are first diagnosed during adolescence. While preclinical experiments suggest that adolescent-onset exposure to ADHD medication is an important factor in the development of substance use disorder (SUD) phenotypes in adulthood, the long-term impact of ADHD medication initiated during adolescence has been largely unexplored in humans. Our analysis of 11,624 adolescent ADHD patients in the Truven database indicates that temporal medication features are the important factors on the health consequences related to SUD and ADHD medication initiation during adolescence.

Blockade of α2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment.

Rationale: Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR.

Objectives: We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR.

Adolescent d-amphetamine treatment in a rodent model of attention deficit/hyperactivity disorder: impact on cocaine abuse vulnerability in adulthood.

Rationale: Stimulant medications for attention-deficit/hyperactivity disorder (ADHD) in adolescents remain controversial with respect to later development of cocaine abuse. Past research demonstrated that adolescent methylphenidate treatment increased several aspects of cocaine self-administration during adulthood using the spontaneously hypertensive rat (SHR) model of ADHD. Presently, we determined effects of the alternate stimulant medication, d-amphetamine, on cocaine self-administration.

Adolescent D-amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood.

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD.

Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation.

This study investigated the combination of environmental enrichment (EE) with cocaine-cue extinction training on reacquisition of cocaine self-administration. Rats were trained under a second-order schedule for which responses were maintained by cocaine injections and cocaine-paired stimuli. During three weekly extinction sessions, saline was substituted for cocaine but cocaine-paired stimuli were presented.

Closing thoughts for cognitive enhancement.

The wide-ranging field of cognition enhancing research along with its ethics as it stands today is summarized. In the forefront are potentially novel drugs and non-pharmacological treatments for cognitive impairment across many different psychiatric and neurologic indications. Today's research will bring new drugs to patients tomorrow, and tomorrow's research will bring new molecular targets to clinical development that should be cognitive domain-specific.

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in spontaneously hypertensive rats (SHRs), a model of ADHD.

Methylphenidate treatment beyond adolescence maintains increased cocaine self-administration in the spontaneously hypertensive rat model of attention deficit/hyperactivity disorder.

Past research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder showed that adolescent methylphenidate treatment enhanced cocaine abuse risk in SHR during adulthood. The acquisition of cocaine self-administration was faster, and cocaine dose-response functions were shifted upward under fixed-ratio and progressive ratio schedules compared to adult SHR that received adolescent vehicle treatment or to control strains that received adolescent methylphenidate treatment. The current study determined if extending treatment beyond adolescence would ameliorate long-term consequences of adolescent methylphenidate treatment on cocaine abuse risk in adult SHR.