Abstract
Introduction
Cocaine hydrochloride is a psychoactive substance extracted from the leaves of plants called Erythroxylum coca. Cocaine is the second most commonly used drug in the world after cannabis; 20 % of cocaine users will become long-term cocaine-dependent patients. Different routes of administration may be recognized: smokable modality, intranasal and intravenous. Cocaine is a potent stimulant of the sympathetic nervous system and causes structural changes on the brain, heart, lung, liver and kidney. It has long been known that use of cocaine may produce alterations to the endocrine system. Research on behavioral and neuroendocrine effects of cocaine dates back several years ago and has increasingly focused on alterations of the hypothalamic–pituitary–adrenal (HPA) axis, which appears to be the chief target of cocaine effects.
Studies
Animal (mainly rats and monkeys) and human studies have clearly shown a close relation between cocaine consumption and overdrive of the HPA axis. Such activation is likely involved, though via a still undefined mechanism, in the behavioral and cardiovascular changes of drug abusers as well as in the reinforcement/relapse phenomena. Further studies of the pathophysiology of cocaine addicts will help to devise new therapeutic strategies for these patients.
Similar content being viewed by others
References
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (2012). Trend report for the evaluation of the 2005–12 EU drugs strategy. EMCDDA, Lisbon
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (2013). European Drug Report 2013: Trends and developments. EMCDDA
Cone EJ (1995) Pharmacokinetics and pharmacodynamics of cocaine. J Anal Toxicol 19:459–478
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) (2013). Perspective on drugs: Emergency health consequences of cocaine use in Europe
Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74
Koob GF (1999) Stress, corticotropin-releasing factor, and drug addiction. Ann N Y Acad Sci 897:27–45
Goeders NE (2002) The HPA axis and cocaine reinforcement. Psychoneuroendocrinology 27:13–33
Johnson EO, Kamilaris TC, Calogero AE, Konstandi M, Chrousos GP (2013) Effects of short- and long-duration hypothyroidism on function of the rat hypothalamic-pituitary-adrenal axis. J Endocrinol Invest 36:104–110
Moldow RL, Fischman AJ (1987) Cocaine induced secretion of ACTH, beta-endorphin, and corticosterone. Peptides 8:819–822
Rivier C, Vale W (1987) Cocaine stimulates adrenocorticotropin (ACTH) secretion through a corticotropin-releasing factor (CRF)-mediated mechanism. Brain Res 422:403–406
Borowsky B, Kuhn CM (1991) Monoamine mediation of cocaine-induced hypothalamo-pituitary-adrenal activation. J Pharmacol Exp Ther 256:204–210
Levy AD, Li QA, Kerr JE et al (1991) Cocaine-induced elevation of plasma adrenocorticotropin hormone and corticosterone is mediated by serotonergic neurons. J Pharmacol Exp Ther 259:495–500
Sarnyai Z, Biro E, Penke B, Telegdy G (1992) The cocaine-induced elevation of plasma corticosterone is mediated by endogenous corticotropin-releasing factor (CRF) in rats. Brain Res 589:154–156
Sarnyai Z, Biro E, Telegdy G (1993) Cocaine-induced elevation of plasma corticosterone is mediated by different neurotransmitter systems in rats. Pharmacol Biochem Behav 45:209–214
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
Koob G, Kreek MJ (2007) Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164:1149–1159
Sarnyai Z, Vecsernyes M, Laczi F, Biro E, Szabo G, Kovacs GL (1992) Effects of cocaine on the contents of neurohypophyseal hormones in the plasma and in different brain structures in rats. Neuropeptides 23:27–31
Rivier C, Lee S (1994) Stimulatory effect of cocaine on ACTH secretion: role of the hypothalamus. Mol Cell Neurosci 5:189–195
Zhou Y, Litvin Y, Piras AP, Pfaff DW, Kreek MJ (2011) Persistent increase in hypothalamic arginine vasopressin gene expression during protracted withdrawal from chronic escalating-dose cocaine in rodents. Neuropsychopharmacology 36:2062–2075
Calogero AE, Gallucci WT, Kling MA, Chrousos GP, Gold PW (1989) Cocaine stimulates rat hypothalamic corticotropin-releasing hormone secretion in vitro. Brain Res 505:7–11
Ago Y, Nakamura S, Baba A, Matsuda T (2008) Neuropsychotoxicity of abused drugs: effects of serotonin receptor ligands on methamphetamine and cocaine-induced behavioral sensitization in mice. J Pharmacol Sci 106:15–21
Goeders NE (1997) A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22:237–259
Goeders NE (2002) Stress and cocaine addiction. J Pharmacol Exp Ther 301:785–789
Haleem DJ, Kennett G, Curzon G (1988) Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesis. Brain Res 458:339–347
Goeders NE, Guerin GF (1996) Effects of surgical and pharmacological adrenalectomy on the initiation and maintenance of intravenous cocaine self-administration in rats. Brain Res 722:145–152
Iranmanesh A, Lizarralde G, Short D, Veldhuis JD (1990) Intensive venous sampling paradigms disclose high frequency adrenocorticotropin release episodes in normal men. J Clin Endocrinol Metab 71:1276–1283
Carnes M, Kalin NH, Lent SJ, Barksdale CM, Brownfield MS (1988) Pulsatile ACTH secretion: variation with time of day and relationship to cortisol. Peptides 9:325–331
Sarnyai Z, Mello NK, Mendelson JH, Nguyen PH, Eros-Sarnyai M (1995) Effects of cocaine and corticotropin-releasing factor on pulsatile ACTH and cortisol release in ovariectomized rhesus monkeys. J Clin Endocrinol Metab 80:2745–2751
Sarnyai Z, Veldhuis JD, Mello NK et al (1995) The concordance of pulsatile ultradian release of adrenocorticotropin and cortisol in male rhesus monkeys. J Clin Endocrinol Metab 80:54–59
Carnes M, Lent SJ, Goodman B, Mueller C, Saydoff J, Erisman S (1990) Effects of immunoneutralization of corticotropin-releasing hormone on ultradian rhythms of plasma adrenocorticotropin. Endocrinology 126:1904–1913
Sarnyai Z, Mello NK, Mendelson JH, Eros-Sarnyai M, Mercer G (1996) Effects of cocaine on pulsatile activity of hypothalamic-pituitary-adrenal axis in male rhesus monkeys: neuroendocrine and behavioral correlates. J Pharmacol Exp Ther 277:225–234
Post RM, Kopanda RT, Black KE (1976) Progressive effects of cocaine on behavior and central amine metabolism in rhesus monkeys: relationship to kindling and psychosis. Biol Psychiatry 11:403–419
Gawin FH, Kleber HD (1985) Neuroendocrine findings in a chronic cocaine abusers: a preliminary report. Br J Psychiatry 147:569–573
Vescovi PP, Coiro V, Volpi R, Passeri M (1992) Diurnal variations in plasma ACTH, cortisol and beta-endorphin levels in cocaine addicts. Horm Res 37:221–224
Vescovi PP, Coiro V, Volpi R, Giannini A, Passeri M (1992) Hyperthermia in sauna is unable to increase the plasma levels of ACTH/cortisol, beta-endorphin and prolactin in cocaine addicts. J Endocrinol Invest 15:671–675
Mendelson JH, Teoh SK, Mello NK, Ellingboe J, Rhoades E (1992) Acute effects of cocaine on plasma adrenocorticotropic hormone, luteinizing hormone and prolactin levels in cocaine-dependent men. J Pharmacol Exp Ther 263:505–509
Teoh SK, Sarnyai Z, Mendelson JH et al (1994) Cocaine effects on pulsatile secretion of ACTH in men. J Pharmacol Exp Ther 270:1134–1138
Negro-Vilar A, Johnston C, Spinedi E, Valenca MM, Lopez F (1987) Physiological role of peptides and amines on the regulation of ACTH secretion. Ann NY Acad Sci 512:219–237
Gambacciani M, Liu JH, Swartz WH, Tueros VS, Rasmussen DD, Yen SS (1987) Intrinsic pulsatility of ACTH release from the human pituitary in vitro. Clin Endocrinol (Oxf) 26:557–563
Sholar MB, Mendelson JH, Mello NK et al (1998) Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men. J Clin Endocrinol Metab 83:966–968
Baumann MH, Gendron TM, Becketts KM, Henningfield JE, Gorelick DA, Rothman RB (1995) Effects of intravenous cocaine on plasma cortisol and prolactin in human cocaine abusers. Biol Psychiatry 38:751–755
Elman I, Breiter HC, Gollub RL et al (1999) Depressive symptomatology and cocaine-induced pituitary-adrenal axis activation in individuals with cocaine dependence. Drug Alcohol Depend 56:39–45
Mendelson JH, Mello NK, Sholar MB, Siegel AJ, Mutschler N, Halpern J (2002) Temporal concordance of cocaine effects on mood states and neuroendocrine hormones. Psychoneuroendocrinology 27:71–82
Phillips K, Luk A, Soor GS, Abraham JR, Leong S, Butany J (2009) Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options. Am J Cardiovasc Drugs 9:177–196
Jacobsen TN, Grayburn PA, Snyder RW et al (1997) Effects of intranasal cocaine on sympathetic nerve discharge in humans. J Clin Invest 99:628–634
Vongpatanasin W, Mansour Y, Chavoshan B, Arbique D, Victor RG (1999) Cocaine stimulates the human cardiovascular system via a central mechanism of action. Circulation 100:497–502
Mittleman MA, Mintzer D, Maclure M, Tofler GH, Sherwood JB, Muller JE (1999) Triggering of myocardial infarction by cocaine. Circulation 99:2737–2741
Silaghi A, Silaghi H, Scridon T, Pais R, Achard V (2012) Glucocorticoid receptors in human epicardial adipose tissue: role of coronary status. J Endocrinol Invest 35:649–654
Heesch CM, Wilhelm CR, Ristich J, Adnane J, Bontempo FA, Wagner WR (2000) Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart 83:688–695
Siegel AJ, Mendelson JH, Sholar MB et al (2002) Effect of cocaine usage on C-reactive protein, von Willebrand factor, and fibrinogen. Am J Cardiol 89:1133–1135
Steffel J, Iseli S, Arnet C, Luscher TF, Tanner FC (2006) Cocaine unbalances endothelial tissue factor and tissue factor pathway inhibitor expression. J Mol Cell Cardiol 40:746–749
O’Leary ME, Hancox JC (2010) Role of voltage-gated sodium, potassium and calcium channels in the development of cocaine-associated cardiac arrhythmias. Br J Clin Pharmacol 69:427–442
Ambre JJ, Belknap SM, Nelson J, Ruo TI, Shin SG, Atkinson AJ Jr (1988) Acute tolerance to cocaine in humans. Clin Pharmacol Ther 44:1–8
Foltin RW, Haney M (2004) Intranasal cocaine in humans: acute tolerance, cardiovascular and subjective effects. Pharmacol Biochem Behav 78:93–101
Mendelson JH, Sholar M, Mello NK, Teoh SK, Sholar JW (1998) Cocaine tolerance: behavioral, cardiovascular, and neuroendocrine function in men. Neuropsychopharmacology 18:263–271
Elman I, Lukas SE, Karlsgodt KH, Gasic GP, Breiter HC (2003) Acute cortisol administration triggers craving in individuals with cocaine dependence. Psychopharmacol Bull 37:84–89
Sinha R, Talih M, Malison R, Cooney N, Anderson GM, Kreek MJ (2003) Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology 170:62–72
Ward AS, Collins ED, Haney M, Foltin RW, Fischman MW (1998) Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans. Behav Pharmacol 9:577–586
Ward AS, Collins ED, Haney M, Foltin RW, Fischman MW (1999) Blockade of cocaine-induced increases in adrenocorticotrophic hormone and cortisol does not attenuate the subjective effects of smoked cocaine in humans. Behav Pharmacol 10:523–529
Quinones-Jenab V (2006) Why are women from Venus and men from Mars when they abuse cocaine? Brain Res 1126:200–203
Najavits LM, Lester KM (2008) Gender differences in cocaine dependence. Drug Alcohol Depend 97:190–194
Evans SM, Foltin RW (2010) Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates? Horm Behav 2010(58):13–21
Mendelson JH, Mello NK, Sholar MB et al (1999) Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle. Neuropsychopharmacology 21:294–303
Halpern JH, Sholar MB, Glowacki J, Mello NK, Mendelson JH, Siegel AJ (2003) Diminished interleukin-6 response to proinflammatory challenge in men and women after intravenous cocaine administration. J Clin Endocrinol Metab 88:1188–1193
Fox HC, Garcia M Jr, Kemp K, Milivojevic V, Kreek MJ, Sinha R (2006) Gender differences in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individuals. Psychopharmacology 185:348–357
Waldrop AE, Price KL, Desantis SM et al (2010) Community-dwelling cocaine-dependent men and women respond differently to social stressors versus cocaine cues. Psychoneuroendocrinology 35:798–806
Jacobsen LK, Giedd JN, Kreek MJ, Gottschalk C, Kosten TR (2001) Quantitative medial temporal lobe brain morphology and hypothalamic-pituitary-adrenal axis function in cocaine dependence: a preliminary report. Drug Alcohol Depend 62:49–56
Buydens-Branchey L, Branchey M, Hudson J, Dorota Majewska M (2002) Perturbations of plasma cortisol and DHEA-S following discontinuation of cocaine use in cocaine addicts. Psychoneuroendocrinology 27:83–97
Fox HC, Hong KA, Paliwal P, Morgan PT, Sinha R (2008) Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females. Psychopharmacology 195:527–536
Vescovi PP (2000) Cardiovascular and hormonal responses to hyperthermic stress in cocaine addicts after a long period of abstinence. Addict Biol 5:91–95
Starkman MN, Giordani B, Berent S, Schork MA, Schteingart DE (2001) Elevated cortisol levels in Cushing’s disease are associated with cognitive decrements. Psychosom Med 63:985–993
Michaud K, Forget H, Cohen H (2009) Chronic glucocorticoid hypersecretion in Cushing’s syndrome exacerbates cognitive aging. Brain Cogn 71:1–8
Starkman MN, Gebarski SS, Berent S, Schteingart DE (1992) Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765
Maheu FS, Mazzone L, Merke DP et al (2008) Altered amygdala and hippocampus function in adolescents with hypercortisolemia: a functional magnetic resonance imaging study of Cushing syndrome. Dev Psychopathol 20:1177–1189
Resmini E, Santos A, Gomez-Anson B et al (2012) Verbal and visual memory performance and hippocampal volumes, measured by 3-Tesla magnetic resonance imaging, in patients with Cushing’s syndrome. J Clin Endocrinol Metab 97:663–671
Jovanovski D, Erb S, Zakzanis KK (2005) Neurocognitive deficits in cocaine users: a quantitative review of the evidence. J Clin Exp Neuropsychol 27:189–204
Di Sclafani V, Tolou-Shams M, Price LJ, Fein G (2002) Neuropsychological performance of individuals dependent on crack-cocaine, or crack-cocaine and alcohol, at 6 weeks and 6 months of abstinence. Drug Alcohol Depend 66:161–171
Fox HC, Jackson ED, Sinha R (2009) Elevated cortisol and learning and memory deficits in cocaine dependent individuals: relationship to relapse outcomes. Psychoneuroendocrinology 34:1198–1207
Di Sclafani V, Truran DL, Bloomer C et al (1998) Abstinent chronic crack-cocaine and crackcocaine/alcohol abusers evidence normal hippocampal volumes on MRI despite persistent cognitive impairments. Addict Biol 3:261–270
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Manetti, L., Cavagnini, F., Martino, E. et al. Effects of cocaine on the hypothalamic–pituitary–adrenal axis. J Endocrinol Invest 37, 701–708 (2014). https://doi.org/10.1007/s40618-014-0091-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-014-0091-8