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S.19.04 Glutamatergic contributions to reward dysfunction in alcohol dependence
S.20. The role of glutamate and metabotropic glutamate receptors for the treatment of neuropsychiatric disorders S.19.03 The role of the subthalamic nucleus in motivational and reward processes C. Baunez1 ° 1 Institut de Neurosciences de la Timone, UMR7289 CNRS & Aix-Marseille Universit´e, Marseille cedex 05, France The subthalamic nucleus (STN) is the current target for the treatment of Parkinson’s disease, but its involvement in non-motor processes has been also demonstrated and led to also target it for the treatment of obsessive compulsive disorders. Here, we will review data obtained in the rat showing the effects of STN inactivation, by either lesions or deep brain stimulation (DBS), on motivation for food (sucrose), cocaine, heroin, alcohol and nicotine. Inactivation of the STN does not affect consummatory processes, but seems to act on incentive motivation (responses to cues associated with a given reward). STN inactivation can induce opposite effects on motivation for natural reward or for various drugs of abuse, decreasing motivation for drugs, while increasing motivation for sweet food reward [1,2]. In parallel, we have also shown that various subpopulations of STN neurons encode rewards of different positive values such as 32 vs 4% sucrose solution [3], sucrose vs cocaine or even positive and negative values such as sucrose vs quinine. Recently, we have shown that inactivation of the STN could prevent the loss of control over cocaine intake in rats. These results suggest that the STN plays a critical and very particular role in motivational processes and should be considered in the classical view of the reward system. Since its inactivation reduces motivation for the drugs without reducing motivation for natural activities (the major objective to treat addiction), the STN could represent an interesting, if not the best, target for the treatment of drug addiction. References [1] Baunez, C., Dias, C., Cador, M., Amalric, M., 2005. The subthalamic nucleus exerts an opposite control on cocaine and natural rewards. Nature Neuroscience 8(4), 484−9. [2] Rouaud, T.*, Lardeux, S.*, Panayotis, N., Paleressompoulle, D., Cador, M., Baunez, C., 2010. Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation. P. Natl. Acad. Sci. USA 107, 1196–1200. [3] Lardeux, S., Pernaud, R., Paleressompoulle, D., Baunez, C., 2009. Beyond the reward pathway: coding of the reward salience and error in the rat subthalamic nucleus. J. Neurophysiol. 102(4), 2526−37.
S.19.04 Glutamatergic contributions to reward dysfunction in alcohol dependence J. Krystal1 ° Haven, USA
1 Yale
University, Department of Psychiatry, New
Purpose: Attempt to integrate a series of studies undertaken over the past 15 years to understand how alterations in glutamatergic signaling in the brain contribute to the human vulnerability to alcohol misuse. This presentation reflects the work of the faculty of the NIAAA Center on the Translational Neuroscience of Alcoholism, which I direct and whose senior faculty includes Stephanie O’Malley (co-Director), Jane Taylor, Ismene Petrakis, Joel Gelernter, Godfrey Pearlson, Anissa Abi-Dargham, Suchitra KrishnanSarin, and Paul Lombroso. It will also link the insights emerging from these studies to emerging approaches to the pharmacotherapy of alcohol abuse and dependence. Methods: See below. Summary of results: This presentation has three components.
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In the first part, it will review evidence that upregulation of NMDA receptors or receptor function contributes to the risk for alcohol misuse by attenuating the dysphoric features of ethanol intoxication and impairing the capacity to accurately assess one’s level of intoxication, thereby promoting heavy drinking. These studies evaluated the dose-related effects of the NMDA receptor antagonists ketamine and memantine in healthy subjects using both behavioral, electrophysiological, and fMRI endpoints. In the second part, it will review recent data suggesting that enhanced NMDA receptor function associated with the familial risk for alcohol misuse distorts cortico-striatal function, enhancing human ventral striatal activation in the context of an opportunity for reward but reducing ventral striatal activation when reward is delayed or uncertain. It will also highlight the interplay of glutamate and dopamine signaling in the striatum. In so doing, it will highlight that ethanol increases human striatal dopamine release in non-dependent individuals but that alcohol dependence is associated with suppression of dopamine release in this region, in part perhaps due to the upregulation in NMDA receptor function. This section of the presentation fMRI and PET imaging studies The third part of this presentation will place these findings in the context of their implications for the transition from the initial drink to the development of habitual alcohol use. It will particularly highlight human laboratory studies of alcohol self-administration among non-treatment-seeking alcohol dependent individuals that contrast the effects of two medications, memantine (which reduced the stimulatory effects of ethanol and alcohol craving but not self-administration) and naltrexone (which increased craving but reduced drinking). These intriguing findings are discussed within the context of distinct neural mechanisms underlying ‘reward driven’ and ‘habitual’ alcohol consumption. Conclusions: The studies presented begin to make the case that enhanced NMDA glutamate receptor function may contribute to the risk for alcohol abuse and dependence by promoting heavy drinking, biasing reward circuitry to promote alcohol-like rewards, contributing to alcohol-related neuroplasticity promoting the addiction process. It also suggests that diverse neural signaling mechanisms may contribute to goal-oriented and habitual drinking, requiring the development of distinctive pharmacotherapies to reduce both types of drinking. Disclosure statement: I will dislcose my conflicts of interest in the first slide of my presentation.
S.20. The role of glutamate and metabotropic glutamate receptors for the treatment of neuropsychiatric disorders S.20.01 The stress impact on glutamate transmission: a key to mood and anxiety disorders M. Popoli1 ° , L. Musazzi1 , G. Treccani1 1 University of Milan, Department of Pharmacological and Biomolecular Sciences, Milan, Italy Dysfunction of the glutamate system is increasingly considered a core feature of neuropsychiatric disorders, including mood and anxiety disorders. Neuroimaging studies have shown consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent
S.19.04 Glutamatergic contributions to reward dysfunction in alcohol dependence J. Krystal1 ° Haven, USA
1 Yale
University, Department of Psychiatry, New
Purpose: Attempt to integrate a series of studies undertaken over the past 15 years to understand how alterations in glutamatergic signaling in the brain contribute to the human vulnerability to alcohol misuse. This presentation reflects the work of the faculty of the NIAAA Center on the Translational Neuroscience of Alcoholism, which I direct and whose senior faculty includes Stephanie O’Malley (co-Director), Jane Taylor, Ismene Petrakis, Joel Gelernter, Godfrey Pearlson, Anissa Abi-Dargham, Suchitra KrishnanSarin, and Paul Lombroso. It will also link the insights emerging from these studies to emerging approaches to the pharmacotherapy of alcohol abuse and dependence. Methods: See below. Summary of results: This presentation has three components.
S141
In the first part, it will review evidence that upregulation of NMDA receptors or receptor function contributes to the risk for alcohol misuse by attenuating the dysphoric features of ethanol intoxication and impairing the capacity to accurately assess one’s level of intoxication, thereby promoting heavy drinking. These studies evaluated the dose-related effects of the NMDA receptor antagonists ketamine and memantine in healthy subjects using both behavioral, electrophysiological, and fMRI endpoints. In the second part, it will review recent data suggesting that enhanced NMDA receptor function associated with the familial risk for alcohol misuse distorts cortico-striatal function, enhancing human ventral striatal activation in the context of an opportunity for reward but reducing ventral striatal activation when reward is delayed or uncertain. It will also highlight the interplay of glutamate and dopamine signaling in the striatum. In so doing, it will highlight that ethanol increases human striatal dopamine release in non-dependent individuals but that alcohol dependence is associated with suppression of dopamine release in this region, in part perhaps due to the upregulation in NMDA receptor function. This section of the presentation fMRI and PET imaging studies The third part of this presentation will place these findings in the context of their implications for the transition from the initial drink to the development of habitual alcohol use. It will particularly highlight human laboratory studies of alcohol self-administration among non-treatment-seeking alcohol dependent individuals that contrast the effects of two medications, memantine (which reduced the stimulatory effects of ethanol and alcohol craving but not self-administration) and naltrexone (which increased craving but reduced drinking). These intriguing findings are discussed within the context of distinct neural mechanisms underlying ‘reward driven’ and ‘habitual’ alcohol consumption. Conclusions: The studies presented begin to make the case that enhanced NMDA glutamate receptor function may contribute to the risk for alcohol abuse and dependence by promoting heavy drinking, biasing reward circuitry to promote alcohol-like rewards, contributing to alcohol-related neuroplasticity promoting the addiction process. It also suggests that diverse neural signaling mechanisms may contribute to goal-oriented and habitual drinking, requiring the development of distinctive pharmacotherapies to reduce both types of drinking. Disclosure statement: I will dislcose my conflicts of interest in the first slide of my presentation.
S.20. The role of glutamate and metabotropic glutamate receptors for the treatment of neuropsychiatric disorders S.20.01 The stress impact on glutamate transmission: a key to mood and anxiety disorders M. Popoli1 ° , L. Musazzi1 , G. Treccani1 1 University of Milan, Department of Pharmacological and Biomolecular Sciences, Milan, Italy Dysfunction of the glutamate system is increasingly considered a core feature of neuropsychiatric disorders, including mood and anxiety disorders. Neuroimaging studies have shown consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent