Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABAA Receptors

The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABAA and glycine receptors in regulating synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc). Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABAA receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10 μM), inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10 μM) and blocked by GABAA receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50 μM in perfusate) only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200 μM in perfusate) decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABAA and glycine receptors are tonically activated and modulate striatal transmission in a partially subregion-specific manner

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.

BackgroundAlcohol 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. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies.MethodsConsenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5‒2 mg; bupropion SR 150‒300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022.DiscussionThe COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction. Study Code COMB-BO8, EudraCT 2018-000048-24, Version 3.2, Lidö & deBejczy, 2020-06-16; https://clinicaltrials.gov identifier NCT04167306

Adult ADHD and emerging models of maladaptive personality: a meta-analytic review

BACKGROUND : ADHD is a highly consequential disorder that is estimated to affect 2.5% of the adult population. Emerging models of psychopathology posit that disorders like ADHD can be usefully situated within general models of individual differences in personality, such as those recently implemented in the DSM and ICD for the diagnosis of personality disorder. Previous research and systematic reviews have linked adult ADHD to the personality traits Conscientious Inhibition and Negative Emotionality. However, there have been some inconsistencies in the literature and research embedding ADHD-personality connections in the DSM-5 and ICD-11 personality disorder models has been limited. The goal of this paper was to systematically review associations between adult ADHD and personality traits, organized within a maladaptive five factor framework. METHOD: A comprehensive literature search yielded 13 papers whose effects were meta-analyzed. RESULTS: Results supported associations between ADHD and low Conscientious Inhibition and high Negative Emotionality. However, interesting patterns of variability were observed, potentially related to issues such as instrumentation and facet variation. CONCLUSION:Results support the clinical application of personality assessment for suggesting risk for ADHD symptoms, and point to important directions for further research

Treatment arms and schematic time line for study visits.

Treatment arms and schematic time line for study visits.</p

Sites participating in the COMB study.

BackgroundAlcohol 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. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies.MethodsConsenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5‒2 mg; bupropion SR 150‒300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022.DiscussionThe COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction. Study Code COMB-BO8, EudraCT 2018–000048–24, Version 3.2, Lidö & deBejczy, 2020-06-16; https://clinicaltrials.gov identifier NCT04167306.</div

Adult ADHD and emerging models of maladaptive personality: a meta-analytic review.

BackgroundADHD is a highly consequential disorder that is estimated to affect 2.5% of the adult population. Emerging models of psychopathology posit that disorders like ADHD can be usefully situated within general models of individual differences in personality, such as those recently implemented in the DSM and ICD for the diagnosis of personality disorder. Previous research and systematic reviews have linked adult ADHD to the personality traits Conscientious Inhibition and Negative Emotionality. However, there have been some inconsistencies in the literature and research embedding ADHD-personality connections in the DSM-5 and ICD-11 personality disorder models has been limited. The goal of this paper was to systematically review associations between adult ADHD and personality traits, organized within a maladaptive five factor framework.MethodA comprehensive literature search yielded 13 papers whose effects were meta-analyzed.ResultsResults supported associations between ADHD and low Conscientious Inhibition and high Negative Emotionality. However, interesting patterns of variability were observed, potentially related to issues such as instrumentation and facet variation.ConclusionResults support the clinical application of personality assessment for suggesting risk for ADHD symptoms, and point to important directions for further research