Two single arm trials of AKL-T01, a digital therapeutic for adolescents and adults with ADHD.

Inattention symptoms represent a key driver of functional impairment in ADHD and often persist into adolescence and adulthood, underscoring a need for novel treatments targeting attentional control. We evaluated AKL-T01-a digital therapeutic that is FDA-cleared for children 8-12 y with ADHD-in adolescents and adults with ADHD in two independent single-arm trials: STARS-ADHD-Adolescent, a 4-week trial in adolescents 13-17 y (n = 162 enrolled), and STARS-ADHD-Adult, a 6-week trial in adults 18 and older (n = 221 enrolled). AKL-T01 was linked with improvements on the Test of Variables of Attention (TOVA) Attention Comparison Score (ACS) of 2.

Midazolam, methamphetamine, morphine and nicotine intake in high-drinking-in-the-dark mice.

The high-drinking-in-the-dark (HDID) lines of mice were selectively bred for achieving high blood alcohol levels in the drinking-in-the-dark (DID) task and have served as a unique genetic risk model for binge-like alcohol intake. However, little is known about their willingness to consume other addictive drugs. Here, we examined (a) whether the HDID-1 and HDID-2 lines of mice would voluntarily consume midazolam, methamphetamine, morphine and nicotine in a DID test and (b) whether the HDID lines differ from their founders, heterogeneous stock/Northport (HS/NPT), in consumption levels of these drugs at the concentrations tested.

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line.

The High Drinking in the Dark (HDID-1) line of mice has been selectively bred for achieving high blood alcohol levels (BALs) in the Drinking in the Dark task, a model of binge-like drinking. Recently, we determined that glucocorticoid receptor (GR) antagonism with either mifepristone or CORT113176 (a selective GR antagonist) reduced binge-like ethanol intake in the HDID-1 mice, but not in their founder line, HS/NPT. Here, we examined whether the selection process may have altered glucocorticoid functioning by measuring (1) plasma corticosterone levels and (2) expression of the genes encoding GR () and two of its chaperone proteins FKBP51 and FKBP52 ( and ) in the brains (nucleus accumbens, NAc) of HDID-1 and HS/NPT mice.

Central nucleus of the amygdala projections onto the nucleus accumbens core regulate binge-like alcohol drinking in a CRF-dependent manner.

Rationale: The nucleus accumbens (NAc) is important for regulating a number of behaviors, including alcohol and substance use. We previously found that chemogenetically manipulating neuronal activity in the NAc core regulates binge-like drinking in mice. The central amygdala (CeA) is also an important regulator of alcohol drinking, and projects to the NAc core.

Long-term alcohol drinking in High Drinking in the Dark mice is stable for many months and does not show alcohol deprivation effects.

We have modelled genetic risk for binge-like drinking by selectively breeding High Drinking in the Dark-1 and -2 (HDID-1 and HDID-2) mice for their propensity to reach intoxicating blood alcohol levels (BALs) after binge-like drinking in a single bottle, limited access paradigm. Interestingly, in standard two-bottle choice (2BC) tests for continuously available alcohol versus water, HDID mice show modest levels of preference. This indicates some degree of independence of the genetic contributions to risk for binge-like and sustained, continuous access drinking.

The impact of Drinking in the Dark (DID) procedural manipulations on ethanol intake in High Drinking in the Dark (HDID) mice.

The High Drinking in the Dark mouse lines (HDID-1 and HDID-2) were selectively bred to achieve high blood ethanol concentrations (BECs) in the Drinking in the Dark (DID) task, a widely used model of binge-like intake of 20% ethanol. There are several components that differentiate DID from other animal models of ethanol intake: time of day of testing, length of ethanol access, single-bottle access, and individual housing. Here, we sought to determine how some of these individual factors contribute to the high ethanol intake observed in HDID mice.

Targeting the Glucocorticoid Receptor Reduces Binge-Like Drinking in High Drinking in the Dark (HDID-1) Mice.

Background: Chronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive-like alcohol intake. GR antagonism can prevent dependence-induced escalation in drinking, but very little is known about the role of GR in regulating high-risk nondependent alcohol intake. Here, we investigate the role of GR in regulating binge-like drinking and aversive responses to alcohol in the High Drinking in the Dark (HDID-1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) in the Drinking in the Dark (DID) test, and in their founder line, the HS/NPT.

Correction to: Transcriptional Regulators as Targets for Alcohol Pharmacotherapies.

Figure 1 was published incorrectly in this chapter. The original chapter was corrected.

Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice.

Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line.

Ethanol acts on KCNK13 potassium channels in the ventral tegmental area to increase firing rate and modulate binge-like drinking.

Alcohol excitation of the ventral tegmental area (VTA) is important in neurobiological processes related to the development of alcoholism. The ionotropic receptors on VTA neurons that mediate ethanol-induced excitation have not been identified. Quinidine blocks ethanol excitation of VTA neurons, and blockade of two-pore potassium channels is among the actions of quinidine.

Regulation of anxiety-like behavior and Crhr1 expression in the basolateral amygdala by LMO3.

The LIM domain only protein LMO3 is a transcriptional regulator that has been shown to regulate several behavioral responses to alcohol. Specifically, Lmo3 null (Lmo3) mice consume more ethanol in a binge-drinking test and show enhanced ethanol-induced sedation. Due to the high comorbidity of alcohol use and anxiety, we investigated anxiety-like behavior in Lmo3 mice.

Transcriptional Regulators as Targets for Alcohol Pharmacotherapies.

Alcohol use disorder (AUD) is a chronic relapsing brain disease that currently afflicts over 15 million adults in the United States. Despite its prevalence, there are only three FDA-approved medications for AUD treatment, all of which show limited efficacy. Because of their ability to alter expression of a large number of genes, often with great cell-type and brain-region specificity, transcription factors and epigenetic modifiers serve as promising new targets for the development of AUD treatments aimed at the neural circuitry that underlies chronic alcohol abuse.

Variability in C-reactive protein is associated with cognitive impairment in women living with and without HIV: a longitudinal study.

Despite the availability of effective antiretroviral therapies, cognitive impairment (CI) remains prevalent in HIV-infected (HIV+) individuals. Evidence from primarily cross-sectional studies, in predominantly male samples, implicates monocyte- and macrophage-driven inflammatory processes linked to HIV-associated CI. Thus, peripheral systemic inflammatory markers may be clinically useful biomarkers in tracking HIV-associated CI.

Cortisol reactivity and emotional memory after psychosocial stress in oral contraceptive users.

Oral contraceptive (OC) users typically show a blunted or no cortisol response to psychosocial stress. Although most OC regimens include both an inactive (dummy) and active pill phase, studies have not systematically investigated cortisol responses during these pill phases. Further, high levels of cortisol following a stressor diminish retrieval of emotional material, but the effects of stress on memory among OC users are poorly understood.

Stellate ganglion blockade and verbal memory in midlife women: Evidence from a randomized trial.

Objectives: In a pilot randomized clinical trial of active stellate ganglion blockade (SGB) versus sham control, SGB significantly reduced the frequency of reported moderate to severe vasomotor symptoms (VMS) and the frequency of physiologic VMS measured using ambulatory skin conductance monitors. Here we examine secondary effects of SGB on verbal learning and memory.

Study Design: In a randomized, sham-controlled study, 36 women met eligibility criteria for cognitive assessments, of whom 17 were randomized to receive fluoroscopy-guided SGB and 19 to sham control.

Menstrual cycle effects on cortisol responsivity and emotional retrieval following a psychosocial stressor.

This article is part of a Special Issue "Estradiol and cognition". Laboratory-induced stress produces elevations in cortisol and deficits in memory, especially when stress is induced immediately before retrieval of emotionally valent stimuli. Sex and sex steroids appear to influence these stress-induced outcomes, though no study has directly compared the effects of laboratory-induced stress on cortisol and emotional retrieval across the menstrual cycle.