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Acamprosate is approved for treatment of alcoholism, but its mechanism of action remains unclear. Animal studies suggest that a persistent hyperglutamatergic state contributes to the pathophysiology of alcoholism, and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.
To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol dependent patients, as measured by proton nuclear magnetic resonance spectroscopy (1H-MRS).
A 4 week, double-blind, placebo-controlled randomized controlled experimental medicine study, with 1H-MRS measures obtained on day 4 and 25.
NIAAA inpatient research unit at the NIH Clinical Center.
Thirty three patients who met the DSM-IV criteria for alcohol dependence and were admitted for medically supervised withdrawal from ongoing alcohol use.
Four weeks of acamprosate (initial oral loading followed by 1998mg daily) or matched placebo, initiated at the time of admission.
The main outcome was the glutamate/creatine ratio (Glu) as determined by single voxel 1H-MRS within the anterior cingulate. Exploratory neuroendocrine, biochemical and behavioral outcomes were also collected, as well as safety/tolerability – related measures.
There was a highly significant suppression of Glu over time by acamprosate (time × treatment interaction: F[1, 29]=13.5, p<0.001). Cerebrospinal fluid (CSF) levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and were unaffected by treatment, but were strongly correlated (R2=0.48, p<0.001) with alcohol dependence severity. Other exploratory outcomes, including repeated Dex/CRH tests, as well as psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate treated subjects, in agreement with the established profile of acamprosate.
MRS measures of central glutamate are reduced over time when acamprosate is initiated at the onset of alcohol abstinence.
www.clinicaltrials.gov Identifier: NCT00106106
Dysregulation of central glutamatergic function has been proposed as a key factor underlying the neural and behavioral pathology of alcoholism, and as a mechanism that could be targeted by pharmacotherapies 1–4. Brain microdialysis in experimental animals has directly shown progressive increase of extracellular glutamate with consecutive cycles of intoxication and withdrawal 5. A persistent hyperglutamatergic state may be linked with progression of dependence, since it is expected to result in chronic Ca++ mediated hyperphosphorylation of the transcription factor CREB 6, a molecular switch into a state of impaired reward circuitry function 7. The persistent switch from low to high alcohol preference that occurs in experimental animals following prolonged intermittent brain alcohol exposure is accompanied by up-regulation of glial glutamate transporter (GLAST) gene expression 8. Up-regulation of GLAST-expression has also been reported in post-mortem brain tissue from human alcoholics 9. GLAST is critical for clearance of extracellular glutamate 10, and its up-regulation following prolonged brain alcohol exposure presumably reflects an adaptation to elevated extracellular glutamate levels. However, despite the extensive animal literature pointing to a role of glutamatergic dysregulation in the pathophysiology of alcohol dependence, limited human data are available to translate these findings.
A translational tool to address the role of glutamatergic dysregulation in alcoholism may be offered by acamprosate, a medication approved for treatment of alcohol dependence that reduces craving and relapse 11. Despite some negative reports 12, meta-analysis of available studies supports the efficacy of acamprosate to increase abstinence 13. Severity of dependence may be a critical factor in determining the efficacy of acamprosate, since the medication robustly suppresses escalated alcohol intake in rats with a prolonged history of dependence, but is ineffective in non-dependent rats consuming modest amounts of alcohol 8. Acamprosate modulates glutamatergic transmission through presently unknown, possibly multiple actions 4. A foundation for translational research on the role of glutamatergic function in alcohol dependence was provided by experiments with null-mutants for the clock gene Per2. In these animals, elevated brain levels of extracellular glutamate were found by microdialysis, due to impaired glutamate clearance by GLAST. As predicted, these mice showed markedly elevated levels of alcohol intake. Acamprosate normalized the elevated glutamate levels in the Per2 mutants, and this was accompanied by a marked reduction of voluntary alcohol intake 14. These findings prompt the hypothesis that clinical efficacy of acamprosate in humans may be related to an ability to suppress central glutamatergic transmission.
Indices of central glutamate levels can be obtained in humans using 1H-MRS. This approach faces considerable technical challenges, and is also complicated by the fact that synaptic glutamate comprises only a minute fraction of the total glutamate in the brain. Despite these challenges, the neurobiological relevance of MRS generated brain glutamate indices is suggested e.g. by consistent findings of decreased glutamatergic measures in the anterior cingulate of subjects with major depression 15–17, and the observation that effective electroconvulsive therapy normalized these spectroscopic findings in depressed patients 16. A prior MRS study has suggested acute modulation of central glutamate by intravenous acamprosate infusion in a small group of healthy volunteers 18. A challenge for MRS studies of brain glutamate has been to resolve measures of glutamate from those of glutamine. Published studies, including that examining the effects of acamprosate in healthy volunteers 18, 19 have therefore typically reported a composite measure, commonly referred to as Glx, that originates from the C2 protons common to glutamate and glutamine, and is detected at a chemical shift of 3.75 parts per million (ppm).
Recently, advances in spectrum acquisition and analysis techniques have allowed the isolation of an unobstructed glutamate signal that originates from the C4 proton of glutamate, detected at 2.35 ppm 20. Here, we used this technique to evaluate whether acamprosate modulates central glutamate in alcohol dependent subjects following initiation of abstinence. Two secondary objectives were also addressed. First, we examined whether MRS indices of central glutamate are related to levels of glutamate obtained in cerebrospinal fluid (CSF), or other patient characteristics. Secondly, we explored whether central glutamate is related to measures of corticotrophin-releasing hormone (CRH; also referred to as corticotrophin-releasing factor, CRF) system function. Neuroadaptations that encompass the CRH system are key in alcohol dependence 6, and activity of glutamatergic synapses can be directly modulated by CRH 21. We therefore used the dexamethason-CRH (dex-CRH) test, a neuroendocrine probe of CRH function22, and examined whether dex-CRH responses would be influenced by acamprosate in parallel with MRS measures of central glutamate.
The flow of subjects is shown in Figure 1, and descriptive subject characteristics are given in Table 1. Alcohol dependent subjects in early withdrawal were admitted to a 28 day inpatient protocol at the NIAAA Inpatient Unit in the NIH Clinical Center. All subjects underwent a telephone pre-screening. They were excluded if they had received any psychiatric medications in the two weeks preceding the study, or had severe psychiatric illness such as dementia or a psychotic disorder. They were also excluded if they were pregnant or had severe complicating medical conditions or HIV. To be eligible, subjects had to be in significant withdrawal, with a Clinical Institute Withdrawal Assessment of Alcohol scale (CIWA-Ar) 23 score >8), or have a blood alcohol level above 0.10 g/dl on admission and be expected to experience significant alcohol withdrawal. Complete eligibility criteria are available at www.clinicaltrials.gov. Informed consent was obtained in accordance with the Declaration of Helsinki and the NIH Institutional Review Board.
Subjects were assessed using the Structured Clinical Interview for DSM IV Diagnosis (SCID IV) 24, and the Addiction Severity Index (ASI) 25. Severity of alcohol dependence was assessed using the Alcohol Dependence Scale (ADS) 26, and alcohol consumption during the preceding 3 months was quantified using time-line follow-back (TLFB) 27. Withdrawal intensity was evaluated using CIWA-Ar every 4 hours while awake for the first 5 days after admission. Diazepam was given as necessary at CIWA-Ar scores > 15. Total benzodiazepine dose, as well as dose received within last 24h prior to the first scan were recorded, and used to control for possible medication effects in subsequent analyses. Psychopathology was assessed twice weekly using the self-report version of the Comprehensive Psychiatric Rating Scale (CPRS-SA) 28. A clinical blood chemistry panel was obtained weekly from each patient. Sleep quality, a potentially important manifestation of central nervous system excitability, was assessed using the Pittsburgh Sleep Quality Index (PSQI) 29. Visual analog scales (VAS) were used to assess common aspects of general wellbeing. Throughout the study, all subjects participated in a standard behavioral inpatient alcohol rehabilitation program, but did not receive any prescription medications other than diazepam as described above. Vitamin B1 (thiamine) supplementation was provided according to clinical guidelines.
After achieving a blood alcohol level of 0g/dl, subjects were randomized to acamprosate or matching placebo. Randomization was by the NIH Clinical Center pharmacy, and was isolated from investigators and clinical staff. A double-blind was achieved by encapsulating commercially obtained acamprosate, and manufacturing matching placebo capsules. For subjects randomized to active treatment, the first 3 acamprosate doses were 1332 mg every 8 hours in an attempt to more rapidly achieve active plasma concentrations, followed by 666 mg acamprosate every 8 hours for the remainder of the study. Plasma concentrations of acamprosate were determined on day 2, 4 and 26 by the SWEDAC accredited Clinical Pharmacology Laboratory of the Karolinska Institute, Stockholm, Sweden.
MRS was carried out on day 4 and 25 following initiation of randomized treatment. Scans were on a 3T scanner using the echo-time-averaged PRESS sequence previously published to detect glutamate’s resonance line at 2.35 ppm and average out the interferences from glutamine, NAA and the macromolecules 20 (Figure 2, main panel). The acquisition parameters were: repetition time=3s, echo interval=6 ms, echo number=32, excitation number=4. Measurement was made from a 2.5 × 2.5 × 2.5 cm3 voxel in the area of anterior cingulate (Inset Figure 2). We chose the anterior cingulate region for MRS because frontal lobe has been implicated in alcoholism 30. Locating the MRS voxel in the anterior cingulate ensured that the data were collected from a homogenous tissue region that contained predominantly gray matter. Technical details on MRS analysis are provided in Supplementary Materials.
CSF samples were obtained as previously described 31, on day 5 and 26 following initiation of treatment (in each case, one day after the resp. MRS scan). Briefly, on the morning of the study, subjects remained in bed except for a brief use of the rest room at approximately 07:00 h. At approximately 09:30 h, blood was collected by venipuncture immediately before the lumbar puncture. The lumbar puncture was performed in the left lateral decubitus position. After obtaining 5 ml for clinical analysis, 12 ml of CSF were collected in a single aliquot, thoroughly mixed, and immediately placed on ice and quickly stored at −70°C. Analysis of CSF glutamate was carried out as described 32. Briefly, a 10μl aliquot of sample was derivatized with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate and analyzed by an Aquity UPLC (Waters, Millford, MA) with fluorescent detection using a MassTrak amino acid kit (Waters, Millford, MA).
The dex-CRH test 22 was carried out as described 33, on day 6–7 and then again day 27–28 after initiation of treatment (in each case, 1 day after the CSF sampling). Briefly, subjects received 1.5 mg dexamethasone (Dexacortal, Organon) at 11 pm. The next day, a standard lunch was served, and an intravenous catheter was inserted before 2 pm. Subjects remained in bed. Baseline blood was obtained at 3:00 pm, followed by administration of 100 μg of human CRH, and serial blood draws for analysis of adrenocorticotropic hormone (ACTH) and cortisol over the next 3h.
Subjects who received medication through the 4 weeks of the experimental study (n=41) were considered for the analyses. The final MRS analysis was restricted to those 33 among the 41 completers for whom measurable spectra could be obtained on both scans (Figure 1). For the behavioral measures, some questionnaires were not returned or were incorrectly filled out, leading to exclusion of that subject, as reflected in the degrees of freedom indicated for the resp. analysis.
Data were examined for homogeneity of variances and distribution, and analyzed using general linear models (GLM, Statistica 6.0, StatSoft, Tulsa, OK). One way (baseline characteristics) or repeated measures (primary and secondary outcomes) ANOVA was used, the latter with treatment (acamprosate vs. placebo) as a between subjects factor, and time as within subjects factor. According to a pre-defined data-analysis plan, potential contributing variables (baseline characteristics, smoking status, diagnoses of comorbid psychiatric disorders, initial and peak CIWA scores, and benzodiazepine dose) were evaluated by initial inclusion in the model, and were retained if they contributed significantly or reduced the residual variance, or were otherwise dropped from the model. Baseline data and secondary outcomes were corrected for multiplicity of testing using the Holm-Bonferroni method 34. VAS-ratings of tolerability were not corrected to avoid a bias against detecting adverse effects.
The randomized groups that did not differ on baseline variables, including alcoholism severity and withdrawal, neither in the subgroup of subjects who successfully completed both MRS scans and generated spectra that could be analyzed (Table 1), nor in the full set of subjects who received medication through the 4 weeks of the study (Table 1S, Supplemental Materials). Among subjects with two viable MRS scans, a larger proportion of acamprosate than placebo patients required one or more benzodiazepine doses for initial withdrawal treatment (Fisher Exact test, two-tailed: p=0.03). However, the mean total benzodiazepine dose did not differ between the groups (Table 1), and the 9 patients who received any dose within 24 hours of the first MRS scan were evenly distributed between the groups (5 in acamprosate and 4 in placebo group). By the time of the second MRS scan, all subjects had been free of benzodiazepines for a minimum of 3 weeks. Steady state acamprosate levels were achieved as predicted by pharmacokinetic modeling of the loading procedure. Plasma concentrations of acamprosate were 248.2±29.0, 250.6±43.2 and 246.4±26.7 ng/ml (mean±SEM) on days 2, 4 and 26 of the study, respectively. Acamprosate was undetectable at any timepoint in plasma of 5 randomly selected placebo-treated subjects included in the analysis as negative controls.
The MRS glutamate measure showed good reliability, with a coefficient of variation of 13%. Acamprosate robustly suppressed central glutamate over time as measured by MRS (treatment × time interaction: F[1,29]=13.5, p<0.001; Figure 3). Post-hoc tests (Newman-Keul) showed that on the second scan, the acamprosate group was significantly lower (p<0.05) than the placebo group. The effect size for this reduction, as measured by Cohen’s D, was appr. 0.95, i.e. “large”. The acamprosate group also showed a significant decrease (p<0.05) from the first to the second scan. In contrast, the placebo group showed a trend (p=0.09) for an increase over time. In this model, sex was retained because it somewhat reduced residual variance, although the original model that did not include sex was also significant (F[1,31]=10.1, p=0.003). None of the other potentially contributing variables was significant, showed a trend for significance, or reduced residual variance Notably, variables that did not contribute significantly to the model (p>0.5) were measures of withdrawal severity (initial and peak CIWA-Ar scores), benzodiazepine treatment (yes/no), the total benzodiazepine dose received, and the benzodiazepine dose received within the last 24h prior to the scan, indicating that neither withdrawal intensity nor medication effects were confounds in the MRS analysis. Furthermore, results were not affected by co-morbid diagnoses of mood, anxiety, and other substance use disorders, nor by smoking status (yes/no) and level of nicotine dependence (measured by the Fagerstrom score). The acamprosate effect was also robust in that it remained when the analysis was restricted to subjects in whom automated fit of spectra was successful (n=27; placebo: 15; acamprosate: 12; treatment × time F[1,23]=5.9, p=0.02). Because the MRS measure of glutamate is based on the ratio of glutamate/creatine, we also explored whether our results might be confounded by changes in creatine levels. In contrast to its effect on the glu/creatine ratio, acamprosate had no significant or trend-level effect to alter neither the NAA/creatine ratio, nor the choline/creatine ratio, and these measures were also stable over time (Table 2). This suggests that the effect of acamprosate to suppress the glutamate/creatine ratio is specific, and unlikely to be caused by changes in creatine levels.
CSF levels of glutamate in the subset of subjects in whom both spinal taps were successful (n=20, placebo: 14, acamprosate: 6) were unaffected by treatment (F[1,17]=0.23, p=0.63). Furthermore, in the subjects in whom both measures were obtained, CSF glutamate showed no correlation or trend for correlation with MRS measures, neither in the early (R2=0.03, p=0.46) nor the late phase (R2<0.01, p=0.97). However, a highly significant correlation between alcohol dependence severity, measured as ADS scores, and CSF glutamate was found on the second spinal tap (R2=0.48, p<0.001; Figure 4). Because this correlation included both acamprosate and placebo patients, it was further explored using stepwise regression with treatment and baseline characteristics as predictors. Both forward and backward procedures converged on a model that only retained the ADS score as predictor. In contrast to the correlation between ADS and central glutamate found on the second spinal tap, no such correlation was found on the first tap (R2=0.22, p=0.30).
Diurnal cortisol was unaffected by treatment both in early (main effect: F[1,21]=0.87, p=0.36; treatment × time: F[7,147]=0.98, p=0.45) and in late (main effect: F[1,25]=1.09, p=0.31; treatment × time: F[7,175]=1.91, p=0.07) withdrawal. Similarly, ACTH and cortisol responses in the dex-CRH test were unaffected by treatment in the early (ACTH: main effect F[1,26]=0.01, p=0.92, treatment × time F[9,234]=1.79, p=0.07; cortisol: main effect F[1, 27]=0.94, p=0.34, treatment × time F[9, 243]=1.58, p=0.12) as well as the late (ACTH: main effect F[1,27]=0.82, p=0.37, treatment × time F[9,243]=0.90, p=0.53; cortisol: main effect F[1,27]=0.02, p =0.89, treatment × time F[9,243]=0.40, p=0.94) study phase. There was also no treatment effect when ACTH and cortisol responses were analyzed as area under the curve (data not shown).
No serious adverse effects were associated with acamprosate treatment. None of the subjects dropped out because they were unable to tolerate acamprosate, although one subject taking placebo dropped out after two days because she thought study drug was causing auditory hallucinations. Acamprosate was well tolerated. We found no treatment effects on withdrawal ratings, psychiatric symptoms or sleep (CIWA-Ar, CPRS-SA or PSQI, respectively), or on blood chemistry measures. Among VAS measures, there was a main treatment effect (F[1,34]=5.37, p=0.03) and treatment × time interaction (F[4,136]=3.05, p=0.02) on “Sleepiness”, and a main treatment effect (F[1,34]=4.7, p<0.04) and treatment × time interaction (F[4, 136]=2.40, p=0.05) on “Stomach aches”, but not on other measures. Acamprosate patients showed higher sleepiness on Day 8 (Newman-Keuls post-hoc test, p<0.05), but not on subsequent days. Stomach aches were absent during the first week, but rose over time, and were significantly higher in acamprosate patients on Day 18 (Newman-Keuls post-hoc test, p<0.05). There was no treatment effect of acamprosate on the amount of benzodiazepines required to treat withdrawal (F[1,39]=0.03, p=0.87).
The key finding of the present study is that acamprosate, given to alcohol dependent subjects on initiation of abstinence, markedly suppressed MRS measures of central glutamate over 4 weeks of treatment. Advances in spectrum acquisition and analysis allowed us to obtain a glutamate signal mostly uncontaminated by glutamine. Because steady state plasma concentrations of acamprosate were reached already on day two, the delayed onset of acamprosate action is unlikely to be explained by pharmacokinetics. Interpretation of the MRS measures on day 4 of acamprosate treatment may be complicated, because severity of alcoholism, acute withdrawal, benzodiazepines and acamprosate may all have an impact on the ACC glutamate concentration at this time point. For two reasons, we do not believe that these are major limitations. First, measures of dependence severity, withdrawal intensity, or benzodiazepine use did not contribute to the results when included in the analysis. Secondly and more importantly, no effect of acamprosate was observed at the early timepoint, when the impact of these confounds might be expected. Instead, the acamprosate effect was observed at a time when subjects had been free of both withdrawal symptoms and benzodiazepine for about 3 weeks. Furthermore, analyses of other brain metabolites, such as NAA and choline, suggest that the acamprosate effect is specific, and not driven by changes in e.g. creatine levels.
Limited data are available on MRS measures of glutamate in alcoholics during withdrawal and early protracted abstinence. One prior study, using a combined glutamate + glutamine measure, did not find changes over time in alcoholics, and also did not find a difference between patients and controls after controlling for tissue composition 19. This paper did find an influence of smoking status on the combined MRS measure. We therefore controlled for this as a potential confound in our study, but did not find any influence of this factor. Because all but 5 of our subjects were smokers, we did not have adequate power to assess an independent influence of smoking, something that was not an objective of the study. Another paper reported serial MRS scans in alcoholics during early abstinence, but did not provide measures of glutamate or glutamine, which were stated to be too hard to resolve 35.
Although important methodological differences exist, a picture of acamprosate action emerges from our findings that is in general agreement with available animal data 3, 4, 36. When alcohol abstinence is initiated in alcohol dependent individuals, brain levels of glutamate show a tendency to rise in placebo treated subjects, but are suppressed by acamprosate treatment. These data were obtained from the cingulate cortex, and it remains to be established whether other brain areas are similarly affected. Nevertheless, to the extent a persistent rise in glutamate contributes to craving and relapse in alcoholism as has been commonly hypothesized, our data support the notion that acamprosate may exert its therapeutic effect by counteracting this pathophysiological process. It is important to note that our data do not directly address the question whether elevated levels of brain glutamate are present in alcohol dependent patients compared to healthy subjects. The spectroscopic method used to determine central glutamate relies on a ratio vs. creatine. Our control data with NAA and choline ratios make it unlikely that acamprosate treatment per se would confound the glutamate measure by affecting creatine levels. It remains unknown, however, whether alcohol dependence might influence the spectroscopy results, e.g. through structural changes, in ways that would differentially affect the glutamate and the choline signal, making a comparison between alcoholics and normals difficult to interpret.
A hyperglutamatergic state has also been implicated in the hyperexcitability of alcohol withdrawal 3, 4, 36. An ability of acamprosate to suppress central glutamate might therefore also be expected to suppress acute alcohol withdrawal symptoms. However, in agreement with a previous study 37, we did not find any acamprosate effect on acute withdrawal. These findings are consistent with the delayed nature of the acamprosate effect on central glutamate levels observed in our study. Acute withdrawal symptoms subside within 3 – 5 days, while no effect of acamprosate on MRS measures of central glutamate was found after 4 days. Acamprosate was inactive at this timepoint despite steady state plasma levels that were ultimately effective. Pharmacokinetics could nevertheless be relevant for the lack of acamprosate effect on acute withdrawal, because it is not known whether brain concentrations are in immediate equilibrium with the plasma compartment. Alternatively, the delayed onset of acamprosate action may reflect a slow, possibly indirect pharmacodynamic mechanism. Finally, our evaluation of sleep quality with the PSQI also failed to show a significant effect of acamprosate. This is in contrast to a previous study, in which acamprosate had a beneficial effect on polysomnographic measures of sleep architecture. The delayed nature of acamprosate actions may be equally critical in this case, since the previous study initiated acamprosate treatment eight days before the onset of withdrawal 38.
We found that CSF levels of glutamate were not correlated with central glutamate as measured by MRS, and were unaffected by acamprosate treatment. In contrast, CSF glutamate levels in protracted withdrawal were strongly correlated with severity of alcohol dependence. Two mutually non-exclusive mechanisms may account for these observations. First, increased CSF levels of glutamate are observed in both stroke and trauma, where they are caused by an efflux of cytosolic glutamate from neurons and astrocytes 39. Significant loss of gray matter occurs over time in alcoholism 30, and animal models have directly demonstrated cell death following a period of intoxication 40, 41. Thus, an efflux of cytosolic glutamate from damaged cells, similar to that observed with trauma and stroke, might occur following a period of intoxication. Secondly, a gradient of glutamate is normally maintained between blood and the CSF compartment by an energy dependent transport mechanism across the choroid plexus endothelium (CPE), protecting the nervous system from high (appr. 0.2mM) plasma glutamate concentrations. Thiamine deficiency resulting from heavy alcohol use results in impaired ability of CPE cells to maintain the blood – CSF glutamate gradient 42. If the degree of this impairment increases with the severity of alcohol dependence, a correlation of the type that was observed would be expected. Although we provided standard clinical thiamine supplementation, it has been suggested that impairment of CPE dependent transport in chronic alcohol dependence may become lasting.
Both the mechanisms discussed here point to sources of CSF glutamate other than the transmitter pool. The observation that CSF glutamate was unaffected by our pharmacological intervention is also consistent with this notion. In contrast, the pool of glutamate reflected by MRS was uncorrelated with CSF levels, and was sensitive to acamprosate. This indicates that it originates from a pool distinct from that contributing to glutamate in CSF, and one that is likely to be more closely related to neurotransmission. Finally, our data leave unresolved the question why CSF levels of glutamate in protracted, but not in early abstinence were strongly correlated with alcohol dependence severity. It may be speculated that CSF levels in early withdrawal are mostly influenced by state-related factors with high individual variability, such as e.g. nutritional status. Following a month in the highly standardized environment of the inpatient care unit, state-related factors may play a lesser role, while remaining variance is to a higher extent accounted for by trait-like factors, such as alcoholism severity.
Finally, up-regulation of hypothalamic-pituitary-adrenal (HPA)-axis reactivity, measured by dex-CRH responses, has been reported in the first weeks following initiation of alcohol abstinence 43, and may offer a window on central CRH activity, which is suggested by animal studies to be up-regulated following a prolonged history of brain alcohol exposure 44. We therefore explored whether a modulation of dex-CRH test responses by acamprosate would indicate that glutamatergic and CRH-related neuroadaptations in alcoholism are related to each other. However, in agreement with another recent study 45, we found no effect of acamprosate on the dex-CRH response, neither in early nor in protracted abstinence. Probes more directly tapping into central CRH function, such as positron emission tomography (PET) ligands for central CRH receptors, may be needed to address a possible relationship between neuroadaptations that encompass glutamate and CRH systems in alcoholism.
In conclusion, we find that 1H-MRS spectroscopy is a valuable, non-invasive translational tool to study measures of glutamate function in alcoholism. Although it cannot be excluded that our finding reflect a lowering of glutamate by acamprosate in a compartment not directly relevant to neurotransmission, this interpretation is made less likely by the concordance between our finding and available animal data 5, 14. MRS offers an attractive surrogate marker for early human evaluation of candidate therapeutics that target the glutamatergic system.
The authors thank K. Rice, B.A. for data collection and entry, M.J. Phillips, B.S. and K. Smith for help with manuscript preparation, and NIH Clinical Center Pharmaceutical Development Services for formulating drug and placebo. Supported by NIAAA intramural research funding.
None of the authors has any conflicts of interest to declare.