Classics in chemical neuroscience: Diazepam (valium)

ACS Chemical Neuroscience

Volumn 5, Issue 4, 2014, Pages 253-260

  Calcaterra, Nicholas E ^a   Barrow, James C ^a,b  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b LIEBER INSTITUTE FOR BRAIN DEVELOPMENT   (United States)

Author keywords

anxiety; benzodiazepine; Diazepam; GABA; hypnotic; sedative; Valium

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; BARBITURIC ACID DERIVATIVE; BENZODIAZEPINE; BENZODIAZEPINE DERIVATIVE; DIAZEPAM; HYPNOTIC SEDATIVE AGENT;

ALCOHOL WITHDRAWAL; AMNESIA; ANXIETY; ANXIETY DISORDER; ATAXIA; BRAIN ELECTROPHYSIOLOGY; CONFUSION; CONVULSION; DEMETHYLATION; DEPRESSION; DIZZINESS; DRUG BIOAVAILABILITY; DRUG DEPENDENCE; DRUG HYDROXYLATION; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; EPILEPSY; HUMAN; HYDROGEN BOND; INSOMNIA; MOLECULAR WEIGHT; MUSCLE SPASM; NEUROSCIENCE; PRIORITY JOURNAL; PSYCHOPHARMACOLOGY; RESPIRATORY ARREST; RESTLESS LEGS SYNDROME; REVIEW; SEDATION; SEIZURE; STEADY STATE; SYNTHESIS; TACHYCARDIA; TREATMENT INDICATION; ANXIETY DISORDERS; CHEMICALLY INDUCED; DOSE RESPONSE; DRUG DESIGN; DRUG OVERDOSE; RESPIRATION DISORDERS; SEIZURES;

ANXIETY DISORDERS; DIAZEPAM; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; DRUG OVERDOSE; HUMANS; RESPIRATION DISORDERS; SEIZURES;

EID: 84898948608     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/cn5000056     Document Type: Review

References (90)

1. Kessler, R. C., Chiu, W. T., Demler, O., and Walters, E. E. (2005) Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Arch. Gen. Psychiat. 62 (6) 617-627 (Pubitemid 40973437)
2. Baenninger, A., Costa e Silva, J. A., Hindmarch, I., Moeller, H. J., and Rickels, K. (2004) Good Chemistry: The Life and Legacy of Valium Inventor Leo Sternbach, McGraw Hill, New York.
3. Valium (Diazepam), Physician's Desk Reference Online http://www.pdr.net/ drug-summary/valium?druglabelid=2100. Accessed December 20, 2013.
4. Nutt, D. J. and Malizia, A. L. (2001) New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder Br. J. Psychiatry 179 (5) 390-396 (Pubitemid 33097160)
5. Zakusov, V. V., Ostrovskaya, R. U., Kozhechkin, S. N., Markovich, V. V., Molodavkin, G. M., and Voronina, T. A. (1977) Further Evidence for Gaba-Ergic Mechanisms in Action of Benzodiazepines Arch. Int. Pharmacol. 229 (2) 313-326 (Pubitemid 8225713)
6. Greenblatt, D. J. and Shader, R. I. (1978) Dependence, Tolerance, and Addiction to Benzodiazepines-Clinical and Pharmacokinetic Considerations Drug Metab. Rev. 8 (1) 13-28 (Pubitemid 9121266)
7. Wager, T. T., Hou, X. J., Verhoest, P. R., and Villalobos, A. (2010) Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties ACS Chem. Neurosci. 1 (6) 435-449
8. Sternbach, L. H., Kaiser, S., and Reeder, E. (1960) Quinazoline 3-Oxide Structure of Compounds Previously Described in the Literature as 3.1.4-Benzoxadiazepines J. Am. Chem. Soc. 82 (2) 475-479
9. Stempel, A., Reeder, E., and Sternbach, L. H. (1965) Quinazolines and 1,4-Benzodiazepines. XXVII. Mechanism of Ring Enlargement of Quinazoline 3-Oxides with Alkali to 1,4-Benzodiazepin-2-1 4-Oxides J. Org. Chem. 30 (12) 4267-4271
10. Sternbach, L. and Reeder, E. (1961) Quinazolines and 1,4-Benzodiazepines. II. Rearrangement of 6-Chloro-2-Chlormethyl-4-Phenylquinazoline 3-Oxide into 2-Amino Derivatives of 7-Chloro-5-Phenyl-3H-1,4-Benzodiazepine 4-Oxide J. Org. Chem. 26 (4) 1111-1118
11. Randall, L. O., Schallek, W., Heise, G. A., Keith, E. F., and Bagdon, R. E. (1960) The Psychosedative Properties of Methaminodiazepoxide J. Pharmacol. Exp. Ther. 129 (2) 163-171
12. Sternbach, L. and Reeder, E. (1961) Quinazolines and 1,4-Benzodiazepines 0.4. Transformations of 7-Chloro-2-Methylamino-5-Phenyl-3h-1,4-Benzodiazepine 4-Oxide J. Org. Chem. 26 (12) 4936-4941
13. Sternbach, L., Keller, O., Metlesics, W., and Reeder, E. (1961) Quinazolines and 1,4-Benzodiazepines. III. Substituted 2-Amino-5-Phenyl-3H-1,4- Benzodiazepine 4-Oxides J. Org. Chem. 26 (11) 4488-4497
14. Sternbach, L. (1959) 1,4-Benzodiazepine 4-Oxides. U.S. Patent US2893992.
15. Sternbach, L. H. (1971) 1,4-Benzodiazepines-Chemistry and Some Aspects of Structure-Activity Relationship Angew. Chem., Int. Ed. 10 (1) 34-43
16. Reeder, E. and Sternbach, L. (1968) 5-Aryl-3H-1,4-benzodiazepin-2(1h)- ones. U.S. Patent US3371085.
17. Gates, M. (1980) New Synthesis of Diazepam J. Org. Chem. 45 (9) 1675-1681 (Pubitemid 10027129)
18. Ishikura, M., Mori, M., Ikeda, T., Terashima, M., and Ban, Y. (1982) New Synthesis of Diazepam and the Related 1,4-Benzodiazepines by Means of Palladium-Catalyzed Carbonylation J. Org. Chem. 47 (12) 2456-2461
19. Sternbach, L. H. (1979) Benzodiazepine Story J. Med. Chem. 22 (1) 1-7
20. Ainsworth, S. (2013) Mother's Little Helper Still Rocking Nurse Prescribing 11 (5) 255-256
21. Valium Prescribing Information: http://www.gene.com/download/pdf/valium- prescribing.pdf. Accessed December 20, 2013.
22. International League Against Epilepsy, Worldwide AED Database. http://www.ilae.org/Visitors/Centre/AEDs/index.cfm. Accessed December 20, 2013.
23. Lindsley, C. W. (2012) The Top Prescription Drugs of 2011 in the United States: Antipsychotics and Antidepressants Once Again Lead CNS Therapeutics ACS Chem. Neurosci. 3 (8) 630-631
24. Mandelli, M., Tognoni, G., and Garattini, S. (1978) Clinical Pharmacokinetics of Diazepam Clin. Pharmacokinet. 3 (1) 72-91 (Pubitemid 8287275)
25. Klotz, U., Antonin, K. H., and Bieck, P. R. (1976) Pharmacokinetics And Plasma Binding Of Diazepam In Man, Dog, Rabbit, Guinea-Pig And Rat J. Pharmacol. Exp. Ther. 199 (1) 67-73
26. Vozeh, S. (1981) Pharmacokinetics of the Benzodiazepines in the Elderly Patient Schweiz. Med. Wochenschr. 111 (47) 1789-1793
27. Zingales, I. A. (1973) Diazepam Metabolism during Chronic Medication-Unbound Fraction in Plasma, Erythrocytes and Urine J. Chromatogr. 75 (1) 55-78
28. Ono, S., Hatanaka, T., Miyazawa, S., Tsutsui, M., Aoyama, T., Gonzalez, F. J., and Satoh, T. (1996) Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: Role of CYP2B6, 2C19 and the 3A subfamily Xenobiotica 26 (11) 1155-1166 (Pubitemid 26398070)
29. Greenblatt, D. J., Divoll, M. K., Soong, M. H., Boxenbaum, H. G., Harmatz, J. S., and Shader, R. I. (1988) Desmethyldiazepam Pharmacokinetics- Studies Following Intravenous and Oral Desmethyldiazepam, Oral Clorazepate, and Intravenous Diazepam J. Clin. Pharmacol. 28 (9) 853-859 (Pubitemid 19012994)
30. Andersson, T., Miners, J. O., Veronese, M. E., and Birkett, D. J. (1994) Diazepam Metabolism by Human Liver-Microsomes Is Mediated by Both S-Mephenytoin Hydroxylase and Cyp3A Isoforms Br. J. Clin. Pharmacol. 38 (2) 131-137 (Pubitemid 24247754)
31. Hooper, W. D., Watt, J. A., Mckinnon, G. E., and Reilly, P. E. B. (1992) Metabolism of Diazepam and Related Benzodiazepines by Human Liver-Microsomes Eur. J. Drug Metab. Pharmacokinet. 17 (1) 51-59
32. Hillesta, L., Hansen, T., Melsom, H., and Drivenes, A. (1974) Diazepam Metabolism in Normal Man 0.1. Serum Concentrations and Clinical Effects after Intravenous, Intramuscular, and Oral-Administration Clin. Pharmacol. Ther. 16 (3) 479-484
33. Hillesta, L., Hansen, T., and Melsom, H. (1974) Diazepam Metabolism in Normal Man 0.2. Serum Concentration and Clinical Effect after Oral-Administration and Cumulation Clin. Pharmacol. Ther. 16 (3) 485-489
34. Desta, Z., Zhao, X. J., Shin, J. G., and Flockhart, D. A. (2002) Clinical significance of the cytochrome P4502C19 genetic polymorphism Clin. Pharmacokinet. 41 (12) 913-958 (Pubitemid 35168437)
35. Bertilsson, L. (1995) Geographical Interracial Differences in Polymorphic Drug Oxidation-Current State of Knowledge of Cytochromes P450 (Cyp) 2d6 and 2c19 Clin. Pharmacokinet. 29 (3) 192-209
36. Fukasawa, T., Suzuki, A., and Otani, K. (2007) Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines J. Clin. Pharm. Ther. 32 (4) 333-341 (Pubitemid 47063159)
37. Perucca, E., Gatti, G., Cipolla, G., Spina, E., Barel, S., Soback, S., Gips, M., and Bialer, M. (1994) Inhibition of Diazepam Metabolism by Fluvoxamine-a Pharmacokinetic Study in Normal Volunteers Clin. Pharmacol. Ther. 56 (5) 471-476 (Pubitemid 24370353)
38. Clark, W. G., Brater, D. C., and Johnson, A. R. (1992) Goth's Medical Pharmacology, CV Mosby, St. Louis, MO.
39. Greenblatt, D. J., Shader, R. I., and Kochweser, J. (1975) Pharmacokinetics In Clinical Medicine-Oxazepam Versus Other Benzodiazepines Dis. Nerv. Syst. 36 (5) 6-13
40. Heel, R. C., Brogden, R. N., Speight, T. M., and Avery, G. S. (1981) Temazepam-A Review Of Its Pharmacological Properties And Therapeutic Efficacy As An Hypnotic Drugs 21 (5) 321-340 (Pubitemid 12164171)
41. Mohler, H. and Okada, T. (1977) Gaba Receptor-Binding with H-3(+) Bicuculline-Methiodide in Rat CNS Nature 267, 65-67
42. Squires, R. F. and Braestrup, C. (1977) Benzodiazepine Receptors in Rat-Brain Nature 266, 732-734
43. Braestrup, C. and Squires, R. F. (1977) Specific Benzodiazepine Receptors in Rat-Brain Characterized by High-Affinity [Diazepam-H-3] Binding (Affinity Binding Diazepam Anxiolytic Activity Brain Membranes Regional Distribution) Proc. Natl. Acad. Sci. U.S.A. 74 (9) 3805-3809
44. Mohler, H. and Okada, T. (1977) Benzodiazepine Receptor-Demonstration in Central Nervous-System Science 198 (4319) 849-851 (Pubitemid 8214700)
45. Willow, M., Kuenzel, E. A., and Catterall, W. A. (1984) Inhibition of Voltage-Sensitive Sodium-Channels in Neuro-Blastoma Cells and Synaptosomes by the Anticonvulsant Drugs Diphenylhydantoin and Carbamazepine Mol. Pharmacol. 25 (2) 228-234 (Pubitemid 14173328)
46. Mclean, M. J. and Macdonald, R. L. (1988) Benzodiazepines, but Not Beta-Carbolines, Limit High-Frequency Repetitive Firing of Action-Potentials of Spinal-Cord Neurons in Cell-Culture J. Pharmacol. Exp. Ther. 244 (2) 789-795 (Pubitemid 18076630)
47. Taft, W. C. and Delorenzo, R. J. (1984) Micromolar-Affinity Benzodiazepine Receptors Regulate Voltage-Sensitive Calcium Channels In Nerve-Terminal Preparations Proc. Natl. Acad. Sci. U.S.A. 81 (10) 3118-3122 (Pubitemid 14110689)
48. Papadopoulos, V., Baraldi, M., Guilarte, T. R., Knudsen, T. B., Lacapere, J. J., Lindemann, P., Norenberg, M. D., Nutt, D., Weizman, A., Zhang, M. R., and Gavish, M. (2006) Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function Trends Pharmacol. Sci. 27 (8) 402-409 (Pubitemid 44069585)
49. Venneti, S., Lopresti, B. J., and Wiley, C. A. (2006) The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: From pathology to imaging Prog. Neurobiol. 80 (6) 308-322 (Pubitemid 46107737)
50. Miller, J. A. and Richter, J. A. (1985) Effects of Anticonvulsants In vivo on High-Affinity Choline Uptake In vitro in Mouse Hippocampal Synaptosomes Br. J. Pharmacol. 84 (1) 19-25 (Pubitemid 15169053)
51. Oishi, R., Nishibori, M., Itoh, Y., and Saeki, K. (1986) Diazepam-Induced Decrease in Histamine Turnover in Mouse-Brain Eur. J. Pharmacol. 124 (3) 337-342 (Pubitemid 16090474)
52. Grandison, L. (1982) Suppression of Prolactin Secretion by Benzodiazepines In vivo Neuroendocrinology 34 (5) 369-373 (Pubitemid 12142651)
53. Battistin, L., Varotto, M., Berlese, G., and Roman, G. (1984) Effects of Some Anticonvulsant Drugs on Brain Gaba Level and Gad and Gaba-T Activities Neurochem. Res. 9 (2) 225-231 (Pubitemid 14132665)
54. Sieghart, W. (1995) Structure and Pharmacology of Gamma-Aminobutyric Acid(a) Receptor Subtypes Pharmacol. Rev. 47 (2) 181-234
55. Atack, J. R. (2005) The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics Expert Opin. Invest. Drugs 14 (5) 601-618 (Pubitemid 40790282)
56. Mamalaki, C., Stephenson, F. A., and Barnard, E. A. (1987) The Gabaa/Benzodiazepine Receptor Is a Heterotetramer of Homologous Alpha-Subunit and Beta-Subunit EMBO J. 6 (3) 561-565
57. Puia, G., Vicini, S., Seeburg, P. H., and Costa, E. (1991) Influence of Recombinant Gamma-Aminobutyric Acid-a Receptor Subunit Composition on the Action of Allosteric Modulators of Gamma-Aminobutyric Acid-Gated Cl- Currents Mol. Pharmacol. 39 (6) 691-696
58. Kanto, J., Kangas, L., and Siirtola, T. (1975) Cerebrospinal-Fluid Concentrations of Diazepam And Its Metabolites In Man Acta Pharmacol. Toxicol. 36 (4) 328-334
59. Facklam, M., Schoch, P., Bonetti, E. P., Jenck, F., Martin, J. R., Moreau, J. L., and Haefely, W. E. (1992) Relationship between Benzodiazepine Receptor Occupancy and Functional-Effects In vivo of 4 Ligands of Differing Intrinsic Efficacies J. Pharmacol. Exp. Ther. 261 (3) 1113-1121
60. Brogden, R. N. and Goa, K. L. (1988) Flumazenil-A Preliminary Review Of Its Benzodiazepine Antagonist Properties, Intrinsic Activity And Therapeutic Use Drugs 35 (4) 448-467
61. Lassen, N. A., Bartenstein, P. A., Lammertsma, A. A., Prevett, M. C., Turton, D. R., Luthra, S. K., Osman, S., Bloomfield, P. M., Jones, T., Patsalos, P. N., Oconnell, M. T., Duncan, J. S., and Andersen, J. V. (1995) Benzodiazepine Receptor Quantification In-Vivo In Humans Using C-11 Flumazenil And Pet-Application Of The Steady-State Principle J. Cereb. Blood Flow Metab. 15 (1) 152-165
62. Huang, Q., He, X. H., Ma, C. R., Liu, R. Y., Yu, S., Dayer, C. A., Wenger, G. R., McKernan, R., and Cook, J. M. (2000) Pharmacophore/receptor models for GABA(A)/BzR subtypes (alpha 1 beta 3 gamma 2, alpha 5 beta 3 gamma 2, and alpha 6 beta 3 gamma 2) via a comprehensive ligand-mapping approach J. Med. Chem. 43 (1) 71-95 (Pubitemid 30055764)
63. Mullins, M. E. (1999) Laboratory confirmation of flunitrazepam in alleged cases of date rape Acad. Emerg. Med. 6 (9) 966-968 (Pubitemid 29421028)
64. Greenblatt, D. J., Woo, E., Allen, M. D., Orsulak, P. J., and Shader, R. I. (1978) Rapid Recovery from Massive Diazepam Overdose J. Am. Med. Assoc. 240 (17) 1872-1874 (Pubitemid 9058797)
65. Finkle, B. S., McCloskey, K. L., and Goodman, L. S. (1979) Diazepam and Drug-Associated Deaths-Survey in the United-States and Canada J. Am. Med. Assoc. 242 (5) 429-434 (Pubitemid 9208822)
66. Breier, A., Charney, D. S., and Nelson, J. C. (1984) Seizures Induced by Abrupt Discontinuation of Alprazolam Am. J. Psychiat. 141 (12) 1606-1607 (Pubitemid 15219768)
67. Brunton, L., Chabner, B., and Knollman, B. (2010) Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth ed., The McGraw-Hill Companies, New York.
68. Allison, C. and Pratt, J. A. (2003) Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence Pharmacol. Ther. 98 (2) 171-195 (Pubitemid 36513774)
69. Longone, P., Impagnatiello, F., Guidotti, A., and Costa, E. (1996) Reversible modification of GABA(A) receptor subunit mRNA expression during tolerance to diazepam-induced cognition dysfunction Neuropharmacology 35 (9-10) 1465-1473 (Pubitemid 27013881)
70. Marley, R. J. and Gallager, D. W. (1989) Chronic Diazepam Treatment Produces Regionally Specific Changes in Gaba-Stimulated Chloride Influx Eur. J. Pharmacol. 159 (3) 217-223 (Pubitemid 19032153)
71. Uusi-Oukari, M. and Korpi, E. R. (2010) Regulation of GABA(A) Receptor Subunit Expression by Pharmacological Agents Pharmacol. Rev. 62 (1) 97-135
72. Crawley, J. N. (2007) What's Wrong with My Mouse, 2 nd ed., John Wiley and Sons, Hoboken, NJ.
73. Ninan, P. T., Cole, J. O., and Yonkers, K. A. (1998) Nonbenzodiazepine Anxiolytics. In Textbook of Psychopharmacology (Schatzberg, A. F. and Nemeroff, C. B., Eds.), Second ed., American Psychiatric Publishing, Washington, D.C.
74. Lader, M. (1991) History of Benzodiazepine Dependence J. Subst. Abuse Treat. 8 (1-2) 53-59
75. Polc, P., Mohler, H., and Haefely, W. (1974) Effect Of Diazepam On Spinal-Cord Activities-Possible Sites And Mechanisms Of Action Arch. Pharmacol. 284 (4) 319-337
76. Richards, J. G., Schoch, P., Haring, P., Takacs, B., and Mohler, H. (1987) Resolving Gaba-a Benzodiazepine Receptors-Cellular and Subcellular-Localization in the CNS with Monoclonal-Antibodies J. Neurosci. 7 (6) 1866-1886 (Pubitemid 17119808)
77. Sieghart, W. (2006) Structure, Pharmacology, and Function of GABA(A) Receptor Subtypes Adv. Pharmacol. 54, 231-263
78. Nayeem, N., Green, T. P., Martin, I. L., and Barnard, E. A. (1994) Quaternary Structure of the Native Gaba(a) Receptor Determined by Electron-Microscopic Image-Analysis J. Neurochem. 62 (2) 815-818
79. File, S. E. (1990) The History of Benzodiazepine Dependence-a Review of Animal Studies Neurosci. Biobehav. Rev. 14 (2) 135-146 (Pubitemid 20159550)
80. Hallstrom, C. and Lader, M. (1981) Benzodiazepine Withdrawal Phenomena Int. Pharmacopsychiatry 16 (4) 235-244 (Pubitemid 12187872)
81. Abraham, J. (2002) Transnational industrial power, the medical profession and the regulatory state: adverse drug reactions and the crisis over the safety of Halcion in the Netherlands and the UK Soc. Sci. Med. 55 (9) 1671-1690 (Pubitemid 35286888)
82. Wysowski, D. K. and Barash, D. (1991) Adverse Behavioral Reactions Attributed to Triazolam in the Food-and-Drug-Administrations Spontaneous Reporting System Arch. Intern. Med. 151 (10) 2003-2008
83. Degenhardt, L., Roxburgh, A., Van Beek, I., Hall, W. D., Robinson, M. K. F., Ross, J., and Mant, A. (2008) The effects of the market withdrawal of temazepam gel capsules on benzodiazepine injecting in Sydney, Australia Drug Alcohol Rev. 27 (2) 145-151
84. Weintraub, M., Singh, S., Byrne, L., Maharaj, K., and Guttmacher, L. (1991) Consequences of the 1989 New-York-State Triplicate Benzodiazepine Prescription Regulations J. Am. Med. Assoc. 266 (17) 2392-2397
85. Druid, H., Holmgren, P., and Ahlner, J. (2001) Flunitrazepam: an evaluation of use, abuse and toxicity Forensic Sci. Int. 122 (2-3) 136-141 (Pubitemid 32979236)
86. Woods, J. H. (1998) Problems and opportunities in regulation of benzodiazepines J. Clin. Pharmacol. 38 (9) 773-782 (Pubitemid 28450399)
87. Stahl, S. M. (2002) Don't ask, don't tell, but benzodiazepines are still the leading treatments for anxiety disorder J. Clin. Psychiatry 63 (9) 756-757
88. Uhlenhuth, E. H., Balter, M. B., Ban, T. A., and Yang, K. (1999) Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997 Eur. Neuropsychopharmacol. 9, 393-398
89. Baldwin, D. S., Anderson, I. M., Nutt, D. J., Bandelow, B., Bond, A., Davidson, J. R. T., den Boer, J. A., Fineberg, N. A., Knapp, M., Scott, J., Wittchen, H. U., and British Association for Psychopharmacology (2005) Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology J. Psychopharmacol. 19, 567-596 (Pubitemid 41578819)
90. Braestrup, C. and Squires, R. F. (1978) Pharmacological Characterization Of Benzodiazepine Receptors In The Brain Eur. J. Pharmacol. 48, 263-270