GABAergic mechanisms in alcohol dependence.

The target of alcohol's effect on the central nervous system has been sought for more than 50 years in the brain's GABA system. The behavioral and emotional effects of alcohol in humans and rodents are very similar to those of barbiturates and benzodiazepines, and GABA receptors have been shown to be one of the sites of alcohol action. The mechanisms of GABAergic inhibition have been a hotspot of research but have turned out to be complex and controversial.

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.

Somatostatin-Expressing Neurons in the Ventral Tegmental Area Innervate Specific Forebrain Regions and Are Involved in Stress Response.

Expanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Previously we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighboring dopaminergic neurons (Nagaeva et al., 2020).

Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.

Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers.

Periodontitis may predict the use of prescription medicines later in life, a database study.

Medications used for the treatment of diseases also affect oral health. We investigated how having/not having periodontitis at baseline in 1985 was associated with purchases of medicines in the long term. The study paradigm is in the oral health-systemic health connections.

Effects of acute lysergic acid diethylamide on intermittent ethanol and sucrose drinking and intracranial self-stimulation in C57BL/6 mice.

Background: Psychedelics, like lysergic acid diethylamide (LSD), are again being studied as potential therapies for many neuropsychiatric disorders, including addictions. At the same time, the acute effects of psychedelics on rewarding behaviours have been scarcely studied.

Aims: The current study aimed to clarify if LSD decreases binge-like ethanol drinking in mice, and whether the observed acute effects on ethanol consumption are generalizable to a natural reinforcer, sucrose, and if the effects resulted from aversive or reward-attenuating effects caused by LSD.

Electrophysiological Properties of Neurons: Current-Clamp Recordings in Mouse Brain Slices and Firing-Pattern Analysis.

Characterization of an electrically active cell, such as a neuron, demands measurement of its electrical properties. Due to differences in gene activation, location, innervation patterns, and functions, the millions of neurons in the mammalian brain are tremendously diverse in their membrane characteristics and abilities to generate action potentials. These features can be measured with a patch-clamp technique in whole-cell current-clamp configuration followed by detailed post-hoc analysis of firing patterns.

Mice Lacking GABA Receptor Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs.

In the brain, extrasynaptically expressed ionotropic, subunit-containing γ-aminobutyric acid A-type receptors (δ-GABARs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused drug-induced modulation of receptor ionophores affecting chloride ion-mediated inhibitory tonic currents. Often, a transgenic mouse model genetically lacking the δ-GABARs (δ-KO) has been used to study the roles of δ-GABARs in brain functions, because a specific antagonist of the δ-GABARs is still lacking.

Alcohol Co-Administration Changes Mephedrone-Induced Alterations of Neuronal Activity.

Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own.

Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task.

While interest in psychedelic drugs in the fields of psychiatry and neuroscience has re-emerged in recent last decades, the general understanding of the effects of these drugs remains deficient. In particular, there are gaps in knowledge on executive functions and goal-directed behaviors both in humans and in commonly used animal models. The effects of acute doses of psychedelic lysergic acid diethylamide (LSD) on reward-driven decision making were explored using the mouse version of the Iowa Gambling Task.

Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area.

The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles.

Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA Receptors to Histamine Receptor 3 Antagonists.

Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA.

Conditioned Aversion and Neuroplasticity Induced by a Superagonist of Extrasynaptic GABA Receptors: Correlation With Activation of the Oval BNST Neurons and CRF Mechanisms.

THIP (gaboxadol), a superagonist of the δ subunit-containing extrasynaptic GABA receptors, produces persistent neuroplasticity in dopamine (DA) neurons of the ventral tegmental area (VTA), similarly to rewarding drugs of abuse. However, unlike them THIP lacks abuse potential and induces conditioned place aversion in mice. The mechanism underlying the aversive effects of THIP remains elusive.

Attenuation of Novelty-Induced Hyperactivity of Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.

Gene-targeted mice with deficient AMPA receptor GluA1 subunits ( mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the mice, while not affecting the wild-type littermate controls.

Multiple actions of fenamates and other nonsteroidal anti-inflammatory drugs on GABA receptors.

The nonsteroidal anti-inflammatory drug (NSAID) niflumic acid, a fenamate in structure, has many molecular targets, one of them being specific subtypes of the main inhibitory ligand-gated anion channel, the GABA receptor. Here, we report on the effects of other fenamates and other classes of NSAIDs on brain picrotoxinin-sensitive GABA receptors, using an autoradiographic assay with [S]TBPS as a ligand on mouse brain sections. We found that the other fenamates studied (flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid) affected the autoradiographic signal at low micromolar concentrations in a facilitatory-like allosteric fashion, i.

Dopaminergic-GABAergic interplay and alcohol binge drinking.

The dopamine D receptor (DR), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of DR increases GABA α6 subunit in the ventral striatum.

GABA receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine.

Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABA receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABA receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine.

Normal extinction and reinstatement of morphine-induced conditioned place preference in the GluA1-KO mouse line.

Extinction and reinstatement of morphine-induced conditioned place preference were studied in glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor GluA1 subunit-deficient mice (global GluA1-KO mice). In line with previous findings, both acquisition and expression of conditioned place preference to morphine (20 mg/kg, subcutaneously) were fully functional in GluA1 KO mice compared with wild-type littermate controls (GluA1-WT), thus enabling the study of extinction. With a 10-session extinction paradigm, the GluA1 KO mice showed complete extinction similar to that of the GluA1-WT mice.

Conditioned Reward of Opioids, but not Psychostimulants, is Impaired in GABA-A Receptor δ Subunit Knockout Mice.

Extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ-GABA Rs) are emerging as targets for a number of neuropsychopharmacological drugs, including the direct GABA site agonist gaboxadol and neuroactive steroids. Among other regions, these δ-GABA Rs are functionally expressed in the ventral tegmental area (VTA), the cell body region of mesocorticolimbic dopamine (DA) system important for motivated behaviours, and in the target region, the nucleus accumbens. Gaboxadol and neurosteroids induce VTA DA neuron plasticity ex vivo, by inhibiting the VTA GABA neurons, and aversive place conditioning, which are absent in the δ-GABA R knockout mice (δ-KO).

Addiction-related interactions of pregabalin with morphine in mice and humans: reinforcing and inhibiting effects.

The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts.

Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABA Receptor γ2 Subunit in the Cerebellum.

Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABA receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABA receptor-mediated synaptic inhibition in selected neuronal populations.

Neurotoxicity of Ammonia.

Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected.

Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors.

Opioid antagonist treatments reduce alcohol drinking in rodent models and in alcohol-dependent patients, with variable efficacy across different studies. These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high-dose administration of the short-acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism.

Mitochondrial respiratory dysfunction due to the conversion of substituted cathinones to methylbenzamides in SH-SY5Y cells.

The increased use of cathinone-type designer drugs, known as legal highs, has led to concerns about their potential neurotoxicity due to their similarity to methamphetamine (METH). Therefore, closer investigations of their toxic effects are needed. We investigated the effects of the cathinones 4-methylmethcathinone (4-MMC) and 3,4-methylenedioxymethcathinone (MDMC) and the amphetamine METH on cytotoxicity and mitochondrial respiration in SH-SY5Y neuroblastoma cells.