Pharmacological, Biochemical, and Behavioral Analyses of Depression: Animal Models

  • Robert M. Zacharko
  • Hymie Anisman


It has been posited that stressful events may precipitate depression in humans (Abramson et al, 1978; Akiskal and McKinney, 1973; Anisman and Zacharko, 1982a). Alternatively, it is not unlikely that such events may simply exacerbate symptoms in already depressed individuals (Slater and Roth, 1969), or that the response to stressors may be symptomatic of an already existant depression (Hudgens et al. 1967; Morrison et al., 1968). Although it is clear that stressful events may profoundly influence the behavior of animals in various testing paradigms, the mechanisms subserving these behavioral alterations remain to be fully elucidated. Furthermore, there is still some question as to whether these behavioral changes can legitimately be considered as valid models of human depression (Willner, 1985). Among other things, several forms of depression exist, and even in one type of depression the symptoms presented may vary considerably across individuals. Indeed, the view has been expressed that depression may be a biochemically heterogeneous illness, wherein the symptoms may be a consequence of serotonin (5-HT) or norepinephrine (NE) neuronal dysfunction and possibly dopamine (DA) variations as well (Jimerson and Post, 1984; Schildkraut, 1978; van Praag, 1978, 1984).


Nucleus Accumbens Locus Coeruleus Inescapable Shock Escape Performance Escapable Shock 
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  1. Abramson LY, Seligman MEP, Teasdale JD (1978): Learned helplessness in humans: Critique and reformulation. J Abnorm Psychol 87:49–74PubMedGoogle Scholar
  2. Ahluwalia P, Zacharko RM, Anisman H (1985): Dopamine variations associated with acute and chronic stressors. Soc Neurosci Abst 11:49Google Scholar
  3. Akiskal HS, McKinney WT (1973): Depressive disorders: Toward a unified hypothesis. Science 182:20–29PubMedGoogle Scholar
  4. Anisman H (1984): Vulnerability to depression: Contribution of stress. In: Neurobiology of Mood Disorders, Post RM, Ballenger JC, eds. Baltimore: Williams & WilkinsGoogle Scholar
  5. Anisman H, Zacharko RM (1982a): Depression: The predisposing influence of stress. Behav Brain Sci 5:89–137Google Scholar
  6. Anisman H, Zacharko RM (1982b); Stimulus change influences escape performance: Deficits induced by uncontrollable stress and by haloperidol. Pharmacol Biochem Behav 17:263–269PubMedGoogle Scholar
  7. Anisman H, Zacharko RM (1986): Behavioral and neurochemical consequences associated with stressors. In: Stress-induced Analgesia, Kelley DD, ed. Ann New York Acad Sci 467:205–225Google Scholar
  8. Anisman H, deCantanzaro D, Remington G (1978): Escape performance following exposure to inescapable shock: Deficits in motor response maintenance. J Exp Psychol [Anim Behav] 4:197–218Google Scholar
  9. Anisman H, Glazier SJ, Sklar LS (1981a): Cholinergic influences on escape deficits produced by uncontrollable stress. Psychopharmacology 74:81–87PubMedGoogle Scholar
  10. Anisman H, et al., (1985): Stressor invoked exacerbation of amphetamine-elicited perseveration. Pharmacol Biochem Behav 23:173–183PubMedGoogle Scholar
  11. Anisman H, et al., (1987): Variations of norepinephrine concentrations following chronic stressor application. Pharmacol Biochem Behav 26:653–659PubMedGoogle Scholar
  12. Anisman H, Hamilton M, Zacharko RM (1984): Cue and response choice acquisition and reversal after exposure to uncontrollable shock: Induction of response perseveration. J Exper Psychol 10:229–243Google Scholar
  13. Anisman H, Irwin J, Sklar LS (1979a): Deficits of escape performance following catecholamine depletion: Implications for behavioral deficits induced by uncontrollable stress. Psychopharmacology 64:163–170PubMedGoogle Scholar
  14. Anisman H, Kokkinidis L, Sklar LS (1981b): Contribution of neurochemical change to stress-induced behavioral deficits. In: Theory in Psychopharmacology Cooper SJ, ed. London: Academic PressGoogle Scholar
  15. Anisman H, Pizzino A, Sklar LS (1980b): Coping with stress, norepinephrine depletion and escape performance. Brain Research 191:583–588PubMedGoogle Scholar
  16. Anisman H, Remington G, Sklar LS (1979b): Effects of inescapable shock on subsequent escape performance: Catecholaminergic and cholinergic mediation of response initiation and maintenance. Psychopharmacology 61:107–124PubMedGoogle Scholar
  17. Anisman H, Ritch M, Sklar LS (1981c): Noradrenergic and dopaminergic interactions in escape behavior: Analysis of uncontrollable stress effects. Psychopharmacology 74:263–268PubMedGoogle Scholar
  18. Anisman H, Suissa A, Sklar LS (1980a): Escape deficits induced by uncontrollable stress; Antagonism by dopamine and norepinephrine agonists. Behav Neur Biol 28:34–47Google Scholar
  19. Antelman SM, Chiodo LA (1983): Amphetamine as a stressor. In: Stimulants: Neurochemical Behavwral and Clinical Perspectives, Creese I, ed. New York: Raven Press.Google Scholar
  20. Aston-Jones G, Bloom FE (1981): Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J Neurosci 1:887–900PubMedGoogle Scholar
  21. Aston-Jones G, Foote SL, Bloom FE (1984): Anatomy and physiology of locus coeruleus neurons: Functional implications. In: Norepinephrine: Clinical Aspects, Ziegler MG, Lake CR, eds. Baltimore: Williams & WilkinsGoogle Scholar
  22. Beley A, et al, (1976): Time dependent changes in the rate of noradrenaline synthesis in various rat brain areas during cold exposure. Pflugers Arch 368:225–229Google Scholar
  23. Blanc G, et al., (1980): Response to stress of mesocortical-frontal dopaminergic neurons in rats after long term isolation. Nature 284:265–276PubMedGoogle Scholar
  24. Bolles RC (1970): Species-specific defense reactions and avoidance learning. Psychol Rev 77:32–48Google Scholar
  25. Bowers WJ, Zacharko RM, Anisman H (1985): Repeated stressor or desmethylimipramine effects on footshock induced depression of self-stimulation. Soc Neurosci Abst 11:51Google Scholar
  26. Bowers WJ, Zacharko RM, Anisman H (1987): Evaluation of stressor effects on intracranial self-stimulation from the nucleus accumbens and the substantia nigra in a current intensity paradigm. Behav Brain Res 23:85–93PubMedGoogle Scholar
  27. Brown L, Rosellini RA, Samuels OB, Riley EP (1982): Evidence for a serotonergic mechanism of the learned helplessness phenomenon. Pharmacol Bwchem Behav 17:877–883Google Scholar
  28. Bruto V, Anisman H (1983): Alterations of exploratory patterns induced by uncontrollable shock. Behav Neural Bwl 37:302–316Google Scholar
  29. Cassens G, et al., (1980): Alterations in brain norepinephrine metabolism induced by environmental stimuli previously paired with inescapable shock. Science 209:1138–1140PubMedGoogle Scholar
  30. Deutch AY, Tam S-Y, Roth RH (1985): Footshock and conditioned stress increase 3,4-dihydroxyphenylacetic acid (DOPAC) in the ventral tegmental area but not substantia nigra. Brain Research 333:143–146PubMedGoogle Scholar
  31. Drugan RC, et al., (1984): Librium prevents the analgesia and shuttlebox escape deficit typically observed following inescapable shock. Pharmacol Bwchem Behav 21:749–754Google Scholar
  32. Dunn AJ, File SA (1983): Cold restraint alters dopamine metabolism in frontal cortex, nucleus accumbens and neostriatum. Physiol Behav 31:511–513PubMedGoogle Scholar
  33. Dunn AJ, Kramarcy NR (1984): Neurochemical responses in stress: Relationships between the hypothalamic-pituitary adrenal and catecholamine systems. In: Handbook of Psychopharmacology, Iversen LL, Iversen SD, Snyder SH, eds. New York: Plenum PressGoogle Scholar
  34. Fadda F, et al., (1978): Stress induced increase in 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the cerebral cortex and in nucleus accumbens: Reversal by diazepam. Life Sci 23:2219–2224PubMedGoogle Scholar
  35. Fekete MIK, et al, (1981): Effects of anxiolytic drugs on the catecholamine and DOP AC (3,4-dihydroxyphenylacetic acid) levels in brain cortical areas and on corticosterone and prolactin secretion in rats subjected to stress. Psychoneuroendo 6:113–120Google Scholar
  36. Glazer HI, Weiss JM (1976a): Long-term and transitory interference effects. J Exper Psychot Anim Behav Proc 2:191–201Google Scholar
  37. Glazer HI, Weiss JM (1976b): Long term interference effect: An alternative to “Learned Helplessness”. J Exp Psychol [Anim Behav] 2:202–213Google Scholar
  38. Hamilton ME, Zacharko RM, Anisman H (1986): Influence of p-chloroamphetamine and methysergide on the escape deficits provoked by inescapable shock Psychopharmacology 90:203–206PubMedGoogle Scholar
  39. Heninger GR, Charney DS (1987): Mechanism of action of antidepressant treatments: Implications for the etiology and treatment of depressive disorders. In: Psychopharmacology: The Third Generation of Progress, Meltzer HY, ed. New York: Raven PressGoogle Scholar
  40. Herman JP, et al., (1982): Differential effects of inescapable footshock and stimuli previously paired with inescapable footshocks on dopamine turnover in cortical and limbic areas of the rat. Life Sci 30:2207–2214PubMedGoogle Scholar
  41. Herman JP, Stinus L, Le Moal M (1984): Repeated stress increases locomotor response to amphetamine. Psychopharmacology 84:431–435PubMedGoogle Scholar
  42. Herve D, et al., (1979): Differences in the reactivity of the mesocortical dopaminergic neurons to stress in the Balb/C and C57/BL6 mice. Life Sci 25:1659–1664PubMedGoogle Scholar
  43. Hudgens R, Morrison J, Barchha R (1967): Life events and onset of primary affective disorders. Arch Gen Psychiatry 16:134–145PubMedGoogle Scholar
  44. Irwin J, et al., (1986): Central norepinephrine and plasma corticosterone following acute and chronic stressors: Influence of social isolation and handling. Pharmacol Biochem Behav 24:1151–1154PubMedGoogle Scholar
  45. Irwin J, Ahluwalia P, Anisman H (1986): Sensitization of norepinephrine activity following acute and chronic footshock. Brain Res 376:98–103Google Scholar
  46. Irwin J, Suissa A, Anisman H (1980): Differential effects of inescapable shock on escape performance and discrimination learning in a water escape task. J Exp Psychol [Anim Behav] 6:21–40Google Scholar
  47. Jackson RL, Alexander RH & Maier SF (1980): Learned helplessness, inactivity and associative deficits: Effects of inescapable shock on response choice escape learning. J Exp Psychol [Anim Behav] 6:1–20Google Scholar
  48. Jimerson DC, Post RM (1984): Psychomotor stimulants and dopamine agonists in depression. In Neurobiology of Mood Disorders, Post RM, Ballenger JC, eds. Baltimore: Williams & WilkinsGoogle Scholar
  49. Katz RJ (1982): Animal model of depression: Pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav 16:965–968PubMedGoogle Scholar
  50. Katz RJ (1981a): Animal models and human depressive disorders. Neurosci Biobehav Rev, 5:231–246PubMedGoogle Scholar
  51. Katz RJ (1981b): Animal models of depression: Effects of electroconvulsive shock therapy. Neurosci Biobehav Rev 5:273–277PubMedGoogle Scholar
  52. Katz RJ, Sibel M (1982): Further analysis of the specificity of a novel animal model of depression: Effects of an antihistaminic, antipsychotic and anxiolytic compound. Pharmacol Biochem Behav 16:979–982PubMedGoogle Scholar
  53. Kobayashi RM, et al., (1976): Selective alterations of catecholamines and tyrosine hydroxylase activity in the hypothalamus following acute and chronic stress. In: Catecholamines and Stress. Usdin E, Kvetnansky R, Kopin IJ, eds. Oxford: Pergamon PressGoogle Scholar
  54. Kvetnansky R, et al., (1976): Catecholamines in individual hypothalamic nuclei in stressed rats. In: Catecholamines and Stress Usdin E, Kvetnansky R, Kopin IJ, eds. Oxford: Pergamon PressGoogle Scholar
  55. MacLennan AJ, Maier SF (1983): Coping and stress-induced potentiation of stimulant stereotypy in the rat. Science 219:1091–1093PubMedGoogle Scholar
  56. Maier SF, Seligman MEP (1976): Learned helplessness: Theory and evidence. J Exp Psychol [Gen] 105:3–46Google Scholar
  57. Minor TR, Jackson RL, Maier SF (1984): Effects of task-irrelevant cues and reinforcement delay on choice escape learning following inescapable shock: Evidence for a deficit in selective attention. J Exp Psychol [Anim Behav] 10:543–556Google Scholar
  58. Morrison J, Hudgens R, Barchha R (1968): Life events and psychiatric illness. B J Psychiatry 114:423–432Google Scholar
  59. Noll KM, Davis JM, DeLeon-Jones, F (1985): Medication and somatic therapies in the treatment of depression. In: Handbook of Depression, Beckham EE, Leber WR, eds. New York: Dorsey PressGoogle Scholar
  60. Nomura S, et al., (1981): Stress and β-adrenergic receptor binding in the rat’s brain. Brain Res 224:199–203PubMedGoogle Scholar
  61. Palkovits M, et al., (1976): Effects of stress on serotonin and tryptophan hydroxylase activity of brain nucleis. In: Catecholamines and Stress, Usdin E, Kvetnansky R, Kopin IJ, eds. Oxford: Pergamon PressGoogle Scholar
  62. Petty F, Sherman AD (1982): A neurochemical differentiation between exposure to stress and the development of learned helplessness. Drug Devel Res 2:43–45Google Scholar
  63. Platt JE, Stone EA (1982): Chronic restraint stress elicits a positive antidepressant response on the forced swim test. Eur J Pharmacol 82:179–181PubMedGoogle Scholar
  64. Prince CR, Ahluwalia P, Anisman H (1986a): Catecholamine and corticoid variations associated with prepared and contraprepared defensive responses. Soc Neurosci Abs, 12:1060Google Scholar
  65. Prince CR, Anisman H (1984): Acute and chronic stress effects on performance in a forced-swim task. Behav Neur Biol 84:99–119Google Scholar
  66. Prince CR, Collins C, Anisman H (1986b): Stressor-provoked response patterns in a swim task: Modification by diazepam. Pharmacol Biochem Behav 24:323–328PubMedGoogle Scholar
  67. Richardson JS (1984): Brain part monoamines and the neuroendocrine mechanisms activated by immobilization stress in the rat. Int J Neurosci 23:57–68PubMedGoogle Scholar
  68. Rosellini RA (1978): Inescapable shock interferes with the acquisition of a free appetitive operant. Anim Learn Behav 6:155–159Google Scholar
  69. Rosellini RA, et al., (1984): Uncontrollable shock proactively increases sensitivity to response-reinforcer independence in rats. J Exp Psychol [Anim Behav] 10:346–359Google Scholar
  70. Rosellini RA, DeCola JP, Shapiro NR (1982): Cross-motivational effects of inescapable shock are associative in nature. J Exp Psychol [Anim Behav] 8:376–388Google Scholar
  71. Roth KA, Mefford IM, Barchas JD (1982): Epinephrine, norepinephrine, dopamine and serotonin: Differential effects of acute and chronic stress on regional brain amines. Brain Res 239:417–424PubMedGoogle Scholar
  72. Schildkraut JJ (1978): Current status of the catecholamine hypothesis of affective disorders. In: Psychopharmacology: A Generation of Progress, Lipton MA, DiMascio A, Killam KF, eds. New York: Raven PressGoogle Scholar
  73. Shanks N, Anisman H (1987): Strain specific behavioral effects of inescapable shock and desmethylimipramine. Soc Neurosci Abstr 13:660Google Scholar
  74. Shanks N, Anisman H (1988): Stressor provoked disturbances in six strains of mice. Behav Neurosci, in pressGoogle Scholar
  75. Sherman AD, et al., (1979): A neuropharmacologically relevant animal model of depression. Neuropharmacology 18:891–893PubMedGoogle Scholar
  76. Sherman AD, Petty F (1980): Neurochemical basis of the action of anti-depressants on learned helplessness. Behav Neur Biol 30:119–134Google Scholar
  77. Sherman AD, Sacquitne JL, Petty F (1982): Pharmacologic specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16:449–454PubMedGoogle Scholar
  78. Slater S, Roth M (1969): Mayer Gross Clinical Psychiatry. Baltimore: Williams & WilkinsGoogle Scholar
  79. Stone EA (1979): Subsensitivity to norepinephrine as a link between adaptation to stress and antidepressant therapy: An hypothesis. Research Comm Psychol Psychiat Behav 4:241–255Google Scholar
  80. Stone EA (1983): Problems with current catecholamine hypotheses of antidepressant agents. Behav Brain Sci 6:535–577Google Scholar
  81. Stone EA, et al., (1984): Reduction of the cAMP response to norepinephrine in rat cerebral cortex following repeated restraint stress. Psychopharmacology 82:403–405PubMedGoogle Scholar
  82. Stone EA, Platt JE (1982): Brain noradrenergic receptors and resistance to stress. Brain Res 237:405–414PubMedGoogle Scholar
  83. Sulser F (1978): Functional aspects of the norepinephrine receptor coupled adenylate cyclase system in the limbic forebrain and its modification by drugs which precipitate or alleviate depression: Molecular approaches to an understanding of affective disorders. Pharmako Neuropsycho 11:43–52Google Scholar
  84. Sulser F (1982): Antidepressant drug research: Its impact on neurobiology and psychobiology. In: Typical and Atypical Antidepressants: Molecular Mechanisms, Costa E, Racagni, G, eds. New York: Raven PressGoogle Scholar
  85. Szostak C, Anisman H (1985): Stimulus perseveration in a water maze following exposure to uncontrollable shock. Behav Neur Biol 43:178–198Google Scholar
  86. Tanaka M, et al., (1982): Time-related differences in noradrenaline turnover in rat brain regions by stress. Pharmacol Biochem Behav 16:315–319PubMedGoogle Scholar
  87. Telegdy G, Vermes M (1976): Changes induced by stress in the activity of the serotonergic system in limbic brain structures. In: Catecholamines and Stress. Usdin E, Kvetnansky R, Kopin IJ, eds. Oxford: Pergamon PressGoogle Scholar
  88. Telner J, Singhai RL (1981): Effects of nortriptyline treatment on learned helplessness in the rat. Pharmacol Biochem Behav 14:823–826PubMedGoogle Scholar
  89. Thierry AM, et al., (1968): Effects of stress on the metabolism of norepinephrine, dopamine and serotonin in the central nervous system of the rat. J Pharmacol Exper Therap 163:163–171Google Scholar
  90. Thierry AM, et al., (1976): Selective activation of the mesocortical DA system by stress. Nature 263:242–244PubMedGoogle Scholar
  91. Tissari AH, et al., (1979): Footshock stress accelerates non-striatal dopamine synthesis without activating tyrosine hydroxylase. Arch Pharmacol 308:155–158Google Scholar
  92. Tsuda A, Tanaka M (1985): Differential changes in noradrenaline turnover in specific region of rat brain produced by controllable and uncontrollable shocks. Behav Neurosci 99:802–817PubMedGoogle Scholar
  93. U’Pritchard DC, Kvetnansky R (1980): Central and peripheral adrenergic receptors in acute and repeated immobilization stress. In: Second International Symposium in Catecholamines and Stress, Usdin E, Kvetnansky R, Kopin IJ, eds. New York: Elsevier-DuttonGoogle Scholar
  94. van Praag HM (1978): Amine hypotheses of affective disorders. In: Handbook of Psychopharmacology, Iversen LL, Iversen SD, Snyder SH, eds. New York: Plenum PressGoogle Scholar
  95. van Praag HM (1984): Depression, suicide, and serotonin metabolism in the brain. In: Neurobiology of Mood Disorders, Post RM, Ballenger JM, eds. Baltimore: Williams & WilkinsGoogle Scholar
  96. Vetulani J (1983): Alpha-1 up, beta down: A counterproposal to Stone. Behav Brain Sci 4:560–561Google Scholar
  97. Vetulani J (1984): Studies on the neurochemical basis of action of antidepressant drugs and electroconvulsive treatment. Pol J Pharmacol Pharm 36:101–116PubMedGoogle Scholar
  98. Vetulani J, et al., (1984): Alpha-up beta-down adrenergic regulation—a possible mechanism of action of antidepressant treatments. Pol J Pharmacol Pharm 36:321–328Google Scholar
  99. Watanabe H (1984): Activation of dopamine synthesis in mesolimbic dopamine neurons by immobilization stress in the rat. Neuropharmacology 23:1335–1338PubMedGoogle Scholar
  100. Weiss JM, et al., (1975): Effects of chronic exposure to stressors on avoidance-escape behavior and on brain norepinephrine. Psychosom Med 37:522–534PubMedGoogle Scholar
  101. Weiss JM, et al., (1979): Coping behavior and stress-induced behavioral depression: Studies of the role of brain catecholamines. In: The Psychobiology of Depressive Disorders, Depue RA, ed. New York: Academic PressGoogle Scholar
  102. Weiss JM, Glazer HI (1975): Effects of acute exposure to stressors on subsequent avoidance-escape behavior. Psychol Med 37:499–521Google Scholar
  103. Weiss JM, et al., (1981): Behavioral depression produced by an uncontrollable stressor: Relationship to norepinephrine, dopamine and serotonin levels in various regions of rat brain. Brain Res Rev 3:167–205Google Scholar
  104. Weiss JM, Goodman PA (1985): Neurochemical mechanisms underlying stress-induced depression. In: Stress and Coping, Field T, McCabe P, Schneiderman N, eds. New Jersey: Lawrence ErlbaumGoogle Scholar
  105. Weiss JM, Glazer HI & Pohorecky LA (1976): Coping behavior and neurochemical changes: An alternative explanation for the original “learned helplessness” experiments. In: Animal Models in Human Psychobiology, Serban G, Kling A, eds. New York: Plenum PressGoogle Scholar
  106. Willner P (1984): The validity of animal models of depression. Psychopharmacology 83:1–16PubMedGoogle Scholar
  107. Willner P (1985): Depression: A Psychobiological Synthesis. New York: John Wiley & SonsGoogle Scholar
  108. Zacharko RM, et al., (1983): Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes. Behav Brain Res 9:129–141PubMedGoogle Scholar
  109. Zacharko RM, et al., (1984b): Prevention of stressor-induced disturbances of self-stimulation by desmethylimipramine. Brain Res 321:175–179PubMedGoogle Scholar
  110. Zacharko RM, et al., (1987): Strain-specific effects of inescapable shock on intracranial self-stimulation from the nucleus accumbens. Brain Res 426:164–168PubMedGoogle Scholar
  111. Zacharko RM, Bowers WJ, Anisman H (1984a): Responding for brain stimulation: Stress and desmethylimipramine. Prog Neurol Psychopharmacol Biol Psychiatry 8:601–606Google Scholar

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© Birkhäuser Boston 1989

Authors and Affiliations

  • Robert M. Zacharko
  • Hymie Anisman

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