Effect of Acamprosate on Magnetic Resonance Spectroscopy Measures of Central Glutamate in Detoxified Alcohol-Dependent Individuals

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112

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.

Section: Discussionmentioning

confidence: 80%

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

Griffin

Haun

Hazelbaker

et al. 2013

129

112

“…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). Seemingly in agreement with these observations, mGluR2/3 agonists can affect alcohol-related behaviors.…”

Section: Introductionmentioning

confidence: 68%

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

Augier

Dulman

Rauffenbart

et al. 2016

Self Cite

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.

“…Acamprosate dampens hyperglutamatergic activity in excessively ethanol drinking mice, thereby reducing alcohol intake (Mann et al 2008;Spanagel et al, 2005). In a recent double-blind, placebo-controlled study, which applied magnetic resonance spectroscopy acamprosate also reduced glutamate levels in the brains of detoxified alcoholdependent patients (Umhau et al, 2010). Although the effects of acamprosate on glutamate levels are well documented, the molecular mode of action of this drug and the putative interaction between acamprosate and glutamate receptors remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

Spanagel

Vengeliene

Jandeleit³

et al. 2013

Self Cite

130

Alcoholism is one of the most prevalent neuropsychiatric diseases, having an enormous health and socioeconomic impact. Along with a few other medications, acamprosate (Campral-calcium-bis (N-acetylhomotaurinate)) is clinically used in many countries for relapse prevention. Although there is accumulated evidence suggesting that acamprosate interferes with the glutamate system, the molecular mode of action still remains undefined. Here we show that acamprosate does not interact with proposed glutamate receptor mechanisms. In particular, acamprosate does not interact with NMDA receptors or metabotropic glutamate receptor group I. In three different preclinical animal models of either excessive alcohol drinking, alcohol-seeking, or relapse-like drinking behavior, we demonstrate that N-acetylhomotaurinate by itself is not an active psychotropic molecule. Hence, the sodium salt of N-acetylhomotaurinate (i) is ineffective in alcohol-preferring rats to reduce operant responding for ethanol, (ii) is ineffective in alcohol-seeking rats in a cue-induced reinstatement paradigm, (iii) and is ineffective in rats with an alcohol deprivation effect. Surprisingly, calcium salts produce acamprosatelike effects in all three animal models. We conclude that calcium is the active moiety of acamprosate. Indeed, when translating these findings to the human situation, we found that patients with high plasma calcium levels due to acamprosate treatment showed better primary efficacy parameters such as time to relapse and cumulative abstinence. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.