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Review article: Biomedical intelligence

Vol. 141 No. 4142 (2011)

Is there a way to curb benzodiazepine addiction?

  • AL Lalive
  • U Rudolph
  • C Lüscher
  • KR Tan
DOI
https://doi.org/10.4414/smw.2011.13277
Cite this as:
Swiss Med Wkly. 2011;141:w13277
Published
10.10.2011

Summary

Benzodiazepines are widely prescribed drugs used to treat anxiety and insomnia, induce muscle relaxation, control epileptic seizures, promote anaesthesia or produce amnesia. Benzodiazepines are also abused for recreational purposes and the number of benzodiazepine abusers is unfortunately increasing. Within weeks of chronic use, tolerance to the pharmacological effects can develop and withdrawal becomes apparent once the drug is no longer available, which are both conditions indicative of benzodiazepine dependence. Diagnosis of addiction (i.e. compulsive use despite negative consequences) may follow in vulnerable individuals. Here, we review the historical and current use of benzodiazepines from their original synthesis, discovery and commercialisation to the recent identification of the molecular mechanism by which benzodiazepines induce addiction. These results have identified the mechanisms underlying the activation of midbrain dopamine neurons by benzodiazepines, and how these drugs can hijack the mesocorticolimbic reward system. Such knowledge calls for future developments of new receptor subtype specific benzodiazepines with a reduced addiction liability.

References

  1. Sternbach LH. The benzodiazepine story. J Psychoactive Drugs. 1983;15:15–7.
  2. Birdwood G, Craven M. Letter. Outmoded barbiturates. Br Med J. 1975;1:148.
  3. Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABA(A) receptor subtypes and addiction. Trends in Neurosci. 2011;34:188–97.
  4. Woods JH, Katz JL, Winger G. Benzodiazepines: use, abuse, and consequences. Pharmacol Rev. 1992;4:151–347.
  5. Sigel E, Buhr A. The benzodiazepine binding site of GABAA receptors. Trends Pharmacol Sci. 1997;18:425–9.
  6. Wieland HA, Lüddens H, Seeburg PH. A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J Biol Chem. 1992;267:1426–9.
  7. Yang W, Drewe JA, Lan NC. Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site. Eur J Pharmacol. 1995;291:319–25.
  8. Korpi ER, Seeburg PH. Natural mutation of GABAA receptor alpha 6 subunit alters benzodiazepine affinity but not allosteric GABA effects. Eur J Pharmacol. 1993;247:23–7.
  9. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, et al. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 1999;401:796–800.
  10. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci. 2000;3:587–92.
  11. Löw K, Crestani F, Keist R, Benke D, Brünig I, et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science. 2000;290:131–4.
  12. Crestani F, Löw K, Keist R, Mandelli M, Möhler H, et al. Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol. 2001;59:442–5.
  13. Crestani F, Keist R, Fritschy J-M, Benke D, Vogt K, et al. Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Nat Acad Sci. 2002;99:8980–5.
  14. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci. 2002;22:5572–80.
  15. Cheng VY, Martin LJ, Elliott EM, Kim JH, Mount HTJ, et al. Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate. J Neurosci. 2006;26:3713–20.
  16. Tan KR, Brown M, Labouèbe G, Yvon C, Creton C, et al. Neural bases for addictive properties of benzodiazepines. Nature. 2010;463:769–74.
  17. Salzman C. Addiction to benzodiazepines. The Psychiatric quarterly. 1998;69:251–61.
  18. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89:1455–9.
  19. Gabbard GO. (2007) American Psychiatric Publishing 209-211.
  20. http://en.wikipedia.org/wiki/Benzodiazepines - cite_note-isbn0-19-856667-0-85.
  21. Colvin R. United States of America: Addicus Books (2008)74–76.
  22. Wagner FA, Anthony JC. From first drug use to drug dependence; developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology. 2002;26:479–88.
  23. Rooney S, Kelly G, Bamford L, Sloan D, O’Connor JJ. Co-abuse of opiates and benzodiazepines. Ir J Med Sc. 1999;168:1,36–41.
  24. Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psy. 1999;156:34–40.
  25. Enoch MA. Goldman D. The genetics of alcoholism and alcohol abuse. Cur Psy Rep. 2001;3:144–51.
  26. Goldman D, Oroszi G, Ducci F. The genetics of addictions: uncovering the genes. Nat Rev Gen. 2005;6:521–32.
  27. Merikangas KR, Mehta RL, Molnar BE, Walters EE, Swendsen JD, et al. Comorbidity of substance use disorders with mood and anxiety disorders: results of the International Consortium in Psychiatric Epidemiology. Add Behav. 1998;23:893–907.
  28. Hu X, Oroszi G, Chun J, Smith TL, Goldman D, et al. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alc Clin Exp Res. 2005;29:8–16.
  29. Schuckit MA, Mazzanti C, Smith TL, Ahmed U, Radel M, et al. Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study. Biol Psy. 1999;45:647–51.
  30. Iwata N, Cowley DS, Radel M, Roy-Byrne PP, Goldman D. Relationship between a GABAA alpha 6 Pro385Ser substitution and benzodiazepine sensitivity. Am J Psy. 1999;156:1447–9.
  31. White FJ, Kalivas PW. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alc Dep. 1998;51:141–53.
  32. Nestler EJ. Molecular neurobiology of addiction. Am J Psy. 2001;10:201–17.
  33. McClung CA, Nestler EJ. Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat Neurosci. 2003;6:1208–15.
  34. McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, et al. DeltaFosB: a molecular switch for long-term adaptation in the brain. Brain Res Mol Brain Res. 2004;132:146–54.
  35. Nestler EJ. Review. Transcriptional mechanisms of addiction: role of DeltaFosB. Biol Sci. 2008;363:3245–55.
  36. Maze I, Nestler EJ. The epigenetic landscape of addiction. Annals New York Acad Sci. 2011;1216:99–113.
  37. Ungless MA, Whistler JL, Malenka RC, Bonci A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature. 2001;411:583–7.
  38. Lüscher C, Malenka RC. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron. 2011;69:650–63.
  39. Yamaguchi T, Sheen W, Morales M. Glutamatergic neurons are present in the rat ventral tegmental area. Eur J Neurosci. 2007;25:106–18.
  40. Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science. 1997;275:1593–9.
  41. Ungless MA, Magill PJ, Bolam JP. Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science. 2004;303:2040–2.
  42. Xia Y, Driscoll JR, Wilbrecht L, Margolis EB, Fields HL, Hjelmstad GO. Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area. J Neurosci. 2011;31(21):7811-6.
  43. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Nat Acad Sci. 1988;85:5274–8.
  44. Nestler EJ. Is there a common molecular pathway for addiction? Nat. Neurosci. 2005;8:1445–9.
  45. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacol. 2004;47(Suppl 1):227–41.
  46. Argilli E, Sibley DR, Malenka RC, England PM, Bonci A. Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area. J Neurosci. 2008;28:9092–100.
  47. Brown MTC, Bellone C, Mameli M, Labouèbe G, Bocklisch C, et al. Drug-Driven AMPA Receptor Redistribution Mimicked by Selective Dopamine Neuron Stimulation. PLoS ONE 2010;5: e15870.
  48. Lüscher C, Ungless MA. The mechanistic classification of addictive drugs. PLoS Med. 2006;3:e437.
  49. Johnson SW, North RA. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci. 1992;12:483–8.
  50. Szabo B, Siemes S, Wallmichrath I. Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Euro J Neurosci. 2002;15:2057–61.
  51. Cruz HG, Ivanova T, Lunn M-L, Stoffel M, Slesinger PA, et al. Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat Neurosci. 2004;7:153–9.
  52. Maskos U, Molles BE, Pons S, Besson M, Guiard BP, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature. 2005;436:103–7.
  53. Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005;75:406–33.
  54. Saal D, Dong Y, Bonci A, Malenka RC. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron. 2003;37:577–82.
  55. Mameli M, Halbout B, Creton C, Engblom D, Parkitna JR, et al. Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat Neurosci. 2009;12:1036–41.
  56. Liu Q-, Pu L, Poo M. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature. 2005;437:1027–31.
  57. Wolf ME. The Bermuda Triangle of cocaine-induced neuroadaptations. Trends Neurosci. 2010;33:391–8.
  58. Heikkinen AE, Möykkynen TP, Korpi ER. Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology. 2009;34:290–8.
  59. Anderson KN, Shneerson JM. Drug treatment of REM sleep behavior disorder: the use of drug therapies other than clonazepam. J Clinic Sleep Med. 2009;5:235–9.
  60. Hollister LE, Müller-Oerlinghausen B, Rickels K, Shader RI. Clinical uses of benzodiazepines. J Clinic Psychopharmacol. 1993;13:1S–169S.
  61. Scott-Stevens P, Atack JR, Sohal B, Worboys P. Rodent pharmacokinetics and receptor occupancy of the GABAA receptor subtype selective benzodiazepine site ligand L-838417. Biopharma Drug Disp. 2005;26:13–20.