Rising Taurine and Ethanol Concentrations in Nucleus Accumbens Interact to Produce the Dopamine-Activating Effects of Alcohol
ABSTRACT Alcohol misuse and addiction is a worldwide problem causing enormous individual suffering as well as financial costs for the society. To develop pharmacological means to reduce suffering, we need to understand the mechanisms underlying the effects of ethanol in the brain. Ethanol is known to increase extracellular levels of both dopamine and taurine in the nucleus accumbens (nAc), a part of the brain reward system, but the two events have not been connected. In previous studies we have demonstrated that glycine receptors in the nAc are involved in modulating both basal- and ethanol-induced dopamine output in the same brain region. By means of in vivo microdialysis in freely moving rats we here demonstrate that the endogenous glycine receptor ligand taurine mimics ethanol in activating the brain reward system. Furthermore, administration of systemic ethanol diluted in an isotonic (0.9% NaCl) or hypertonic (3.6% NaCl) saline solution was investigated with respect to extracellular levels of taurine and dopamine in the nAc. We found that ethanol given in a hypertonic solution, contrary to an isotonic solution, failed to increase concentrations of both taurine and dopamine in the nAc. However, a modest, non-dopamine elevating concentration of taurine in the nAc disclosed a dopamine elevating effect of systemic ethanol also when given in a hypertonic solution. We conclude that the elevations of taurine and dopamine in the nAc are closely related and that in order for ethanol to induce dopamine release, a simultaneous increase of extracellular taurine levels in the nAc is required. These data also -provide support for the notion that the nAc is the primary target for ethanol in its dopamine-activating effect after systemic administration and that taurine is a prominent participant in activating the brain reward system.
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ABSTRACT: The identification and functional understanding of the neurocircuitry that mediates alcohol and drug effects that are relevant for the development of addictive behavior is a fundamental challenge in addiction research. Here we introduce an assumption-free construction of a neurocircuitry that mediates acute and chronic drug effects on neurotransmitter dynamics that is solely based on rodent neuroanatomy. Two types of data were considered for constructing the neurocircuitry: (1) information on the cytoarchitecture and neurochemical connectivity of each brain region of interest obtained from different neuroanatomical techniques; (2) information on the functional relevance of each region of interest with respect to alcohol and drug effects. We used mathematical data mining and hierarchical clustering methods to achieve the highest standards in the preprocessing of these data. Using this approach, a dynamical network of high molecular and spatial resolution containing 19 brain regions and seven neurotransmitter systems was obtained. Further graph theoretical analysis suggests that the neurocircuitry is connected and cannot be separated into further components. Our analysis also reveals the existence of a principal core subcircuit comprised of nine brain regions: the prefrontal cortex, insular cortex, nucleus accumbens, hypothalamus, amygdala, thalamus, substantia nigra, ventral tegmental area and raphe nuclei. Finally, by means of algebraic criteria for synchronizability of the neurocircuitry, the suitability for in silico modeling of acute and chronic drug effects is indicated. Indeed, we introduced as an example a dynamical system for modeling the effects of acute ethanol administration in rats and obtained an increase in dopamine release in the nucleus accumbens-a hallmark of drug reinforcement-to an extent similar to that seen in numerous microdialysis studies. We conclude that the present neurocircuitry provides a structural and dynamical framework for large-scale mathematical models and will help to predict chronic drug effects on brain function.Addiction Biology 09/2012; 17(5):827-64. DOI:10.1111/j.1369-1600.2012.00485.x
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ABSTRACT: Introduction: Alcohol dependence is one of the most important psychiatric disorders leading to enormous harm in individuals and indeed within society. Yet, although alcohol dependence is a disease of significant importance, the availability of efficacious pharmacological treatment is still limited. Areas covered: The current review focuses on neurobiological pathways that are the rationale for recent preclinical and clinical studies testing novel compounds that could be used as treatments for alcohol dependence. These neurobiological mechanisms include the: glutamatergic, dopaminergic and GABA mediated pathways as well as neuroendocrine systems. There is also an interest in the approaches for influencing chromatin structure. Expert opinion: There are several compounds in Phase I and Phase II clinical studies that have produced potentially useful results for the treating alcoholism. Further evaluation is still necessary, and the implementation of Phase III studies will help to elucidate the usefulness of these compounds. It is important that personalized approaches (e.g., pharmacogenomics) are investigated in these later studies, as the efficacy of different compounds may vary substantially between subgroups of patients.Expert Opinion on Investigational Drugs 08/2014; 24(1):1-14. DOI:10.1517/13543784.2014.954037