Abstract
Previous studies have demonstrated that exposure to psychostimulant drugs can produce a lasting cross-sensitization to the behavioral effects of stress. The main purpose the present study was, therefore, to determine the effects of psychostimulant cross-sensitization on the stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Rats were given a series of injections of d-amphetamine or vehicle in a regimen that has been shown previously to induce cross-sensitization to a stressor. After two weeks, half the animals in the drug and vehicle-treated conditions were subjected to 30 min restraint stress; the remaining animals served as non-stressed controls. Animals were then sacrificed and trunk blood was assayed for CORT and ACTH. Prior d-amphetamine had no effect upon levels of CORT and ACTH in the non-stressed animals. Following 30 min restraint stress, however, levels of both hormones were significantly higher in drug-treated animals compared to controls. A second experiment confirmed behavioral sensitization to the current schedule of d-amphetamine injections, and demonstrated neuroendocrine sensitization of ACTH and CORT to a subsequent drug challenge. The augmented release of CORT and ACTH observed in d-amphetamine-treated rats might have important implications for human disorders in which processes resembling neurochemical sensitization have been hypothesized to play an etiological role.
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References
Antelman SM, Eichler AJ, Black CA, Kocan D . (1980): Interchangeability of stress and amphetamine in sensitization. Science 207: 329–331
Badiani A, Jakob A, Rodaros D, Stewart J . (1996): Sensitization of stress-induced feeding in rats repeatedly exposed to brief restraint: the role of corticosterone. Brain Res 710: 35–44
Basso AM, Gioino G, Molina VA, Cancela LM . (1999): Chronic amphetamine facilitates immunosuppression in response to a novel aversive stimulus: reversal by haloperidol pretreatment. Pharmacol Biochem Behav 62: 307–314
Brown ES, Rush AJ, McEwen BS . (1999): Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacology 21: 474–484
Budziszewska B, Jaworska-Feil L, Lason . (1995): Repeated amphetamine administration down-regulates glucocorticoid, but not mineralocorticoid, receptors in the hippocampus. Pol J Pharmacol 47: 401–406
Cador M, Dumas S, Cole BJ, Mallet J, Koob GF, Le Moal M, Stinus L . (1992): Behavioral sensitization induced by psychostimulants or stress: search for a molecular basis and evidence for a CRF-dependent phenomenon. Ann N Y Acad Sci 654: 416–420
Castner SA, Goldman-Rakic PS . (1999): Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys. Neuropsychopharmacology 20: 10–28
Cole BJ, Cador M, Stinus L, Rivier C, Rivier J, Vale W, Le Moal M, Koob GF . (1990): Critical role of the hypothalamic pituitary adrenal axis in amphetamine-induced sensitization of behavior. Life Sci 47: 1715–1720
Cregler LL . (1989): Adverse health consequences of cocaine abuse. J Natl Med Assoc 81: 27–38
Day HE, Campeau S, Watson SJ Jr, Akil H . (1999): Expression of alpha(1b) adrenoceptor mRNA in corticotropin-releasing hormone-containing cells of the rat hypothalamus and its regulation by corticosterone. J Neurosci 19: 10098–10106
Day JC, Koehl M, Deroche V, Le Moal M, Maccari S . (1998): Prenatal stress enhances stress- and corticotropin-releasing factor-induced stimulation of hippocampal acetylcholine release in adult rats. J Neurosci 18: 1886–1892
De Bosscher K, Vanden Berghe W, Haegeman G . (2000): Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. J Neuroimmunol 109: 16–22
Deroche V, Marinelli M, Le Moal M, Piazza PV . (1997): Glucocorticoids and behavioral effects of psychostimulants. II: cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels. J Pharmacol Exp Ther 281: 1401–1407
Dohrenwend BP . (2000): The role of adversity and stress in psychopathology: some evidence and its implications for theory and research. J Health Soc Behav 41: 1–19
Duncan GE, Sheitman BB, Lieberman JA . (1999): An integrated view of pathophysiological models of schizophrenia. Brain Res Brain Res Rev 29: 250–264
Ehlert U, Straub R . (1998): Physiological and emotional response to psychological stressors in psychiatric and psychosomatic disorders. Ann N Y Acad Sci 851: 477–486
Erb S, Shaham Y, Stewart J . (1996): Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period. Psychopharmacology 128: 408–412
Folkow B . (1997): Physiological aspects of the “defence” and “defeat” reactions. Acta Physiol Scand Suppl 640: 34–37
Goldstein DS . (1990): Neurotransmitters and stress. Biofeedback Self Regul 15: 243–271
Hamamura T, Fibiger HC . (1993): Enhanced stress-induced dopamine release in the prefrontal cortex of amphetamine-sensitized rats. Eur J Pharmacol 237: 65–71
Haney M, Maccari S, Le Moal M, Simon H, Piazza PV . (1995): Social stress increases the acquisition of cocaine self-administration in male and female rats. Brain Res 698: 46–52
Harris GC, Williams JT . (1992): Sensitization of locus ceruleus neurons during withdrawal from chronic stimulants and antidepressants. J Pharmacol Exp Ther 261: 476–483
Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, Nemeroff CB . (2000): Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284: 592–597
Henry JP . (1992): Biological basis of the stress response. Integr Physiol Behav Sci 27: 66–83
House RV, Thomas PT, Bhargava HN . (1994): Comparison of immune functional parameters following in vitro exposure to natural and synthetic amphetamines. Immunopharmacol Immunotoxicol 16: 1–21
Jacobson L, Sapolsky R . (1991): The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 12: 118–134
Johnson EO, Kamilaris TC, Chrousos GP, Gold PW . (1992): Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis. Neurosci Biobehav Rev 16: 115–130
Kaneko M, Kaneko K, Shinsako J, Dallman MF . (1981): Adrenal sensitivity to adrenocorticotropin varies diurnally. Endocrinology 109: 70–75
Keller DS, Wilson A . (1994): Affectivity in cocaine and opiate abusers. Psychiatry 57: 333–347
Kim CK, Osborn JA, Weinberg J . (1996): Stress reactivity in fetal alcohol syndrome. In Abel EL (ed), Fetal Alcohol Syndrome: from Mechanism to Prevention. Boca Raton, CRC Press, pp 215–235
Koob GF, Caine SB, Parsons L, Markou A, Weiss F . (1997): Opponent process model and psychostimulant addiction. Pharmacol Biochem Behav 57: 513–521
Koob GF, Le Moal M . (2001): Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24: 97–129
Kreek MJ, Koob GF . (1998): Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51: 23–47
Laruelle M . (2000): The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 31: 371–384
Liang SW, Boyce WT . (1993): The psychobiology of childhood stress. Curr Opin Pediatr 5: 545–551
Lieberman JA, Sheitman BB, Kinon BJ . (1997): Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology 17: 205–229
Lin D, Koob GF, Markou A . (2000): Time-dependent alterations in ICSS thresholds associated with repeated amphetamine administrations. Pharmacol Biochem Behav 65: 407–417
MacLennan AJ, Maier SF . (1983): Coping and the stress-induced potentiation of stimulant stereotypy in the rat. Science 219: 1091–1093
Mantsch JR, Saphier D, Goeders NE . (1998): Corticosterone facilitates the acquisition of cocaine self-administration in rats: opposite effects of the type II glucocorticoid receptor agonist dexamethasone. J Pharmacol Exp Ther 287: 72–80
Markou A, Koob GF . (1991): Postcocaine anhedonia. An animal model of cocaine withdrawal. Neuropsychopharmacology 4: 17–26
Markou A, Kosten TR, Koob GF . (1998): Neurobiological similarities in depression and drug dependence: a self-medication hypothesis. Neuropsychopharmacology 18: 135–174
McEwen BS . (1998): Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci 840: 833–844
McEwen BS . (2000): Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 22: 108–124
Muck-Seler D, Pivac N, Jakovljevic M, Brzovic Z . (1999): Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patients. Biol Psychiatry 45: 1433–1439
Mutschler NH, Miczek KA . (1998): Withdrawal from i.v. cocaine “binges” in rats: ultrasonic distress calls and startle. Psychopharmacology 135: 161–168
Pani L, Porcella A, Gessa GL . (2000): The role of stress in the pathophysiology of the dopaminergic system. Mol Psychiatry 5: 14–21
Paulson PE, Camp DM, Robinson TE . (1991): Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Psychopharmacology 103: 480–492
Pitman DL, Ottenweller JE, Natelson BH . (1990): Effect of stressor intensity on habituation and sensitization of glucocorticoid responses in rats. Behav Neurosci 104: 28–36
Plotsky PM, Owens MJ, Nemeroff CB . (1998): Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr Clin North Am 21: 293–307
Post RM . (1992): Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149: 999–1010
Prasad BM, Ulibarri C, Sorg BA . (1998): Stress-induced cross-sensitization to cocaine: effect of adrenalectomy and corticosterone after short- and long-term withdrawal. Psychopharmacology 136: 24–33
Robinson TE, Becker JB, Young EA, Akil H, Castaneda E . (1987): The effects of footshock stress on regional brain dopamine metabolism and pituitary beta-endorphin release in rats previously sensitized to amphetamine. Neuropharmacology 26: 679–691
Sapolsky RM, Romero LM, Munck AU . (2000): How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21: 55–89
Sarnyai Z, Dhabhar FS, McEwen BS, Kreek MJ . (1998): Neuroendocrine-related effects of long-term, ‘binge’ cocaine administration: diminished individual differences in stress-induced corticosterone response. Neuroendocrinology 68: 333–344
Schmidt ED, Tilders FJ, Binnekade R, Schoffelmeer AN, De Vries TJ . (1999): Stressor- or drug-induced sensitization of the corticosterone response is not critically involved in the long-term expression of behavioural sensitization to amphetamine. Neuroscience 92: 343–352
Schmidt ED, Tilders FJ, Janszen AW, Binnekade R, De Vries TJ, Schoffelmeer AN . (1995): Intermittent cocaine exposure causes delayed and long-lasting sensitization of cocaine-induced ACTH secretion in rats. Eur J Pharmacol 285: 317–321
Segal DS, Kuczenski R . (1997): Repeated binge exposures to amphetamine and methamphetamine: behavioral and neurochemical characterization. J Pharmacol Exp Ther 282: 561–573
Shilling PD, Kelsoe JR, Segal DS . (1996): Hippocampal glucocorticoid receptor mRNA is up-regulated by acute and down-regulated by chronic amphetamine treatment. Mol Brain Res 38: 156–160
Tidey JW, Miczek KA . (1997): Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology 130: 203–212
Trovero F, Brochet D, Tassin J, Drieu K . (1999): Ginkgo biloba extract Egb761 reduces the development of amphetamine-induced behavioral sensitization: effects on hippocampal type II corticosteroid receptors. Brain Res 818: 135–139
Vanderschuren LJ, Schmidt ED, De Vries TJ, Van Moorsel CA, Tilders FJ, Schoffelmeer AN . (1999): A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine, and neurochemical sensitization in rats. J Neurosci 19: 9579–9586
Weinberg J, Bezio S . (1987): Alcohol-induced changes in pituitary-adrenal activity during pregnancy. Alcohol Clin Exp Res 11: 274–280
Weinberg J, Taylor AN, Gianoulakis C . (1996): Fetal ethanol exposure: hypothalamic-pituitary-adrenal and beta-endorphin responses to repeated stress. Alcohol Clin Exp Res 20: 122–131
Wills TA, Vaccaro D, McNamara G, Hirky AE . (1996): Escalated substance use: a longitudinal grouping analysis from early to middle adolescence. J Abnorm Psychol 105: 166–180
Young EA, Vazquez D . (1996): Hypercortisolemia, hippocampal glucocorticoid receptors, and fast feedback. Mol Psychiatry 1: 149–159
Acknowledgements
This research was made possible by a grant from the Canadian Institutes of Health Research to AGP, from the National Institute on Alcohol Abuse and Alcoholism grant AA07789 to JW, and an Alberta Heritage Foundation for Medical Research Scholarship to CEH.
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Barr, A., Hofmann, C., Weinberg, J. et al. Exposure to Repeated, Intermittent d-amphetamine Induces Sensitization of HPA Axis to a Subsequent Stressor. Neuropsychopharmacol 26, 286–294 (2002). https://doi.org/10.1016/S0893-133X(01)00308-6
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DOI: https://doi.org/10.1016/S0893-133X(01)00308-6
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