How Do Personality Dysfunction and Maladaptive Personality Traits Predict Time to Premature Discontinuation of Pharmacological Treatment of ADHD?

Objectives: Non-adherence to medication is common in the adult ADHD clinical group. The goal of this pre-registered study was to examine whether the DSM-5 Alternative Model of Personality Disorder (AMPD), generality personality dysfunction (LPFS-BF 2.0) or maladaptive personality traits (PID-5), can predict time to premature discontinuation of pharmacological treatment beyond other known factors.

Separate mechanisms regulating accumbal taurine levels during baseline conditions and following ethanol exposure in the rat.

Ethanol-induced dopamine release in the nucleus accumbens (nAc) is associated with reward and reinforcement, and for ethanol to elevate nAc dopamine levels, a simultaneous increase in endogenous taurine is required within the same brain region. By employing in vivo microdialysis in male Wistar rats combined with pharmacological, chemogenetic and metabolic approaches, our aim with this study was to identify mechanisms underlying ethanol-induced taurine release. Our results demonstrate that the taurine elevation, elicited by either systemic or local ethanol administration, occurs both in presence and absence of action potential firing or NMDA receptor blockade.

Conceptualizing adult ADHD with the DSM alternative model of personality disorder.

Personality traits and personality disorders are related to ADHD and indicate dysfunction in clinical populations. The goals of this study were to examine how the DSM-5 Alternative Model of Personality Disorder (AMPD) a) indicates the presence of ADHD and b) communicates information about dysfunction over and above ADHD diagnosis. A sample of 330 adult psychiatric patients with and without ADHD (60% female; mean age 33 years) were assessed for ADHD symptoms, personality impairment, maladaptive personality traits, and functional life impairment domains.

Pre- and postsynaptic signatures in the prelimbic cortex associated with "alcohol use disorder" in the rat.

The transition to alcohol use disorder (AUD) involves persistent neuroadaptations in executive control functions primarily regulated by the medial prefrontal cortex. However, the neurophysiological correlates to behavioral manifestations of AUD are not fully defined. The association between cortical neuroadaptations and behavioral manifestations of addiction was studied using a multi-symptomatic operant model based on the DSM-5 diagnostic criteria for AUD.

Alcohol and the dopamine system.

The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system.

AUD in perspective.

Alcohol is a major cause of pre-mature death and individual suffering worldwide, and the importance of diagnosing and treating AUD cannot be overstated. Given the global burden and the high attributable factor of alcohol in a vast number of diseases, the need for additional interventions and the development of new medicines is considered a priority by the World Health Organization (WHO). As of today, AUD is severely under-treated with a treatment gap nearing 90%, strikingly higher than that for other psychiatric disorders.

A randomized, double-blind, placebo-controlled, multicentre trial on the efficacy of varenicline and bupropion in combination and alone for treatment of alcohol use disorder: Protocol for the COMB study.

Background: Alcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence.

Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum.

Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS.

Regulation of ethanol-mediated dopamine elevation by glycine receptors located on cholinergic interneurons in the nucleus accumbens.

Alcohol use disorder is one of the major psychiatric disorders worldwide, and there are many factors and effects contributing to the disorder, for example, the experience of ethanol reward. The rewarding and reinforcing properties of ethanol have been linked to activation of the mesolimbic dopamine system, an effect that appears to involve glycine receptors (GlyRs) in the nucleus accumbens. On which neuronal subtypes these receptors are located is, however, not known.

Acamprosate reduces ethanol intake in the rat by a combined action of different drug components.

Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as relapse prevention therapy. The mechanism underlying its effect has in some studies been attributed to the calcium moiety and not to the N-acetylhomotaurine part of the compound. We recently suggested that the dopamine elevating effect of acamprosate is mediated both by N-acetylhomotaurine and calcium in a glycine receptor dependent manner.

The GlyT1-inhibitor Org 24598 facilitates the alcohol deprivation abolishing and dopamine elevating effects of bupropion + varenicline in rats.

Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied.

Subregion specific neuroadaptations in the female rat striatum during acute and protracted withdrawal from nicotine.

Epidemiological studies and clinical observations suggest that nicotine, a major contributor of the global burden of disease, acts in a partially sex specific manner. Still, preclinical research has primarily been conducted in males. More research is thus required to define the effects displayed by nicotine on the female brain.

Free-access intravenous alcohol self-administration in social drinkers and individuals with alcohol use disorder: Evaluation of relationships with phosphatidylethanol and self-reported alcohol consumption.

Background: The free-access (FA) intravenous alcohol self-administration (IV-ASA) paradigm is an experimental approach that can identify modulators of alcohol consumption in humans. Moreover, the outcome measures of IV-ASA paradigms are associated with self-reported alcohol intake using the timeline follow-back method (TLFB). To evaluate how FA IV-ASA reflects drinking in real life, we examined the relationship between an objective marker of recent alcohol intake, phosphatidylethanol in blood (B-PEth), and TLFB and measures obtained during IV-ASA in individuals with alcohol use disorder (AUD) and social drinkers (SD).

Acute and chronic effects by nicotine on striatal neurotransmission and synaptic plasticity in the female rat brain.

Introduction: Tobacco use is in part a gendered activity, yet neurobiological studies outlining the effect by nicotine on the female brain are scarce. The aim of this study was to outline acute and sub-chronic effects by nicotine on the female rat brain, with special emphasis on neurotransmission and synaptic plasticity in the dorsolateral striatum (DLS), a key brain region with respect to the formation of habits.

Methods: microdialysis and electrophysiology were performed in nicotine naïve female Wistar rats, and following sub-chronic nicotine exposure (0.

Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration.

Aims: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population).

Sodium acamprosate and calcium exert additive effects on nucleus accumbens dopamine in the rat.

Acamprosate (Campral® - calcium-bis[N-acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect.

Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial.

Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation.

Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients.

Sustained inhibitory transmission but dysfunctional dopamine D2 receptor signaling in dorsal striatal subregions following protracted abstinence from amphetamine.

Behavioral sensitization to amphetamine is a complex phenomenon that engages several neurotransmitter systems and brain regions. While dysregulated signaling in the mesolimbic dopamine system repeatedly has been linked to behavioral sensitization, later research has implicated dorsal striatal circuits and GABAergic neurotransmission in contributing to behavioral transformation elicited by amphetamine. The aim of this study was thus to determine if repeated amphetamine exposure followed by abstinence would alter inhibitory neurotransmission in dorsal striatal subregions.

The glycine-containing dipeptide leucine-glycine raises accumbal dopamine levels in a subpopulation of rats presenting a lower endogenous dopamine tone.

Interventions that elevate glycine levels and target the glycine receptor (GlyR) in the nucleus Accumbens (nAc) reduce ethanol intake in rats, supposedly by acting on the brain reward system via increased basal and attenuated ethanol-induced nAc dopamine release. Glycine transport across the blood brain barrier (BBB) appears inefficient, but glycine-containing dipeptides elevate whole brain tissue dopamine levels in mice. This study explores whether treatment with the glycine-containing dipeptides leucine-glycine (Leu-Gly) and glycine-leucine (Gly-Leu) by means of a hypothesized, facilitated BBB passage, alter nAc glycine and dopamine levels and locomotor activity in two rodent models.

Differential and long-lasting changes in neurotransmission in the amygdala of male Wistar rats during extended amphetamine abstinence.

Amphetamine addiction is associated with maladaptive actions that promotes continued use despite negative consequences, and a high risk of relapse even after protracted abstinence. Considering the role of the amygdala in regulating incentive motivation and reward-based behavior, the aim of this study was to assess neuroadaptations in subregions of the amygdala elicited by a brief period of discontinuous amphetamine exposure (2.0 mg/kg/day, 5 days) followed by abstinence (2 weeks, 1 month, 3 months) in male Wistar rats.

Astrocytes modulate extracellular neurotransmitter levels and excitatory neurotransmission in dorsolateral striatum via dopamine D2 receptor signaling.

Astrocytes provide structural and metabolic support of neuronal tissue, but may also be involved in shaping synaptic output. To further define the role of striatal astrocytes in modulating neurotransmission we performed in vivo microdialysis and ex vivo slice electrophysiology combined with metabolic, chemogenetic, and pharmacological approaches. Microdialysis recordings revealed that intrastriatal perfusion of the metabolic uncoupler fluorocitrate (FC) produced a robust increase in extracellular glutamate levels, with a parallel and progressive decline in glutamine.

Differential dopamine release by psychosis-generating and non-psychosis-generating addictive substances in the nucleus accumbens and dorsomedial striatum.

Schizophrenia is associated with three main categories of symptoms; positive, negative and cognitive. Of these, only the positive symptoms respond well to treatment with antipsychotics. Due to the lack of effect of antipsychotics on negative symptoms, it has been suggested that while the positive symptoms are related to a hyperdopaminergic state in associative striatum, the negative symptoms may be a result of a reduced dopamine (DA) activity in the nucleus accumbens (nAc).

Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.

Background: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration.