Glutamatergic targets for new alcohol medications

Holmes, Andrew; Spanagel, Rainer; Krystal, John H.

doi:10.1007/s00213-013-3226-2

Cited by 173 publications

(153 citation statements)

References 222 publications

(268 reference statements)

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“…The above finding, however, represents the first identification of a possible common molecular target of ethanol and baclofen in brain and further underscores the central position of GluT in regulating synaptic functions in brain. It also potentially expands the ''glutamatergic'' hypothesis of alcoholism perhaps providing an additional therapeutic target [122,123].…”

Section: Eaat1/glast: Possible Role In Alcoholism?mentioning

confidence: 99%

GLAST But Not Least—Distribution, Function, Genetics and Epigenetics of l-Glutamate Transport in Brain—Focus on GLAST/EAAT1

et al. 2015

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Synaptically released L-glutamate, the most important excitatory neurotransmitter in the CNS, is removed from extracellular space by fast and efficient transport mediated by several transporters; the most abundant ones are EAAT1/GLAST and EAAT2/GLT1. The review first summarizes their location, functions and basic characteristics. We then look at genetics and epigenetics of EAAT1/GLAST and EAAT2/GLT1 and perform in silico analyses of their promoter regions. There is one CpG island in SLC1A2 (EAAT2/GLT1) gene and none in SLC1A3 (EAAT1/GLAST) suggesting that DNA methylation is not the most important epigenetic mechanism regulating EAAT1/GLAST levels in brain. There are targets for specific miRNA in SLC1A2 (EAAT2/GLT1) gene. We also note that while defects in EAAT2/GLT1 have been associated with various pathological states including chronic neurodegenerative diseases, very little is known on possible contributions of defective or dysfunctional EAAT1/GLAST to any specific brain disease. Finally, we review evidence of EAAT1/GLAST involvement in mechanisms of brain response to alcoholism and present some preliminary data showing that ethanol, at concentrations which may be reached following heavy drinking, can have an effect on the distribution of EAAT1/GLAST in cultured astrocytes; the effect is blocked by baclofen, a GABA-B receptor agonist and a drug potentially useful in the treatment of alcoholism. We argue that more research effort should be focused on EAAT1/GLAST, particularly in relation to alcoholism and drug addiction.

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Section: Eaat1/glast: Possible Role In Alcoholism?mentioning

confidence: 99%

GLAST But Not Least—Distribution, Function, Genetics and Epigenetics of l-Glutamate Transport in Brain—Focus on GLAST/EAAT1

et al. 2015

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“…It is considered that they have a significant role in the occurrence of alcohol addiction, primarily due to modulation of other neurotransmitting systems, while numerous studies confirm the role of SHT in all alcohol addiction aspects. We believe today that the lack of serotonergic transmissions leads to increased inclination to alcohol intake [29][30][31] and is also connected to the impulsive and aggressive behavior that is often present in alcohol addicts 32,33 . This especially relates to Cloninger type 2 alcohol addict we shall later speak more about 34 .…”

Section: Serotoninmentioning

confidence: 99%

Neurobiological Bases of Alcohol Addiction

Matošić¹,

Marušić²,

Vidrih³

et al. 2016

ACC

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SUMMARY -Alcohol addiction is a heterogeneous psychiatric disorder according to both phenotype and etiology. Difference in phenotype characteristics manifests in the manner the addiction arises, history of the alcoholic and history of drinking, comorbid disorders, and the phenomenon of abstinence difficulties. Concerning the etiology of alcoholism, the disease itself is considered to be a consequence of an interactive influence of the environment and genetic factors. Numerous researches conducted in the last decades discovered many aspects of the biochemical, cell and molecular bases of alcohol addiction, leading to a conclusion that alcoholism is, like many other addictions, a brain disease. By recognizing alcoholism as a disease which basically implies changes of the neurobiological mechanisms, as well as a clear genetic basis, it was supposed that the disease, having its basis solely in the symptomatology, is essentially heterogeneous. By trying to solve the problem of a clinically heterogeneous nature of the disease during the last fifty years, various sub-classifications of such patients have been suggested. According to Cloninger, subtypes of alcoholism differ also according to changes in the brain neurotransmission systems, i.e. it is supposed that patients suffering from alcoholism type 1 have a more pronounced dopaminergic transmission deficit, while dopaminergic transmission is not disturbed significantly in patients diagnosed with alcoholism type 2, who, however, have a significant lack of serotonergic transmission. In such a way, Cloninger actually presented the basis of the so-called neurobiological alcoholism model. Since he has connected differences in neurotransmission with differences in personality characteristics, this model is also known as the psychobiological model of alcoholism. The characteristic of alcoholism type 1 is avoiding damage (Harm Avoidance, HA) decreased dopamine transmission and increased serotonin transmission, while the significant characteristic of alcoholism type 2 is seeking for excitement (Novelty Seeking, NS), unchanged dopamine transmission and decreased serotonin transmission. These neurochemical differences among alcoholism subtypes represent the basis for a different therapy approach. Intake of alcohol changes different gene expression in the human brain. The inheritance model of alcoholism is not fully explained, however, it is considered that the disease is connected to a larger gene number included in neurotransmission, cell mechanisms and general metabolic function, with a simultaneous influence of the environment. The contribution of genetic factors is stronger in certain types of alcoholism and thus we have been confronted in the last years of alcoholism research with studies researching the connections of some alcoholism subtypes with the polymorphism phenomenon in the genes coding the synaptic proteins included in the alcoholism etiology. The primary role of monoamine oxidase (MAO) in the brain is catalysis of deamination of the oxidative neurotransmitter a...

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“…Over all, chronic ethanol exposure causes long-lasting alterations in the expression of glutamatergic receptors and transporters, producing a hyperglutamatergic state [101][102][103][104]. Pharmacological modulation of astrocytic clearance of glutamate might thus indirectly mitigate behavioral responses caused by ethanol exposure.…”

Section: Astrocytic Amino Acid Transporters and Ethanolmentioning

confidence: 99%

Astrocyte Function in Alcohol Reward and Addiction

Adermark¹

2015

J Alcohol Drug Depend

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Glial cells, particularly astrocytes, play essential roles in the regulation of neurotransmission, metabolism, and supply of energy substrates for synaptic transmission. One astrocyte can receive inputs from several hundreds of synapses, and synchronized neuronal activity correlates with astrocyte calcium signaling. Astrocyte pathology is a common feature of ethanol exposure in both humans and animal models, and brief alcohol intake is sufficient to cause long-lasting changes in astrocyte gene expression, activity and proliferation. Recent research also suggests that astrocytes shape the rewarding sensation of ethanol, and might be involved in modulating alcohol consumption. Considering the role of astrocytes in regulating glutamate homeostasis, a crucial component of alcohol abuse disorders, the astrocyte might be an important target for the development of new pharmacological treatments of alcoholism.Keywords: Alcohol; Astrocytes; Astroglia; Glia; GFAP; Dopamine; Ethanol AstrocytesThe astroglial cell, or astrocyte, is the most numerous cell type of the glial cell family. Astrocytes give structural and metabolic support to surrounding neurons and are pivotal for neuronal functioning and signal processing in the CNS [1,2] (Figure 1). The end feet of astrocytic processes encapsulate blood vessels and participate in building up the blood brain barrier [3,4]. The contact with blood vessels also enables the astrocytes to provide neurons with lactate under anaerobic conditions [1,5] (Figure 1). The astrocyte was first acknowledged as the primary cell type responsible for potassium buffering [6], and combined with the clearance of amino acids from the extracellular space, astrocytes warrants a high signal to noise ratio, and reduced receptor desensitization [7,8]. One single astrocyte can enwrap several neuronal somata and receive inputs from thousands of synapses, enabling them to sense and integrate synaptic activity [9,10]. Activation of astrocytes also appears to be a crucial component for the induction of synaptic plasticity mechanisms, and both long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus may be regulated by astrocytes [11,12].Astrocytes enwrap both presynaptic and postsynaptic terminals, forming the tripartite synapse. Astrocytic end feet encapsulate blood vessels, enabling the astrocyte to give metabolic support to surrounding neurons. Astrocytic clearance of neuroactive substances is crucial for synaptic transmission. The excitatory amino acid glutamate (Glu) is rapidly metabolized to its non-excitable precursor glutamine (Gln), released back to the extracellular space, and taken up by neurons for synthesis of glutamate or GABA. See text for further details. Astrocytic transportersOne of the most prominent functions of the astrocyte is the clearance of glutamate, and astrocytic glutamate transporters EAAT2 (GLT-1) and EAAT1 (GLAST) are the most abundant transporters for removal of glutamate in the brain [13]. Impaired astrocytic glutamate clearance appears to contribut...

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Glutamatergic targets for new alcohol medications

Cited by 173 publications

References 222 publications

GLAST But Not Least—Distribution, Function, Genetics and Epigenetics of l-Glutamate Transport in Brain—Focus on GLAST/EAAT1

GLAST But Not Least—Distribution, Function, Genetics and Epigenetics of l-Glutamate Transport in Brain—Focus on GLAST/EAAT1

Neurobiological Bases of Alcohol Addiction

Astrocyte Function in Alcohol Reward and Addiction

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