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Molecular Medicine

, Volume 19, Issue 1, pp 135–148 | Cite as

Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

  • Sonja M. Wojcik
  • Martesa Tantra
  • Beata Stepniak
  • Kwun-nok M. Man
  • Katja Müller-Ribbe
  • Martin Begemann
  • Anes Ju
  • Sergi Papiol
  • Anja Ronnenberg
  • Artem Gurvich
  • Yong Shin
  • Iris Augustin
  • Nils Brose
  • Hannelore Ehrenreich
Research Article

Abstract

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I-associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders.

Notes

Acknowledgments

We are indebted to all patients for their participation in the GRAS study and all collaborating GRAS centers for their support. We are grateful to all colleagues who contributed to the GRAS data collection. We would also like to thank Astrid Zeuch, Astrid Ohle and the members of the DNA sequencing core facility for excellent technical assistance. This work was supported by the Max Planck Society, the MaxPlanck-Förderstiftung, and the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain.

Supplementary material

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References

  1. 1.
    Kessler RC, et al. (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry. 62:593–602.CrossRefPubMedGoogle Scholar
  2. 2.
    Pasche S. (2012) Exploring the comorbidity of anxiety and substance use disorders. Curr. Psychiatry Rep. 14:176–81.CrossRefPubMedGoogle Scholar
  3. 3.
    Swendsen J, et al. (2010) Mental disorders as risk factors for substance use, abuse and dependence: results from the 10-year follow-up of the National Comorbidity Survey. Addiction. 105:1117–28.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Conway KP, Compton W, Stinson FS, Grant BF. (2006) Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J. Clin. Psychiatry. 67:247–57.CrossRefPubMedGoogle Scholar
  5. 5.
    Myrick H, Brady K. (2003) Current review of the comorbidity of affective, anxiety, and substance use disorders. Curr. Opin. Psychiatry. 16:261–70.Google Scholar
  6. 6.
    Bandelow B, et al. (2012) Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int. J. Psychiatry Clin. Pract. 16:77–84.CrossRefPubMedGoogle Scholar
  7. 7.
    Baker AL, Thornton LK, Hiles S, Hides L, Lubman DI. (2012) Psychological interventions for alcohol misuse among people with co-occurring depression or anxiety disorders: a systematic review. J. Affect. Disord. 139:217–29.CrossRefPubMedGoogle Scholar
  8. 8.
    Hettema JM, Neale MC, Kendler KS. (2001) A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am. J. Psychiatry. 158:1568–78.CrossRefPubMedGoogle Scholar
  9. 9.
    Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. (2005) The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch. Gen. Psychiatry. 62:182–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Ducci F, Goldman D. (2012) The genetic basis of addictive disorders. Psychiatr. Clin. North Am. 35:495–519.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hovatta I, Barlow C. (2008) Molecular genetics of anxiety in mice and men. Ann. Med. 40:92–109.CrossRefPubMedGoogle Scholar
  12. 12.
    Hamilton SP. (2009) Linkage and association studies of anxiety disorders. Depress. Anxiety. 26:976–83.CrossRefPubMedGoogle Scholar
  13. 13.
    Wang JC, Kapoor M, Goate AM. (2012) The genetics of substance dependence. Annu. Rev. Genomics Hum. Genet. 13:241–61.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gelernter J, Kranzler HR. (2010) Genetics of drug dependence. Dialogues Clin. Neurosci. 12:77–84.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Buckland PR. (2008) Will we ever find the genes for addiction? Addiction. 103:1768–76.CrossRefPubMedGoogle Scholar
  16. 16.
    Marmorstein NR. (2012) Anxiety disorders and substance use disorders: different associations by anxiety disorder. J. Anxiety Disord. 26:88–94.CrossRefPubMedGoogle Scholar
  17. 17.
    DeMartini KS, Carey KB. (2011) The role of anxiety sensitivity and drinking motives in predicting alcohol use: a critical review. Clin. Psychol. Rev. 31:169–77.CrossRefPubMedGoogle Scholar
  18. 18.
    Zavos HM, Gregory AM, Eley TC. (2012) Longitudinal genetic analysis of anxiety sensitivity. Dev. Psychol. 48:204–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Kushner MG, Thuras P, Abrams K, Brekke M, Stritar L. (2001) Anxiety mediates the association between anxiety sensitivity and coping-related drinking motives in alcoholism treatment patients. Addict. Behav. 26:869–85.CrossRefPubMedGoogle Scholar
  20. 20.
    Baldwin DS, Allgulander C, Bandelow B, Ferre F, Pallanti S. (2012) An international survey of reported prescribing practice in the treatment of patients with generalised anxiety disorder. World J. Biol. Psychiatry. 13:510–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Canteras NS, Resstel LB, Bertoglio LJ, Carobrez Ade P, Guimaraes FS. (2010) Neuroanatomy of anxiety. Curr. Top. Behav. Neurosci. 2:77–96.CrossRefPubMedGoogle Scholar
  22. 22.
    Gratacos M, et al. (2007) Candidate genes for panic disorder: insight from human and mouse genetic studies. Genes Brain Behav. 6 (Suppl. 1):2–23.CrossRefPubMedGoogle Scholar
  23. 23.
    Koch H, Hofmann K, Brose N. (2000) Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform. Biochem. J. 349:247–53.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Shiratsuchi T, et al. (1998) Cloning and characterization of BAP3 (BAI-associated protein 3), a C2 domain-containing protein that interacts with BAI1. Biochem. Biophys. Res. Commun. 251:158–65.CrossRefPubMedGoogle Scholar
  25. 25.
    Varoqueaux F, et al. (2002) Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proc. Natl. Acad. Sci. U. S. A. 99:9037–42.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gorman JM, Kent JM, Sullivan GM, Coplan JD. (2000) Neuroanatomical hypothesis of panic disorder, revised. Am. J. Psychiatry. 157:493–505.CrossRefPubMedGoogle Scholar
  27. 27.
    Gross CT, Canteras NS. (2012) The many paths to fear. Nat. Rev. Neurosci. 13:651–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Wojcik SM, Brose N. (2007) Regulation of membrane fusion in synaptic excitation-secretion coupling: speed and accuracy matter. Neuron. 55:11–24.CrossRefPubMedGoogle Scholar
  29. 29.
    Feldmann J, et al. (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 115:461–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Shirakawa R, et al. (2004) Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets. J. Biol. Chem. 279:10730–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Begemann M, et al. (2010) Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch. Gen. Psychiatry. 67:879–88.CrossRefPubMedGoogle Scholar
  32. 32.
    Ribbe K, et al. (2010) The cross-sectional GRAS sample: a comprehensive phenotypical data collection of schizophrenic patients. BMC Psychiatry. 10:91.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ferraro TN, et al. (1999) Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice. J. Neurosci. 19:6733–9.CrossRefPubMedGoogle Scholar
  34. 34.
    American Psychiatric Association (APA). (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th ed., text revision. Washington (DC): APA. 992 pp.Google Scholar
  35. 35.
    Kay SR, Fiszbein A, Opler LA. (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13:261–76.CrossRefPubMedGoogle Scholar
  36. 36.
    Cronbach LJ. (1951) Coefficient alpha and the internal structure of tests. Psychometrika. 16:297–334.CrossRefGoogle Scholar
  37. 37.
    Rubin DB. (1987) Multiple Imputation for Non-Response in Surveys. New York: John Wiley & Sons.CrossRefGoogle Scholar
  38. 38.
    Stefanova N, Ovtscharoff W. (2000) Sexual dimorphism of the bed nucleus of the stria terminalis and the amygdala. Adv. Anat. Embryol. Cell Biol. 158:III–X, 1–78.Google Scholar
  39. 39.
    Qureshi IA, Mehler MF. (2010) Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility. Prog. Brain Res. 186:77–95.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Neutel CI. (2005) The epidemiology of long-term benzodiazepine use. Int. Rev. Psychiatry. 17:189–97.CrossRefPubMedGoogle Scholar
  41. 41.
    Pierce KA, Kirkpatrick DR. (1992) Do men lie on fear surveys? Behav. Res. Ther. 30:415–8.CrossRefPubMedGoogle Scholar
  42. 42.
    McLean CP, Anderson ER. (2009) Brave men and timid women? A review of the gender differences in fear and anxiety. Clin. Psychol. Rev. 29:496–505.CrossRefPubMedGoogle Scholar
  43. 43.
    Stoyanova M, Hope DA. (2012) Gender, gender roles, and anxiety: perceived confirmability of self report, behavioral avoidance, and physiological reactivity. J. Anxiety Disord. 26:206–14.CrossRefPubMedGoogle Scholar
  44. 44.
    Tan KR, Rudolph U, Luscher C. (2011) Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 34:188–97.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Fenoglio KA, et al. (2007) Hypothalamic hamartoma: basic mechanisms of intrinsic epileptogenesis. Semin. Pediatr. Neurol. 14:51–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Aroniadou-Anderjaska V, Fritsch B, Qashu F, Braga MF. (2008) Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy. Epilepsy Res. 78:102–16.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Pinto D, et al. (2005) Genome-wide linkage scan of epilepsy-related photoparoxysmal electroencephalographic response: evidence for linkage on chromosomes 7q32 and 16p13. Hum. Mol. Genet. 14:171–8.CrossRefPubMedGoogle Scholar
  48. 48.
    de Kovel CG, et al. (2010) Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis. Epilepsy Res. 89:286–94.CrossRefPubMedGoogle Scholar
  49. 49.
    Zetterstrom T, Fillenz M. (1990) Local administration of flurazepam has different effects on dopamine release in striatum and nucleus accumbens: a microdialysis study. Neuropharmacology. 29:129–34.CrossRefPubMedGoogle Scholar
  50. 50.
    Invernizzi R, Pozzi L, Samanin R. (1991) Release of dopamine is reduced by diazepam more in the nucleus accumbens than in the caudate nucleus of conscious rats. Neuropharmacology. 30:575–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Finlay JM, Damsma G, Fibiger HC. (1992) Benzodiazepine-induced decreases in extracellular concentrations of dopamine in the nucleus accumbens after acute and repeated administration. Psychopharmacologyy (Berl.). 106:202–8.CrossRefGoogle Scholar
  52. 52.
    Tan KR, et al. (2010) Neural bases for addictive properties of benzodiazepines. Nature. 463:769–74.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    O’Brien DP, White FJ. (1987) Inhibition of non-dopamine cells in the ventral tegmental area by benzodiazepines: relationship to A10 dopamine cell activity. Eur. J. Pharmacol. 142:343–54.CrossRefPubMedGoogle Scholar
  54. 54.
    Heberlein A, Bleich S, Kornhuber J, Hillemacher T. (2008) Neuroendocrine pathways in benzodiazepine dependence: new targets for research and therapy. Hum. Psychopharmacol. 23:171–81.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Sonja M. Wojcik
    • 1
  • Martesa Tantra
    • 2
    • 3
  • Beata Stepniak
    • 2
  • Kwun-nok M. Man
    • 1
    • 3
  • Katja Müller-Ribbe
    • 2
  • Martin Begemann
    • 2
  • Anes Ju
    • 2
  • Sergi Papiol
    • 2
    • 3
  • Anja Ronnenberg
    • 2
  • Artem Gurvich
    • 2
  • Yong Shin
    • 1
  • Iris Augustin
    • 1
  • Nils Brose
    • 1
    • 3
  • Hannelore Ehrenreich
    • 2
    • 3
  1. 1.Department of Molecular NeurobiologyMax Planck Institute of Experimental MedicineGöttingenGermany
  2. 2.Clinical NeuroscienceMax Planck Institute of Experimental MedicineGöttingenGermany
  3. 3.DFG Center for Nanoscale Microscopy and Molecular Physiology of the BrainGöttingenGermany

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