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The Discriminative Stimulus Properties of Drugs Used to Treat Depression and Anxiety

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The Behavioral Neuroscience of Drug Discrimination

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 39))

Abstract

Drug discrimination is a powerful tool for evaluating the stimulus effects of psychoactive drugs and for linking these effects to pharmacological mechanisms. This chapter reviews the primary findings from drug discrimination studies of antidepressant and anxiolytic drugs, including novel pharmacological mechanisms. The stimulus properties revealed from these animal studies largely correspond to the receptor affinities of antidepressant and anxiolytic drugs, indicating that subjective effects may correspond to either therapeutic or side effects of these medications. We discuss drug discrimination findings concerning adjunctive medications and novel pharmacologic strategies in antidepressant and anxiolytic research. Future directions for drug discrimination work include an urgent need to explore the subjective effects of medications in animal models, to better understand shifts in stimulus sensitivity during prolonged treatments, and to further characterize stimulus effects in female subjects. We conclude that drug discrimination is an informative preclinical procedure that reveals the interoceptive effects of pharmacological mechanisms as they relate to behaviors that are not captured in other preclinical models.

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References

  1. Fox HH, Gibas JT (1953) Synthetic tuberculostats. V. Alkylidene derivatives of isonicotinyhydrazine. J Org Chem 18:983–989

    CAS  Google Scholar 

  2. Zeller EA, Barsky J, Fouts JR, Kirchheimer WF, Van Orden LS (1952) Influence of isonicotinic acid hydrazide (INH) and 1-isonicotinyl-2-isopropyl hydrazide (IIH) on bacterial and mammalian enzymes. Experientia 8:349–350

    CAS  Google Scholar 

  3. Youdim MBH (1972) Multiple forms of monoamine oxidase and their properties advances in biochemical psychopharmacology. Raven, New York, pp 67–77

    Google Scholar 

  4. Lopez-Munoz F, Alamo C (2009) Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des 15:1563–1586

    CAS  PubMed  Google Scholar 

  5. Hillhouse TM, Porter JH (2015) A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol 23:1–21

    CAS  PubMed  Google Scholar 

  6. Cusack B, Nelson A, Richelson E (1994) Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl) 114:559–565

    CAS  PubMed  Google Scholar 

  7. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283:1305–1322

    CAS  PubMed  Google Scholar 

  8. Richelson E, Nelson A (1984) Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 230:94–102

    CAS  PubMed  Google Scholar 

  9. Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249–258

    CAS  PubMed  Google Scholar 

  10. Wander TJ, Nelson A, Okazaki H, Richelson E (1986) Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro. Eur J Pharmacol 132:115–121

    CAS  PubMed  Google Scholar 

  11. Benkert O, Laakmann G, Ott L, Strauss A, Zimmer R (1977) Effect of zimelidine (H 102/09) in depressive patients. Arzneimittelforschung 27:2421–3

    CAS  PubMed  Google Scholar 

  12. Sánchez C, Hyttel J (1999) Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 19:467–489

    PubMed  Google Scholar 

  13. Owens JM, Knight DL, Nemeroff CB (2002) Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Encéphale 28:350–355

    CAS  PubMed  Google Scholar 

  14. Millan MJ, Gobert A, Lejeune F, Newman-Tancredi A, Rivet J-M, Auclair A, Peglion J-L (2001) S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298:565–580

    CAS  PubMed  Google Scholar 

  15. Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH (2006) Desvenlafaxine succinate: a New serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther 318:657–665

    CAS  PubMed  Google Scholar 

  16. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT (2001) Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 25:871–880

    CAS  PubMed  Google Scholar 

  17. Bang-Andersen B, Ruhland T, Jorgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mork A, Stensbol TB (2011) Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 54:3206–3221

    CAS  PubMed  Google Scholar 

  18. Hasselmann H (2014) Scopolamine and depression: a role for muscarinic antagonism? CNS Neurol Disord Drug Targets 13:673–683

    CAS  PubMed  Google Scholar 

  19. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354. doi: 10.1016/s0006-3223(99)00230-9

  20. Naughton M, Clarke G, O'Leary OF, Cryan JF, Dinan TG (2014) A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord 156:24–35

    CAS  PubMed  Google Scholar 

  21. Huang J, Ho BT (1974) The effect of pretreatment with iproniazid on the behavioral activities of beta-phenylethylamine in rats. Psychopharmacology (Berl) 35:77–81

    CAS  Google Scholar 

  22. Overton DA (1982) Comparison of the degree of discriminability of various drugs using the T-maze drug discrimination paradigm. Psychopharmacology (Berl) 76:385–395

    CAS  PubMed  Google Scholar 

  23. Chen JG, Sachpatzidis A, Rudnick G (1997) The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding. J Biol Chem 272:28321–28327

    CAS  PubMed  Google Scholar 

  24. Jones SR, Garris PA, Wightman RM (1995) Different effects of cocaine and nomifensine on dopamine uptake in the caudate-putamen and nucleus accumbens. J Pharmacol Exp Ther 274:396–403

    CAS  PubMed  Google Scholar 

  25. Ritz MC, Cone EJ, Kuhar MJ (1990) Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study. Life Sci 46:635–645

    CAS  PubMed  Google Scholar 

  26. Colpaert FC, Niemegeers CJ, Janssen PA (1979) Discriminative stimulus properties of cocaine: neuropharmacological characteristics as derived from stimulus generalization experiments. Pharmacol Biochem Behav 10:535–546

    CAS  PubMed  Google Scholar 

  27. Colpaert FC, Niemegeers CJ, Janssen PA (1980) Evidence that a preferred substrate for type B monoamine oxidase mediates stimulus properties of MAO inhibitors: a possible role for beta-phenylethylamine in the cocaine cue. Pharmacol Biochem Behav 13:513–517

    CAS  PubMed  Google Scholar 

  28. Yasar S, Justinova Z, Lee SH, Stefanski R, Goldberg SR, Tanda G (2006) Metabolic transformation plays a primary role in the psychostimulant-like discriminative-stimulus effects of selegiline [(R)-(-)-deprenyl]. J Pharmacol Exp Ther 317:387–94

    CAS  PubMed  Google Scholar 

  29. Carpene C, Collon P, Remaury A, Cordi A, Hudson A, Nutt D, Lafontan M (1995) Inhibition of amine oxidase activity by derivatives that recognize imidazoline I2 sites. J Pharmacol Exp Ther 272:681–688

    CAS  PubMed  Google Scholar 

  30. Ozaita A, Olmos G, Boronat MA, Lizcano JM, Unzeta M, Garcia-Sevilla JA (1997) Inhibition of monoamine oxidase A and B activities by imidazol(ine)/guanidine drugs, nature of the interaction and distinction from I2-imidazoline receptors in rat liver. Br J Pharmacol 121:901–912

    CAS  PubMed  Google Scholar 

  31. Jordan S, Jackson HC, Nutt DJ, Handley SL (1996) Discriminative stimulus produced by the imidazoline I2 site ligand, 2 -BFI. J Psychopharmacol 10:273–278

    CAS  PubMed  Google Scholar 

  32. MacInnes N, Handley SL (2002) Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine. Br J Pharmacol 135:1227–1234

    CAS  PubMed  Google Scholar 

  33. Crissman AM, O’Donnell JM (2002) Effects of antidepressants in rats trained to discriminate centrally administered isoproterenol. J Pharmacol Exp Ther 302:606–611

    CAS  PubMed  Google Scholar 

  34. Shearman G, Miksic S, Lal H (1978) Discriminative stimulus properties of desipramine. Neuropharmacology 17:1045–1048

    CAS  PubMed  Google Scholar 

  35. Baker LE, Riddle EE, Saunders RB, Appel JB (1993) The role of monoamine uptake in the discriminative stimulus effects of cocaine and related compounds. Behav Pharmacol 4:69–79

    CAS  PubMed  Google Scholar 

  36. Spealman RD (1995) Noradrenergic involvement in the discriminative stimulus effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 275:53–62

    CAS  PubMed  Google Scholar 

  37. Cunningham KA, Callahan PM (1991) Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat. Psychopharmacology (Berl) 104:177–180

    CAS  PubMed  Google Scholar 

  38. Tella SR, Goldberg SR (2001) Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909. Prog Neuropsychopharmacol Biol Psychiatry 25:639–656

    CAS  PubMed  Google Scholar 

  39. Kleven MS, Koek W (1998) Discriminative stimulus properties of cocaine: enhancement by monoamine reuptake blockers. J Pharmacol Exp Ther 284:1015–1025

    CAS  PubMed  Google Scholar 

  40. Schechter MD (1983) Discriminative stimulus control with imipramine: transfer to other anti-depressants. Pharmacol Biochem Behav 19:751–754

    CAS  PubMed  Google Scholar 

  41. Zhang L, Barrett JE (1991) Imipramine as a discriminative stimulus. J Pharmacol Exp Ther 259:1088–1093

    CAS  PubMed  Google Scholar 

  42. Barrett JE, Zhang L (1991) Involvement of 5-HT1A activity in the discriminative stimulus effects of imipramine. Pharmacol Biochem Behav 38:407–410

    CAS  PubMed  Google Scholar 

  43. U'Prichard DC, Greenberg DA, Snyder SH (1977) Binding characteristics of a radiolabeled agonist and antagonist at central nervous system alpha noradrenergic receptors. Mol Pharmacol 13:454–73

    CAS  PubMed  Google Scholar 

  44. Li PP, Warsh JJ, Sibony D, Chiu A (1988) Assessment of rat Brain Alpha1-adrenoceptor binding and activation of inositol phospholipid turnover following chronic imipramine treatment. Neurochem Res 13:1111–1118

    CAS  PubMed  Google Scholar 

  45. Kelley BM, Porter JH (1997) The role of muscarinic cholinergic receptors in the discriminative stimulus properties of clozapine in rats. Pharmacol Biochem Behav 57:707–719

    CAS  PubMed  Google Scholar 

  46. Hoenicke EM, Vanecek SA, Woods JH (1992) The discriminative stimulus effects of clozapine in pigeons: involvement of 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors. J Pharmacol Exp Ther 263:276–284

    CAS  PubMed  Google Scholar 

  47. Setola V, Dukat M, Glennon RA, Roth BL (2005) Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor. Mol Pharmacol 68:20–33

    CAS  PubMed  Google Scholar 

  48. Newman ME, Shapira B, Lerer B (1998) Evaluation of central serotonergic function in affective and related disorders by the fenfluramine challenge test: a critical review. Int J Neuropsychopharmacol 1:49–69

    CAS  PubMed  Google Scholar 

  49. Goudie AJ (1977) Discriminative stimulus properties of fenfluramine in an operant task: an analysis of its cue function. Psychopharmacology (Berl) 53:97–102

    CAS  PubMed  Google Scholar 

  50. Rothman RB, Clark RD, Partilla JS, Baumann MH (2003) (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters. J Pharmacol Exp Ther 305:1191–1199

    CAS  PubMed  Google Scholar 

  51. McElroy JF, Feldman RS (1984) Discriminative stimulus properties of fenfluramine: evidence for serotonergic involvement. Psychopharmacology (Berl) 83:172–178

    CAS  PubMed  Google Scholar 

  52. White FJ, Appel JB (1981) A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine. Psychopharmacology (Berl) 73:110–115

    CAS  PubMed  Google Scholar 

  53. McCreary AC, Filip M, Cunningham KA (2003) Discriminative stimulus properties of (+/-)-fenfluramine: the role of 5-HT2 receptor subtypes. Behav Neurosci 117:212–221

    CAS  PubMed  Google Scholar 

  54. Marona-Lewicka D, Nichols DE (1998) Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents. Psychopharmacology (Berl) 138:67–75

    CAS  PubMed  Google Scholar 

  55. Marken PA, Munro JS (2000) Selecting a selective serotonin reuptake inhibitor: clinically important distinguishing features. J Clin Psychiatry 2:205–210

    Google Scholar 

  56. Millan MJ, Gobert A, Girardon S, Dekeyne A (1999) Citalopram elicits a discriminative stimulus in rats at a dose selectively increasing extracellular levels of serotonin vs. dopamine and noradrenaline. Eur J Pharmacol 364:147–150

    CAS  PubMed  Google Scholar 

  57. Millan MJ, Girardon S, Dekeyne A (1999) 5-HT2C receptors are involved in the discriminative stimulus effects of citalopram in rats. Psychopharmacology (Berl) 142:432–444

    CAS  PubMed  Google Scholar 

  58. Dekeyne A, Millan MJ (2003) Discriminative stimulus properties of antidepressant agents: a review. Behav Pharmacol 14:391–407

    CAS  PubMed  Google Scholar 

  59. Uguz F, Sahingoz M, Gungor B, Aksoy F, Askin R (2015) Weight gain and associated factors in patients using newer antidepressant drugs. Gen Hosp Psychiatry 37:46–48

    PubMed  Google Scholar 

  60. Wolff MC, Leander JD (1999) The discriminative stimulus properties of LY233708, a selective serotonin reuptake inhibitor, in the pigeon. Psychopharmacology (Berl) 146:275–279

    CAS  PubMed  Google Scholar 

  61. Berendsen HH, Broekkamp CL (1994) Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedure. Eur J Pharmacol 253:83–89

    CAS  PubMed  Google Scholar 

  62. Gommans J, Bouwknecht JA, Hijzen TH, Berendsen HH, Broekkamp CL, Maes RA, Olivier B (1998) Stimulus properties of fluvoxamine in a conditioned taste aversion procedure. Psychopharmacology (Berl) 140:496–502

    CAS  PubMed  Google Scholar 

  63. Kayir H, Alici T, Goktalay G, Yildirim M, Ulusoy GK, Ceyhan M, Celik T, Uzbay TI (2008) Stimulus properties of venlafaxine in a conditioned taste aversion procedure. Eur J Pharmacol 596:102–106

    CAS  PubMed  Google Scholar 

  64. Winter JC, Helsley S, Fiorella D, Rabin RA (1999) The acute effects of monoamine reuptake inhibitors on the stimulus effects of hallucinogens. Pharmacol Biochem Behav 63:507–513

    CAS  PubMed  Google Scholar 

  65. Awasaki Y, Nojima H, Nishida N (2011) Application of the conditioned taste aversion paradigm to assess discriminative stimulus properties of psychostimulants in rats. Drug Alcohol Depend 118:288–294

    CAS  PubMed  Google Scholar 

  66. Filip M, Chojnacka-Wojcik E, Przegalinski E (1993) Discriminative stimulus properties of (+)-oxaprotiline in rats. Pol J Pharmacol 45:151–156

    CAS  PubMed  Google Scholar 

  67. Dekeyne A, Gobert A, Iob L, Cistarelli L, Melon C, Millan MJ (2001) Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats. Psychopharmacology (Berl) 158:213–218

    CAS  PubMed  Google Scholar 

  68. Millan MJ, Dekeyne A (2007) Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats: a characterization with alpha/beta-adrenoceptor subtype selective ligands, antidepressants, and antagonists at neuropeptide receptors. Int J Neuropsychopharmacol 10:579–593

    CAS  PubMed  Google Scholar 

  69. Jones CN, Howard JL, McBennett ST (1980) Stimulus properties of antidepressants in the rat. Psychopharmacology (Berl) 67:111–118

    CAS  PubMed  Google Scholar 

  70. Howard JL, Jones CN, McBennett ST (1978) Discriminative stimulus properties of antidepressants. In: Colpaert FC, Rosecrans JA (eds) Stimulus properties of drugs: ten years of progress. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 157–166

    Google Scholar 

  71. Andersen PH (1989) The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action. Eur J Pharmacol 166:493–504

    CAS  PubMed  Google Scholar 

  72. Kelley BM, Porter JH, Varvel SA (1995) Mianserin as a discriminative stimulus in rats: asymmetrical cross-generalization with scopolamine. Psychopharmacology (Berl) 120:491–493

    CAS  PubMed  Google Scholar 

  73. Blitzer RD, Becker RE (1985) Characterization of the bupropion cue in the rat: lack of evidence for a dopaminergic mechanism. Psychopharmacology (Berl) 85:173–177

    CAS  PubMed  Google Scholar 

  74. Terry P, Katz JL (1997) Dopaminergic mediation of the discriminative stimulus effects of bupropion in rats. Psychopharmacology (Berl) 134:201–212

    CAS  PubMed  Google Scholar 

  75. Lopez-Munoz F, Ucha-Udabe R, Alamo C (2005) The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat 1:329–343

    CAS  PubMed  Google Scholar 

  76. Tone A (2005) Listening to the past: history, psychiatry, and anxiety. Can J Psychiatry 50:373–380

    PubMed  Google Scholar 

  77. Sigel E, Buhr A (1997) The benzodiazepine binding site of GABAA receptors. Trends Pharmacol Sci 18:425–429

    CAS  PubMed  Google Scholar 

  78. Klepner CA, Lippa AS, Benson DI, Sano MC, Beer B (1979) Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors. Pharmacol Biochem Behav 11:457–462

    CAS  PubMed  Google Scholar 

  79. Pritchett DB, Luddens H, Seeburg PH (1989) Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245:1389–1392

    CAS  PubMed  Google Scholar 

  80. Wisden W, Laurie DJ, Monyer H, Seeburg PH (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci 12:1040–1062

    CAS  PubMed  Google Scholar 

  81. Dämgen K, Lüddens H (1999) Zaleplon displays a selectivity to recombinant GABAA receptors different from zolipdem, zopiclone and benzodiazepines. Neurosci Res Commun 25:139–148

    Google Scholar 

  82. Sanger DJ (2004) The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs 18:9–15

    CAS  PubMed  Google Scholar 

  83. Wieland HA, Luddens H (1994) Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor. J Med Chem 37:4576–4580

    CAS  PubMed  Google Scholar 

  84. Goldberg HL, Finnerty RJ (1979) The comparative efficacy of buspirone and diazepam in the treatment of anxiety. Am J Psychiatry 136:1184–1187

    CAS  PubMed  Google Scholar 

  85. Khouzam HR, Emes R (2002) The use of buspirone in primary care. J Psychosoc Nurs Ment Health Serv 40:34–41

    PubMed  Google Scholar 

  86. Coplan JD, Aaronson CJ, Panthangi V, Kim Y (2015) Treating comorbid anxiety and depression: psychosocial and pharmacological approaches. World J Psychiatry 5:366–378

    PubMed  Google Scholar 

  87. Hirschhorn ID, Winter JC (1975) Differences in the stimulus properties of barbital and hallucinogens. Pharmacol Biochem Behav 3:343–347

    CAS  PubMed  Google Scholar 

  88. York JL (1978) A comparison of the discriminative stimulus effects of ethanol, barbital, and phenobarbital in rats. Psychopharmacology (Berl) 60:19–23

    CAS  PubMed  Google Scholar 

  89. Herling S, Valentino RJ, Winger GD (1980) Discriminative stimulus effects of pentobarbital in pigeons. Psychopharmacology (Berl) 71:21–28

    CAS  PubMed  Google Scholar 

  90. Winger G, Herling S (1982) Discriminative stimulus effects of pentobarbital in rhesus monkeys: tests of stimulus generalization and duration of action. Psychopharmacology (Berl) 76:172–176

    CAS  PubMed  Google Scholar 

  91. Rees DC, Balster RL (1988) Attenuation of the discriminative stimulus properties of ethanol and oxazepam, but not of pentobarbital, by Ro 15-4513 in mice. J Pharmacol Exp Ther 244:592–598

    CAS  PubMed  Google Scholar 

  92. McMillan DE, Li M, Hardwick WC (1997) Discriminative stimulus effects and antipunishment effects of drugs measured during the same session. Pharmacol Biochem Behav 56:161–166

    CAS  PubMed  Google Scholar 

  93. Licata SC, Platt DM, Ruedi-Bettschen D, Atack JR, Dawson GR, Van Linn ML, Cook JM, Rowlett JK (2010) Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)- [1,2,4]triazolo[4,3-b]pyridazine): role of GABA(A) receptor subtypes. Neuropharmacology 58:357–364

    CAS  PubMed  Google Scholar 

  94. Colpaert FC, Desmedt LK, Janssen PA (1976) Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs; relation to some intrinsic and anticonvulsant effects. Eur J Pharmacol 37:113–123

    CAS  PubMed  Google Scholar 

  95. Haug T (1983) Neuropharmacological specificity of the diazepam stimulus complex: effects of agonists and antagonists. Eur J Pharmacol 93:221–227

    CAS  PubMed  Google Scholar 

  96. Young R, Glennon RA (1987) Stimulus properties of benzodiazepines: correlations with binding affinities, therapeutic potency, and structure activity relationships (SAR). Psychopharmacology (Berl) 93:529–533

    CAS  PubMed  Google Scholar 

  97. Woudenberg F, Slangen JL (1989) Discriminative stimulus properties of midazolam: comparison with other benzodiazepines. Psychopharmacology (Berl) 97:466–470

    CAS  PubMed  Google Scholar 

  98. Johanson CE (1991) Discriminative stimulus effects of psychomotor stimulants and benzodiazepines in humans. NIDA Res Monogr 116:181–196

    CAS  Google Scholar 

  99. Johanson CE (1991) Discriminative stimulus effects of diazepam in humans. J Pharmacol Exp Ther 257:634–643

    CAS  PubMed  Google Scholar 

  100. Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, Bartholini G (1986) Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. J Pharmacol Exp Ther 237:649–658

    CAS  PubMed  Google Scholar 

  101. Griffiths RR, Sannerud CA, Ator NA, Brady JV (1992) Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal. J Pharmacol Exp Ther 260:1199–1208

    CAS  PubMed  Google Scholar 

  102. Mintzer MZ, Frey JM, Griffiths RR (1998) Zolpidem is differentiated from triazolam in humans using a three-response drug discrimination procedure. Behav Pharmacol 9:545–559

    CAS  PubMed  Google Scholar 

  103. Rush CR, Baker RW, Rowlett JK (2000) Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans. Exp Clin Psychopharmacol 8:22–36

    CAS  PubMed  Google Scholar 

  104. Millan MJ, Lejeune F, Gobert A (2000) Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents. J Psychopharmacol 14:114–38

    CAS  PubMed  Google Scholar 

  105. Plassat JL, Amlaiky N, Hen R (1993) Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase. Mol Pharmacol 44:229–236

    CAS  PubMed  Google Scholar 

  106. Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW et al (1993) A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron 11:449–458

    CAS  PubMed  Google Scholar 

  107. Tallman JF, Primus RJ, Brodbeck R, Cornfield L, Meade R, Woodruff K, Ross P, Thurkauf A, Gallager DW (1997) I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor. J Pharmacol Exp Ther 282:1011–1019

    CAS  PubMed  Google Scholar 

  108. Hendry JS, Balster RL, Rosecrans JA (1983) Discriminative stimulus properties of buspirone compared to central nervous system depressants in rats. Pharmacol Biochem Behav 19:97–101

    CAS  PubMed  Google Scholar 

  109. Ator NA, Griffiths RR (1986) Discriminative stimulus effects of atypical anxiolytics in baboons and rats. J Pharmacol Exp Ther 237:393–403

    CAS  PubMed  Google Scholar 

  110. Frey JM, Mintzer MZ, Rush CR, Griffiths RR (1998) Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure. Psychopharmacology (Berl) 138:16–26

    CAS  PubMed  Google Scholar 

  111. Cunningham KA, Callahan PM, Appel JB (1987) Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT): implications for understanding the actions of novel anxiolytics. Eur J Pharmacol 138:29–36

    CAS  PubMed  Google Scholar 

  112. Nader MA, Hoffmann S, Gleeson S, Barrett JE (1989) Further characterization of the discriminative stimulus effects of buspirone using monoamine agonists and antagonists in the pigeon. Behav Pharmacol 1:57–67

    PubMed  Google Scholar 

  113. Mansbach RS, Barrett JE (1987) Discriminative stimulus properties of buspirone in the pigeon. J Pharmacol Exp Ther 240:364–9

    CAS  PubMed  Google Scholar 

  114. Schuster CR, Balster RL (1977) The discriminative stimulus properties of drugs. In: Thompson T, Dews PB (eds) Advances in behavioral pharmacology, vol 1. Academic Press, New York, pp 85–138

    Google Scholar 

  115. Sanger DJ (1989) Discriminative stimulus effects of the alpha 2-adrenoceptor antagonist idazoxan. Psychopharmacology (Berl) 99:117–121

    CAS  PubMed  Google Scholar 

  116. Prus AJ, Zornio PA, Schuck CJ, Heerts T, Jacobson SM, Winiarski DA (2010) Discriminative stimulus properties of idazoxan: mediation by both α2 adrenoceptor antagonism and 5‐HT1A receptor agonism. Drug Dev Res 71:261–267

    CAS  Google Scholar 

  117. Kamien JB, Woolverton WL (1990) Buspirone blocks the discriminative stimulus effects of apomorphine in monkeys. Pharmacol Biochem Behav 35:117–120

    CAS  PubMed  Google Scholar 

  118. Nader MA, Woolverton WL (1994) Blockade of the discriminative stimulus effects of d-amphetamine in rhesus monkeys with serotonin 5-HT(1A) agonists. Behav Pharmacol 5:591–598

    CAS  PubMed  Google Scholar 

  119. Callahan PM, Cunningham KA (1997) Modulation of the discriminative stimulus properties of cocaine: comparison of the effects of fluoxetine with 5-HT1A and 5-HT1B receptor agonists. Neuropharmacology 36:373–381

    CAS  PubMed  Google Scholar 

  120. Ator NA (1991) Discriminative stimulus effects of the novel anxiolytic buspirone. Behav Pharmacol 2:3–14

    PubMed  Google Scholar 

  121. Rijnders HJ, Slangen JL (1993) The discriminative stimulus properties of buspirone involve dopamine-2 receptor antagonist activity. Psychopharmacology (Berl) 111:55–61

    CAS  PubMed  Google Scholar 

  122. Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–51

    CAS  PubMed  Google Scholar 

  123. Howland RH (2009) The antidepressant effects of anticholinergic drugs. Psychopharmacology (Berl) 47(6):17–20

    Google Scholar 

  124. Je Jeon W, Dean B, Scarr E, Gibbons A (2015) The role of muscarinic receptors in the pathophysiology of mood disorders: a potential novel Treatment? Curr Neuropharmacol 13:739–749

    CAS  PubMed  Google Scholar 

  125. Kasper S, Moises HW, Beckmann H (1981) The anticholinergic biperiden in depressive disorders. Pharmacopsychiatria 14:195–198

    CAS  PubMed  Google Scholar 

  126. Gillin JC, Lauriello J, Kelsoe JR, Rapaport M, Golshan S, Kenny WM et al (1995) No antidepressant effect of biperiden compared with placebo in depression: a double-blind 6-week clinical trial. Psychiatry Res 58:99–105

    CAS  PubMed  Google Scholar 

  127. Jaffe RJ, Novakovic V, Peselow ED (2013) Scopolamine as an antidepressant: a systematic review. Clin Neuropharmacol 36:24–26

    CAS  PubMed  Google Scholar 

  128. Machado-Vieira R, Henter ID, Zarate Jr CA (in press) New targets for rapid antidepressant action. Prog Neurobiol

    Google Scholar 

  129. Kubena RK, Barry H (1969) Generalization by rats of alcohol and atropine stimulus characteristics in other drugs. Psychopharmacology (Berl) 15:196–206

    CAS  Google Scholar 

  130. Jung M, Pèrio A, Worms P, Biziere K (1988) Characterization of the scopolamine stimulus in rats. Psychopharmacology (Berl) 95:195–199

    CAS  PubMed  Google Scholar 

  131. Friedman RL, Barrett RJ, Sanders-Bush E (1984) Discriminative stimulus properties of quipazine: mediation by serotonin 2 binding sites. J Pharmacol Exp Ther 228:628–635

    CAS  PubMed  Google Scholar 

  132. Yamamoto T, Clark R, Woods JH (1984) Mianserin: discriminative stimulus effects in pigeons. Fed Proc 43:572

    Google Scholar 

  133. Yamamoto T, Walker EA, Woods JH (1991) Agonist and antagonist properties of serotonergic compounds in pigeons trained to discriminate either quipazine or 5-hydroxytrytophan. J Pharmacol Exp Ther 258:999–1007

    CAS  PubMed  Google Scholar 

  134. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M (2004) Pharmacological characterization of the agonist radioligand binding site of 5-HT2A, 5-HT2B and 5-HT2C receptors. Naunyn Schmiedebergs Arch Pharmacol 370:114–123

    CAS  PubMed  Google Scholar 

  135. Machado-Vieira R, Henter ID, Zarate CA Jr (2015) New targets for rapid antidepressant action. Prog Neurobiol S0301-0082(15)30038-1. doi: 10.1016/j.pneurobio.2015.12.001. [Epub ahead of print]

    Google Scholar 

  136. Burgdorf J, Zhang X-I, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskalm JR (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38:729–742

    CAS  PubMed  Google Scholar 

  137. Wang P, Si T (2013) Use of antipsychotics in the treatment of depressive disorders. Shanghai Arch Psychiatry 25:134–140

    CAS  PubMed  Google Scholar 

  138. Ketter TA, Miller S, Dell’Osso B, Wang PW (2016) Treatment of bipolar disorder: review of evidence regarding quetiapine and lithium. J Affect Disord 191:256–273

    CAS  PubMed  Google Scholar 

  139. Sanford M, Keating GM (2012) Quetiapine: a review of its use in the management of bipolar depression. CNS Drugs 26(5):435–460

    CAS  PubMed  Google Scholar 

  140. Hillhouse TM, Shankland Z, Matazel KS, Keiser AA, Prus AJ (2014) The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like behavioral effects in male Sprague-Dawley rats. Exp Clin Psychopharmacol 22:548–556

    PubMed  Google Scholar 

  141. Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL (2008) N-Desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1a agonist, as a putative mediator of quetiapine’s antidepressant activity. Neuropsychopharmacology 33:2303–2312

    CAS  PubMed  Google Scholar 

  142. Smith JA, Goudie AJ (2002) Discriminative stimulus properties in rats of the novel antipsychotic quetiapine. Exp Clin Psychopharmacol 10:376–384

    CAS  PubMed  Google Scholar 

  143. Goudie AJ, Smith JA, Millan MJ (2004) Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine. Psychopharmacology (Berl) 171:212–222

    CAS  PubMed  Google Scholar 

  144. López-Muñoz F, Alamo C (2013) Active metabolites as antidepressant drugs: the role of norquetiapine in the mechanism of action of quetiapine in the treatment of mood disorders. Front Psychiatry 4:102

    PubMed  Google Scholar 

  145. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen H-U (2012) Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res 21:169–184

    PubMed  Google Scholar 

  146. Post RM (1980) Intermittent versus continuous stimulation: effect of time interval on the development of sensitization or tolerance. Life Sci 26:1275–1282

    CAS  PubMed  Google Scholar 

  147. Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672

    CAS  PubMed  Google Scholar 

  148. Drets WC, Furey ML (2010) Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry 67:432–438

    Google Scholar 

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Prus, A.J., Porter, J.H. (2016). The Discriminative Stimulus Properties of Drugs Used to Treat Depression and Anxiety. In: Porter, J.H., Prus, A.J. (eds) The Behavioral Neuroscience of Drug Discrimination. Current Topics in Behavioral Neurosciences, vol 39. Springer, Cham. https://doi.org/10.1007/7854_2016_27

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