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Effects of d-cycloserine on extinction of mesolimbic cue reactivity in alcoholism: a randomized placebo-controlled trial

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Abstract

Rationale

Mesocorticolimbic reactivity to alcohol-associated cues has been shown to be associated with relapse to renewed drinking and to be decreased by cue-exposure-based extinction training (CET). Evidence from preclinical studies suggests that the extinction of conditioned alcohol-seeking behavior might be facilitated by drugs increasing N-methyl-d-aspartate (NMDA) receptor-associated memory consolidation.

Objectives

In this study, we assessed the efficacy of CET treatment supplemented with the partial NMDA-receptor agonist d-cycloserine (DCS) at reducing mesolimbic cue reactivity (CR), craving, and relapse risk in alcoholism.

Methods

In a randomized, placebo-controlled, double-blind study, we recruited 76 recently detoxified abstinent alcohol-dependent patients. Thirty-two (16 DCS, 16 placebo) patients showed cue-induced ventral-striatal activation measured with functional magnetic resonance imaging (fMRI) prior to treatment and were thus included in the efficacy analyses. After inpatient detoxification, patients underwent nine sessions of CET spaced over 3 weeks, receiving either 50 mg DCS or placebo 1 h prior to each CET session. FMRI was conducted before treatment and 3 weeks after treatment onset.

Results

Following treatment with CET plus DCS, cue-induced brain activation in the ventral and dorsal striatum was decreased compared to treatment with CET plus placebo. Elevated posttreatment ventral striatal CR and increased craving (assessed using the Obsessive Compulsive Drinking Scale) were associated with increased relapse risk.

Conclusions

DCS was shown to augment the effect of CET for alcohol-dependent subjects. The interaction between craving and ventral-striatal CR on treatment outcome suggests that CET might be especially effective in patients exhibiting both high craving and elevated CR.

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Acknowledgments

This study was supported by a grant from the Deutsche Forschungsgemeinschaft (grant ID SFB 636, D6) and the Bundesministerium für Bildung und Forschung (NGFN+ grant ID 01 GS08152, SP 13). We would like to thank Daniela Hirsch and Carsten Kern for their assistance in data collection, and Jürgen Weber for his contribution in data preparation. The experiments comply with the current laws of Germany.

Conflict of interest

The authors report no biomedical financial interests or potential conflicts of interestClinicalTrials.gov ID: NCT00926900.

Author contributions

FK, MK, CG, SL, and SVK were responsible for the study concept and design. MK and AJ contributed to recruitment, the acquisition of fMRI, and MRI data. MK and AJ conducted the CET sessions. MK, SH, AJ, and SVK were involved in data administration. FK, MK, PB, SH, IR, and SVK provided the data analysis and interpretation of findings. FK and SVK drafted the manuscript. FK, MK, PB, SH, IR, AJ, CG, RS, KM, SL, and SVK provided critical revision of the manuscript for important intellectual content. All authors critically reviewed content and approved final version for publication.

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Authors and Affiliations

  1. Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Square J5, 68159, Heidelberg, Germany

    Falk Kiefer, Martina Kirsch, Patrick Bach, Sabine Hoffmann, Anne Jorde, Christoph von der Goltz, Karl Mann & Sabine Vollstädt-Klein

  2. Department of Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    Iris Reinhard

  3. Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    Rainer Spanagel

  4. Department of Clinical Psychology and Psychotherapy, University of Bamberg, Bamberg, Germany

    Sabine Loeber

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  1. Falk Kiefer
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  4. Sabine Hoffmann
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  11. Sabine Vollstädt-Klein
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Corresponding author

Correspondence to Sabine Vollstädt-Klein.

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Kiefer, F., Kirsch, M., Bach, P. et al. Effects of d-cycloserine on extinction of mesolimbic cue reactivity in alcoholism: a randomized placebo-controlled trial. Psychopharmacology 232, 2353–2362 (2015). https://doi.org/10.1007/s00213-015-3882-5

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  • DOI: https://doi.org/10.1007/s00213-015-3882-5

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