Loss of glycine receptors in the nucleus accumbens and ethanol reward in an Alzheimer´s Disease mouse model.

Alterations in cognitive and non-cognitive cerebral functions characterize Alzheimer's disease (AD). Cortical and hippocampal impairments related to extracellular accumulation of Aβ in AD animal models have been extensively investigated. However, recent reports have also implicated intracellular Aβ in limbic regions, such as the nucleus accumbens (nAc).

Changes in ethanol effects in knock-in mice expressing ethanol insensitive alpha1 and alpha2 glycine receptor subunits.

Aims: Glycine receptors (GlyRs) are potentiated by physiologically relevant concentrations of ethanol, and mutations in the intracellular loop of α1 and α2 subunits reduced the effect of the drug. Knock-in (KI) mice having these individual mutations revealed that α1 and α2 subunits played a role in ethanol-induced sedation and ethanol intake. In this study, we wanted to examine if the effects of stacking both mutations in a 2xKI mouse model (α1/α2) generated by a selective breeding strategy further impacted cellular and behavioral responses to ethanol.

Molecular Pharmacology of Alkaloids on Inhibitory Receptors.

Indole alkaloids are the main bioactive molecules of the genus plants. Diverse reports have shown the beneficial actions of alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, alkaloids are toxic for mammals.

Neurocytotoxicity of imidacloprid- and acetamiprid-based comercial insecticides over the differentiation of SH-SY5Y neuroblastoma cells.

Neonicotinoids are effective insecticides with specificity for invertebrate nicotinic acetylcholine receptors. Neonicotinoids are chemically stable and tend to remain in the environment for long so concerns about their neurotoxicity in humans do nothing but increase. Herein, we evaluated the chronic toxic effects of acetamiprid- and imidacloprid-based insecticides over the differentiation of human neuroblastoma SH-SY5Y cells, which were exposed to these insecticides at a concentration range similar to that applied to crop fields (0.

Modulation of GABA receptors and of GABAergic synapses by the natural alkaloid gelsemine.

The plant preparations have shown beneficial activity against common diseases, including chronic pain and anxiety. Nevertheless, their clinical uses are limited by their toxicity. Gelsemine, one of the most abundant alkaloids in the plants, have replicated these therapeutic and toxic actions in experimental behavioral models.

Overexpression of wild type glycine alpha 1 subunit rescues ethanol sensitivity in accumbal receptors and reduces binge drinking in mice.

The nucleus accumbens (nAc) is a critical region in the brain reward system since it integrates abundant synaptic inputs contributing to the control of neuronal excitability in the circuit. The presence of inhibitory α1 glycine receptor (GlyRs) subunits, sensitive to ethanol, has been recently reported in accumbal neurons suggesting that they are protective against excessive binge consumption. In the present study, we used viral vectors (AAV) to overexpress mutant and WT α1 subunits in accumbal neurons in D1 Cre and α1 KI mice.

Aging in nucleus accumbens and its impact on alcohol use disorders.

Ethanol is one of the most widely consumed drugs in the world and prolonged excessive ethanol intake might lead to alcohol use disorders (AUDs), which are characterized by neuroadaptations in different brain regions, such as in the reward circuitry. In addition, the global population is aging, and it appears that they are increasing their ethanol consumption. Although research involving the effects of alcohol in aging subjects is limited, differential effects have been described.

GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates.

: Glucokinase Regulatory Protein (GKRP) is the only known endogenous modulator of glucokinase (GK) localization and activity to date, and both proteins are localized in tanycytes, radial glia-like cells involved in metabolic and endocrine functions in the hypothalamus. However, the role of tanycytic GKRP and its impact on the regulation of feeding behavior has not been investigated. Here, we hypothesize that GKRP regulates feeding behavior by modulating tanycyte-neuron metabolic communication in the arcuate nucleus.

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine.

α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson's Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents.

Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors.

Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability associated with sensorial information, motor control, and respiratory functions; all of which are significantly altered during ethanol intoxication.

Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens.

The glycine receptor (GlyR), a ligand-gated ion channel, is critical for inhibitory neurotransmission in brainstem, spinal cord, and in supraspinal regions. Recent data from several laboratories have shown that GlyRs are expressed in the brain reward circuitry and that α1 and α2 are the principal subunits expressed in the nucleus accumbens (nAc). In the present study, we studied the sensitivity to ethanol of homomeric and heteromeric α3 GlyR subunits in HEK293 cells and dissociated neurons from the nAc.

Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.

Intracellular amyloid beta oligomer (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAβo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons.

Presence of ethanol-sensitive and ethanol-insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice.

Background And Purpose: Glycine receptors composed of α1 and β subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol.

Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aβ) oligomers (AβO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AβO deleterious effects provide a way for identifying new molecules with potential anti-AD properties.

Complex Interaction between Resident Microbiota and Misfolded Proteins: Role in Neuroinflammation and Neurodegeneration.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Creutzfeldt-Jakob disease (CJD) are brain conditions affecting millions of people worldwide. These diseases are associated with the presence of amyloid-β (Aβ), alpha synuclein (α-Syn) and prion protein (PrP) depositions in the brain, respectively, which lead to synaptic disconnection and subsequent progressive neuronal death. Although considerable progress has been made in elucidating the pathogenesis of these diseases, the specific mechanisms of their origins remain largely unknown.

Inhibition of the Glycine Receptor alpha 3 Function by Colchicine.

Colchicine is a plant alkaloid that is widely used as a therapeutic agent. It is widely accepted that colchicine reduces the production of inflammatory mediators mainly by altering cytoskeleton dynamics due to its microtubule polymerization inhibitory activity. However, other lines of evidence have shown that colchicine exerts direct actions on the function of ion channels, which are independent of cytoskeleton alterations.

Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade.

Oligomeric β-amyloid peptide (Aβ) is one of the main neurotoxic agents of Alzheimer's disease (AD). Oligomers associate to neuronal membranes, forming "pore-like" structures that cause intracellular calcium and neurotransmitter dyshomeostasis, leading to synaptic failure and death. Through molecular screening targeting the C terminal region of Aβ, a region involved in the toxic properties of the peptide, we detected an FDA approved compound, gabapentin (GBP), with neuroprotective effects against Aβ toxicity.

Ethanol consumption and sedation are altered in mice lacking the glycine receptor α2 subunit.

Background And Purpose: The precise mechanism/s of action of ethanol, although studied for many years, are not well understood. Like other drugs of abuse, ethanol affects dopamine levels in the nucleus accumbens (nAc), an important region of the mesolimbic system, causing a reinforcing effect. It has been shown that glycine receptors (GlyRs) present in the nAc are potentiated by clinically relevant concentrations of ethanol, where α1 and α2 are the predominant subunits expressed.

Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease.

Methods: Based on our previous study that showed that an Aβ-interacting small peptide protected against the toxic effects of amyloid-beta peptide (Aβ), we carried out an array of in silico, in vitro, and in vivo assays to identify a molecule having neuroprotective properties.

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation.

Glycine receptors (GlyRs) are anion-permeable pentameric ligand-gated ion channels (pLGICs). The GlyR activation is critical for the control of key neurophysiological functions, such as motor coordination, respiratory control, muscle tone and pain processing. The relevance of the GlyR function is further highlighted by the presence of abnormal glycinergic inhibition in many pathophysiological states, such as hyperekplexia, epilepsy, autism and chronic pain.

Gonadal hormone-independent sex differences in GABA receptor activation in rat embryonic hypothalamic neurons.

Background And Purpose: GABA receptor functions are dependent on subunit composition, and, through their activation, GABA can exert trophic actions in immature neurons. Although several sex differences in GABA-mediated responses are known to be dependent on gonadal hormones, few studies have dealt with sex differences detected before the critical period of brain masculinisation. In this study, we assessed GABA receptor functionality in sexually segregated neurons before brain hormonal masculinisation.

Inhibitory Actions of Tropeines on the α3 Glycine Receptor Function.

Glycine receptors (GlyRs) are chloride-permeable pentameric ligand-gated ion channels. The inhibitory activity of GlyRs is essential for many physiological processes, such as motor control and respiration. In addition, several pathological states, such as hyperekplexia, epilepsy, and chronic pain, are associated with abnormal glycinergic inhibition.

Large Intracellular Domain-Dependent Effects of Positive Allosteric Modulators on Glycine Receptors.

Glycine receptors (GlyRs) are members of the pentameric ligand-gated ionic channel family (pLGICs) and mediate fast inhibitory neurotransmission in the brain stem and spinal cord. The function of GlyRs can be modulated by positive allosteric modulators (PAMs). So far, it is largely accepted that both the extracellular (ECD) and transmembrane (TMD) domains constitute the primary target for many of these PAMs.

Influence of nonsynaptic α1 glycine receptors on ethanol consumption and place preference.

Here, we used knock-in (KI) mice that have ethanol-insensitive alpha 1 glycine receptors (GlyRs) (KK385/386AA) to examine how alpha 1 GlyRs might affect binge drinking and conditioned place preference. Data show that tonic alpha 1 GlyR-mediated currents were exclusively sensitive to ethanol only in wild-type mice. Behavioral studies showed that the KI mice have a higher intake of ethanol upon first exposure to drinking and greater conditioned place preference to ethanol.