Alcohol

Episodic Ataxia type 2 (EA2), caused by mutations in the CACNA1A gene, results in a loss-of-function of the P/Q type calcium channel, which leads to baseline ataxia, and attacks of dyskinesia, that can last a few hours to a few days. Attacks are brought on by consumption of caffeine, alcohol, and physical or emotional stress. Interestingly, caffeine and stress are common triggers among other episodic channelopathies, as well as causing tremor or shaking in otherwise healthy adults. The mechanism underlying stress and caffeine induced motor impairment remains poorly understood. Utilizing behavior, and in vivo and in vitro electrophysiology in the tottering mouse, a well characterized mouse model of EA2, or WT mice, we first sought to elucidate the mechanism underlying stress-induced motor impairment. We found stress induces attacks in EA2 though the activation of cerebellar alpha 1 adrenergic receptors by norepinephrine (NE) through casein kinase 2 (CK2) dependent phosphorylation. This decreases SK2 channel activity, causing increased Purkinje cell irregularity and motor impairment. Knocking down or blocking CK2 with an FDA approved drug CX-4945 prevented PC irregularity and stress-induced attacks. We next hypothesized caffeine, which has been shown to increase NE levels, could induce attacks through the same alpha 1 adrenergic mechanism in EA2. We found caffeine increases PC irregularity and induces attacks through the same CK2 pathway. Block of alpha 1 adrenergic receptors, however, failed to prevent caffeine-induced attacks. Caffeine instead induces attacks through the block of cerebellar A1 adenosine receptors. This increases the release of glutamate, which interacts with mGluR1 receptors on PC, resulting in erratic firing and motor attacks. Finally, we show a novel direct interaction between mGluR1 and CK2, and inhibition of mGluR1 prior to initiation of attack, prevents the caffeine-induced increase in phosphorylation. These data elucidate the mechanism underlying stress and caffeine-induced motor impairment. Furthermore, given the success of CX-4945 to prevent stress and caffeine induced attacks, it establishes ground-work for the development of therapeutics for the treatment of caffeine and stress induced attacks in EA2 patients and possibly other episodic channelopathies.

SeminarNeuroscience

Role of the gut microbiota in the development of alcohol use disorder

Philippe de Timary

UCLouvain, Belgium, Institute of Neuroscience and Department of Adult Psychiatry

Nov 18, 2021

The gut microbiota is composed of a very large number of bacteria, viruses, fungi and yeasts that play an important role in the body, through the production of a series of metabolites (including neurotransmitters), and through an essential role in the barrier function of the gut and the regulation of immunity and stress response. In this lecture I will present, based mainly on human studies but also on preclinical studies, the evidence for a role of the gut microbiota in the development of alcohol use disorder. I will show the first results of trials to test the effects of nutritional approaches to address these deficits.

SeminarNeuroscienceRecording

Promising Neuroimmune Targets for Alcohol Use Disorder Pathology

Leon Coleman

UNC

Nov 17, 2021

SeminarNeuroscienceRecording

Striatal mechanisms underlying vulnerability for punishment-resistant alcohol drinking

Veronica Alvarez

NIH

Apr 7, 2021

SeminarNeuroscienceRecording

Schizophrenia and Substance Use Disorders: Cracking the Chicken-or-Egg Question

Jibran Khokhar

Department of Biomedical Sciences University of Guelph

Jan 17, 2021

Although substance use disorders (SUDs) occur commonly in patients with schizophrenia and significantly worsen their clinical course, the neurobiological basis of SUDs in schizophrenia is not well understood. Therefore, there is a critical need to understand the mechanisms underlying SUDs in schizophrenia in order to identify potential targets for therapeutic intervention. Since drug use usually begins in adolescence, it is also important to understand the long-term effects of adolescent drug exposure on schizophrenia- and reward- related behaviors and circuitry. This talk will combine pharmacological, behavioral, electrophysiologic (local field potential recordings) and pre-clinical magnetic resonance imaging (resting-state functional connectivity and magnetic resonance spectroscopy) approaches to study these topics with an eye toward developing better treatment approaches.

SeminarNeuroscienceRecording

Social deprivation, coping and drugs: a bad cocktail in the COVID-19 era: evidence from preclinical studies

David Belin

Department of Psychology, University of Cambridge

Dec 7, 2020

The factors that underlie an individual’s vulnerability to switch from controlled, recreational drug use to addiction are not well understood. I will discuss the evidence in rats that in individuals housed in enriched conditions, the experience of drugs in the relative social and sensory impoverishment of the drug taking context, and the associated change in behavioural traits of resilience to addiction, exacerbate the vulnerability to develop compulsive drug intake. I will further discuss the importance of the acquisition of alcohol drinking as a mechanism to cope with distress as a factor of exacerbated vulnerability to develop compulsive alcohol intake. Together these results demonstrate that experiential factors in the drug taking context, which can be substantially driven by social isolation, shape the vulnerability to addiction.

Alcohol

alcohol

Basal Ganglia in addiction

Dopamine receptors dysregulation in BG disease

Elucidating the mechanism underlying Stress and Caffeine-induced motor dysfunction using a mouse model of Episodic Ataxia Type 2

Role of the gut microbiota in the development of alcohol use disorder

Promising Neuroimmune Targets for Alcohol Use Disorder Pathology

Striatal mechanisms underlying vulnerability for punishment-resistant alcohol drinking

Schizophrenia and Substance Use Disorders: Cracking the Chicken-or-Egg Question

Social deprivation, coping and drugs: a bad cocktail in the COVID-19 era: evidence from preclinical studies

Alcohol perturbed locomotor behavior, metabolism, and pharmacokinetics of methamphetamine in rats

BMAL1 in the dorsomedial striatum affects alcohol consumption, affective behavior, and motor function sex-specifically in mice

Chronic alcohol intoxication induces social dominance and aggressive behavior in male mice: Mechanistic and therapeutic approach

Combined treatment with the glycine transporter-1-inhibitor Org24598, varenicline, and bupropion as a new pharmacological treatment concept for alcohol use disorder

Different mechanisms underlie compulsive alcohol self-administration in male and female rats

Differential neuroinflammatory responses to immune challenges in male and female rats prenatally exposed to alcohol

Effects of 5-HT2AR-mGluR2-based interventions on electrophysiological biomarkers in a rat model of alcohol addiction

Examination of adolescent cannabinoid vapour exposure effects on behavioural predictors of addiction and alcohol use disorder features in adult male and female rats

Exploring the role of omega-3/omega-6 balance in long-lasting changes in microglia caused by intermittent alcohol consumption during adolescence

Fecal microbiota transfer reduces alcohol preference in stressed rats

Heavy alcohol drinking during adolescence compromises GABAergic inhibition in adult mouse dentate gyrus granule cells

Impaired expression of the placental angiogenic factor CD146 by prenatal alcohol exposure results in disorganized foetal brain vasculature and neurodevelopmental defects

Impairment of the placenta–cortex transcriptomic signature following prenatal alcohol exposure, leading to dysregulation of angiogenic pathways

The long-term effects of adolescent social stress on alcohol-related behaviors in adulthood

Microglial activation in the anterior cingulate cortex: A biological marker of early adverse events and future vulnerability to develop alcohol use disorder

The mu-opioid receptors in the ventral tegmental area contribute to the high heroin preference shown by Marchigian Sardinian alcohol-preferring rats

Neuronal ensembles of alcohol memories in the nucleus accumbens express a unique transcriptional fingerprint

Neutral sphingomyelinase mediates the comorbidity trias of alcohol abuse, major depression, and bone defects in females

Prenatal alcohol exposure (PAE) leads to dysfunctional formation of excitatory synapses and social impairments in adolescent mice

Role of PRDM2 through the prefrontal projection in stress-induced reinstatement of alcohol seeking: An epigenetic mechanism with translational potential

Selective inhibition of phosphodiesterase 7 enzymes reduces alcohol drinking and seeking in animal models of alcohol use disorders

Sexual dimorphism in compulsive alcohol drinking and its impact on pathological gambling and social dominance: A preclinical study

Unraveling the role of paraventricular thalamic glucagon-like peptide-1 receptors on alcohol-related behaviors in rodents