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Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels

Molecular Psychiatry volume 18, pages 1205–1210 (2013)Cite this article

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Abstract

Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine–glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine–glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single-nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the United States. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene–gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala; the correlation was inversed in opiate abusers as compared with controls. Cumulatively, these results support the hypothesis that there may be significant, genetically influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers.

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Acknowledgements

This work was funded by grants from the National Institute on Drug Abuse, T32DA007135 (MMJ), R01DA006470 (MJB) and R01DA015446 (YLH) and the National Institute of Mental Health, R25MH080663 (MMJ, SM) and U01MH083501 (SM), and the NIH UL1RR029887 (MSSM CTSA). EK was also supported by grant ETT/098/2009.

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Authors and Affiliations

  1. Departments of Psychiatry and Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, USA

    M M Jacobs & Y L Hurd

  2. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    A Ökvist

  3. National Board of Forensic Medicine/Department of Forensic Medicine, Uppsala University, Uppsala, Sweden

    M Horvath

  4. Department of Forensic Medicine, Semmelweis University, Budapest, Hungary

    M Horvath & E Keller

  5. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA

    M J Bannon

  6. Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA

    S Morgello

  7. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    S Morgello & Y L Hurd

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Correspondence to Y L Hurd.

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Jacobs, M., Ökvist, A., Horvath, M. et al. Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels. Mol Psychiatry 18, 1205–1210 (2013). https://doi.org/10.1038/mp.2012.140

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