Translational Magnetic Resonance Spectroscopy Reveals Excessive Central Glutamate Levels During Alcohol Withdrawal in Humans and Rats

Hermann, Derik; Weber‐Fahr, Wolfgang; Sartorius, Alexander; Hoerst, Mareen; Frischknecht, Ulrich; Tunc-Skarka, Nuran; Perreau-Lenz, Stéphanie; Hansson, Anita C.; Krumm, Bertram; Kiefer, Falk; Spanagel, Rainer; Mann, Karl; Ende, Gabriele; Sommer, Wolfgang

doi:10.1016/j.biopsych.2011.07.034

Cited by 180 publications

(189 citation statements)

References 40 publications

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“…Similarly, in rat studies involving magnetic resonance spectroscopy (MRS) analyses, increased glutamate activity has been noted in the prefrontal cortex and basal ganglia (Gu et al, 2013;Zahr et al, 2009). This aligns with recent MRS studies in human alcoholics that show elevated glutamate activity in anterior cingulate and the NAc (Bauer et al, 2013;Hermann et al, 2012). However, it is important to note that in all these studies, glutamate activity was examined during the acute withdrawal period.…”

Section: Introductionsupporting

confidence: 84%

“…As noted above, clinical MRS studies have reported increased glutamate activity in anterior cingulate and NAc in abstinent human alcoholics compared with age-and sexmatched healthy controls (Bauer et al, 2013;Hermann et al, 2012). In another MRS study, acamprosate was found to reduce glutamate levels in anterior cingulate several weeks after abstinence (Umhau et al, 2010).…”

Section: Discussionmentioning

confidence: 84%

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Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Griffin

Haun

Hazelbaker

et al. 2013

Neuropsychopharmacol

129

112

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Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to B3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLU EX ) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLU EX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-b-benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence.

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Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 84%

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Griffin

Haun

Hazelbaker

et al. 2013

Neuropsychopharmacol

129

112

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“…To confirm such oscillatory-like regulation of DA at the membrane level, we analyzed binding sites of D1, D2-like receptors, and DAT in three striatal regions of alcohol-dependent rats at various time points during abstinence according to our previous studies (24,32). A similar temporal pattern of regulation was found for D1 and DAT (Fig.…”

Section: Discussionmentioning

confidence: 66%

Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence

Hirth

Meinhardt

Noori

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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132

128

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A major hypothesis in addiction research is that alcohol induces neuroadaptations in the mesolimbic dopamine (DA) system and that these neuroadaptations represent a key neurochemical event in compulsive drug use and relapse. Whether these neuroadaptations lead to a hypo-or hyperdopaminergic state during abstinence is a long-standing, unresolved debate among addiction researchers. The answer is of critical importance for understanding the neurobiological mechanism of addictive behavior. Here we set out to study systematically the neuroadaptive changes in the DA system during the addiction cycle in alcohol-dependent patients and rats. In postmortem brain samples from human alcoholics we found a strong down-regulation of the D1 receptor-and DA transporter (DAT)-binding sites, but D2-like receptor binding was unaffected. To gain insight into the time course of these neuroadaptations, we compared the human data with that from alcoholdependent rats at several time points during abstinence. We found a dynamic regulation of D1 and DAT during 3 wk of abstinence. After the third week the rat data mirrored our human data. This time point was characterized by elevated extracellular DA levels, lack of synaptic response to D1 stimulation, and augmented motor activity. Further functional evidence is given by a genetic rat model for hyperdopaminergia that resembles a phenocopy of alcohol-dependent rats during protracted abstinence. In summary, we provide a new dynamic model of abstinence-related changes in the striatal DA system; in this model a hyperdopaminergic state during protracted abstinence is associated with vulnerability for relapse.alcoholism | translational studies | dopamine release | in silico analysis | postmortem brain tissue A bout 10% of the total burden of disease in developed countries is caused by alcohol use alone (1). A large proportion of alcohol-related disability results from alcohol addiction. The condition affects more than 12% of the United States population at some point in their lives and is one of the most prevalent psychiatric disorders in Europe (2, 3). The relapsing course of alcoholism is associated with compulsive drinking, loss of control over intake, and emergence of a negative emotional state during abstinence (4). Afflicted individuals go through repeated cycles of alcohol intoxication and withdrawal leading to persistent alterations in brain activity that are hypothesized to drive relapse and compulsive alcohol use even long after detoxification (5).Seminal studies in experimental animals established that alcohol's rewarding properties are associated with increased dopamine (DA) in regions such as the nucleus accumbens (Acb) (6), whereas withdrawal after chronic alcohol use decreases DA neurotransmission (7). In humans, the binding of a DA receptor ligand, typically one for the D2-like receptor subgroup, i.e., [11 C] raclopride, can be monitored by PET. Displacement of the radioligand provides an indirect measure of DA release and has been used to demonstrate alcohol-evoked DA release in...

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“…This observation was recently extended to humans in a translational study that used magnetic resonance spectroscopy (MRS) to measure glutamate levels. Both alcoholdependent rats and alcohol-dependent patients showed increased glutamate levels during acute alcohol withdrawal in corresponding prefrontocortical regions (Hermann et al, 2012). Another MRS study indicated that glutamate levels in the anterior cingulate cortex of alcohol-dependent patients continue to increase over 3 weeks following cessation of alcohol use and that the approved alcoholism medication acamprosate prevents this increase (Umhau et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats

Augier

Dulman

Rauffenbart

et al. 2016

Neuropsychopharmacol

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Group II metabotropic glutamate receptors (mGluR2 and mGluR3) may control relapse of alcohol seeking, but previously available Group II agonists were unable to discriminate between mGluR2 and mGluR3. Here we use AZD8529, a novel positive allosteric mGluR2 modulator, to determine the role of this receptor for alcohol-related behaviors in rats. We assessed the effects of AZD8529 (20 and 40 mg/kg s.c.) on male Wistar rats trained to self-administer 20% alcohol and determined the effects of AZD8529 on self-administration, as well as stress-induced and cue-induced reinstatement of alcohol seeking. The on-target nature of findings was evaluated in Indiana P-rats, a line recently shown to carry a mutation that disrupts the gene encoding mGluR2. The behavioral specificity of AZD8529 was assessed using self-administration of 0.2% saccharin and locomotor activity tests. AZD8529 marginally decreased alcohol self-administration at doses that neither affected 0.2% saccharin self-administration nor locomotor activity. More importantly, cue-but not stress-induced alcohol seeking was blocked by the mGluR2 positive allosteric modulator. This effect of AZD8529 was completely absent in P rats lacking functional mGluR2s, demonstrating the receptor specificity of this effect. Our findings provide evidence for a causal role of mGluR2 in cueinduced relapse to alcohol seeking. They contribute support for the notion that positive allosteric modulators of mGluR2 block relapse-like behavior across different drug categories.

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Translational Magnetic Resonance Spectroscopy Reveals Excessive Central Glutamate Levels During Alcohol Withdrawal in Humans and Rats

Cited by 180 publications

References 40 publications

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence

The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats

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