Relationship between Cortisol and Serotonin Metabolites and Transporters in Alcolholism

A. Heinz; D. W. Jones; G. Bissette; D. Hommer; P. Ragan; M. Knable; S. Wellek; M. Linnoila; D. R. Weinberger

doi:10.1055/s-2002-33197

Pharmacopsychiatry 2002; 35(4): 127-134
DOI: 10.1055/s-2002-33197

Original Paper

Relationship between Cortisol and Serotonin Metabolites and Transporters in Alcolholism

A. Heinz^1, ⁴ , D. W. Jones¹ , G. Bissette³ , D. Hommer² , P. Ragan² , M. Knable¹ , S. Wellek⁴ , M. Linnoila² , D. R. Weinberger¹

¹Clinical Brain Disorders Branch, Intramural Research Program, NIMH, Bethesda, MD, USA
²Laboratory of Clinical Studies, Intramural Research Program, NIAAA, Bethesda, MD, USA
³Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MI, USA
⁴Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

Supported in part by the Deutsche Forschungsgemeinschaft (Az: He 2597/1 - 1)Dr. Linnoila died in February 1998.Parts of this manuscript were orally presented by Dr. Heinz at the 30th Annual Meeting of the Society for Neuroscience in New Orleans, November 6th, 2000.

Abstract

Background: Stress hormone activation may induce clinical depression via an interference with central serotonergic neurotransmission. In alcoholics, a reduction in serotonin transporters was associated with clinical depression, and an activation of cortisol secretion is frequently found during detoxification. We assessed the interaction between stress hormone activation, serotonin transporters, monoamine metabolites in the cerebrospinal fluid (CSF), and mood states in male and female alcoholics and healthy control subjects. Methods: The availability of serotonin transporters was measured with [I-123]β-CIT and SPECT in the raphe area of the brainstem in 31 alcoholics after four weeks of abstinence and in 25 age-matched healthy volunteers. Concentrations of plasma cortisol were measured on the day of the SPECT scan. Within one week after the SPECT scan, we assessed monoamine metabolites and corticotropin-releasing factor (CRF) in the CSF. Results: Clinical depression was associated with a reduction in serotonin transporter availability among male alcoholics. Among male alcoholics and healthy volunteers, CSF 5-HIAA and plasma cortisol concentrations were inversely correlated with the availability of raphe serotonin transporters and positively correlated with the severity of clinical depression. No significant correlations were observed between raphe serotonin transporters and HVA, MHPG and CRF concentrations in the CSF. Conclusion: Our findings support the hypothesis of an interaction between reduced serotonin transporters, stress hormone activation and clinical depression. They confirm the hypothesis that serotonergic neurotransmission dysfunction in alcoholism is limited to male alcoholics. The observed interactions between high cortisol concentrations and reduced serotonin transporter availability warrant further studies in major depression and other neuropsychiatric diseases with implied cortisol activation and serotonergic dysfunction.

Full Text

References

1 Adinoff B, Anton R, Linnoila M, Guidotti A, Nemeroff C B, Bissette G. Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH) and diazepam-binding inhibitor (DBI) during alcohol withdrawal and abstinence. Neuropsychopharmacology. 1996; 15 288-295
2 American Psychiatric Association, Committee on Nomenclature and Statistics. Diagnostic and statistical manual of mental disorders. Revised 3rd ed Washington, DC; American Psychiatric Association 1987
3 Baldwin R M, Zea-Ponce Y, Zoghbi S S, Laruelle M, AJ-Tikritti M S, Sybirska E H. Evaluation of the monoamine uptake site ligand [123-I]methyl 3β-(Iodophenyl)-tropane-2β-carboxylate ([123-I]β-CIT) in non-human primates: pharmacokinetics, biodistribution and SPECT brain imaging coregistered with MRI. Nucl Med Biol. 1993; 5 597-606
4 Baumgarten H G, Grozdanovic Z. Anatomy of central serotonergic projection system. In: Baumgarten HG, Gothert M, editors Handbook of experimental pharmacology. Vol 129. Serotonergic neurons and 5-HT receptors in the CNS. Berlin, Heidelberg; Springer 1997: p. 41-89
5 Beck A T, Ward C H, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961; 4 561-571
6 Blennow K, Wallin A, Gottfnes C G, Karlsson I, Mansson J E, Skoog I. Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18 - 88 years of age. Eur Neuropsychopharmacology. 1993; 3 55-61
7 Carlsson M, Svensson K, Eriksson E, Carlsson A. Rat brain serotonin: biochemical and functional evidence for a sex difference. J Neural Transm. 1985; 63 297-313
8 Carlsson M, Carlsson A. A regional study of sex differences in rat brain serotonin. Prog Neuropsychopharmacol Biol Psychiatry. 1988; 12 53-61
9 4 L J, Chapman J P, Numbers J F, Edell W S, Carpenter B N, Beckfield D. Impulsive nonconformity as a trait contributing to the prediction of psychotic-like and schizotypal symptoms. J Nerv Ment Dis. 1984; 172 681-691
10 Cloninger C R. Neurogenetic adaptive mechanisms in alcoholism. Science. 1987; 236 410-416
11 Dinan T G. Noradrenergic and serotonergic abnormalities in depression: stress-induced dysfunction?. J Clin Psychiatry. 1996; 57 (Suppl 4) 14-18
12 Farde L, Halldin C, Mueller L, Suhara T, Karlsson P, Hall H. PET study of [C-11]β-CIT binding to monoamine transporters in the monkey and human brain. Synapse. 1994; 16 93-103
13 Fils-Aime M L, Eckhardt M J, George D T, Brown G L, Mefford I, Linnoila M. Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics. Arch Gen Psychiatry. 1996; 53 211-216
14 Fisher R E, Morris E D, Alpert N M, Fischman A J. In vivo imaging of neuromodulatory synaptic transmission using PET: a review of relevant neurophysiology. Human Brain Map. 1995; 3 24-34
15 Fumagalli F, Jones S R, Caron M G, Seidler F J, Slotkin T A. Expression of mRNA coding for the serotonin transporter in aged versus young rat brain: differential effects of glucocorticoids. Brain Res. 1996; 719 225-228
16 Gatley S J, Volkow N D, Fowler J S, Dewey S L, Logan J. Sensitivity of striatal [^HC]cocaine binding to decreases in synaptic dopamine. Synapse. 1995; 20 137-144
17 Giros B, Jaber M, Jones S R, Wightman R M, Caron M G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996; 379 606-612
18 Hamilton M A. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23 56-62
19 Hartka E, Johnstone B, Leino E V, Motoyoshi M, Temple M T, Fillmore K M. The collaborative alcohol-related longitudinal project: a meta-analysis of depressive symptomatology and alcohol consumption overtime. Br J Add. 1991; 86 1283-1298
20 Heinz A, Rommelspacher H, Gräf K D, Kürten I, Otto M, Baumgartner A. The hypothalamic-pituitary-gonadal axis, prolactin and cortisol in alcoholics during withdrawal and after three weeks of abstinence and in healthy controls. Psychiatry Res. 1995; 56 81-95
21 Heinz A, Dufeu P, Kuhn S, Dettling M, Gräf K J, Kürten I. Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol-dependent patients. Arch Gen Psychiatry. 1996; 53 1123-1128
22 Heinz A, Higley J D, Jones D W, Gorey J G, Saunders R, Zajicek K. In vivo observation of an association between serotonin transporters and sensitivity to alcohol intoxication. Am J Psychiatry. 1998a; 155 1023-1028
23 Heinz A, Ragan P, Jones D W, Hommer D, Williams W, Knable M B. Reduced serotonin transporters in alcoholism. Am J Psychiatry. 1998b ; 155 1544-1549
24 Heinz A, Saunders R C, Kolachana B S, Bertolino A, Jones D W, Gorey J G. Disinhibition of subcortical dopaminergic neurotransmission in rhesus monkeys with neonatal mesial temporal lesions. Synapse. 1999; 32 71-79
25 Higley J D, Thompson W W, Champoux M, Goldman D, Hasert M F, Kraemer G W. Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoamine metabolites in rhesus monkeys (Macaca mulatta). Arch Gen Psychiatry. 1993; 50 615-623
26 Higley J D, Suomi S J, Linnoila M. A non-human primate model of type II excessive alcohol consumption? Part 1 & 2. Ale Clin Exp Res. 1996; 20 629-651
27 Hollingshead A B. Four factor index of social skills. New Haven; Yale University 1973
28 Iranmanesh A, Veldhuis J D, Johnson M L, Lizarralde G. 24-h pulsatile and circadian patterns of cortisol secretion in man. J Androl. 1989; 10 54-63
29 Irwin M, Schuckit M, Smith T L. Clinical importance of age of onset in type 1 and type 2 primary alcoholics. Arch Gen Psychiatry. 1990; 47 320-324
30 Jagust W J, Eberling J L, Biegon A, Taylor S E, Van Brocklin H F, Jordan S. Iodine-123 - 5-iodo-6-nitroquipazine: SPECT radiotracer to image the serotonin transporter. J Nucl Med. 1996; 37 1207-1214
31 Jones D W, Heinz A, Gorey J G, Lee K S, Knable M B, Urbina R A. A simple, sensitive, and efficient method of directly determining plasma concentrations of the free [I-123]β-CIT at extended times by TLC of ultrafiltrates. J Nucl Med. 1997; 38 (Suppl.) 287
32 Jones D W, Gorey J G, Zajicek K, Das S, Urbina R, Lee K S. Depletion-restoration studies reveal the impact of endogenous dopamine and serotonin on [I-123]β-CIT SPECT imaging in primate brain. J Nucl Med. 1998; 39 (Suppl.) 42
33 Knott P, Haroutunian V, Bierer L, Perl D, Handler M, DeLeon M, Yang R K, Davis K (1989). Correlations post-mortem between ventricular CSF and cortical tissue concentrations of MHPG, 5-HlAA and HVA in Alzheimer’s disease. Biol Psychiatry. 1989; 25 112A
34 Korte S M, Van Duin S, Bouws G AH, Koolhaas J M, Bonus B. Involvement of hypothalamic serotonin activation of the sympathomedullary system and hypothalamo-pituitary-adrenocortical axis in male Wistar rats. Eur J Pharmacol. 1991; 197 225-228
35 Krystal J H, Webb E, Cooney N L, Kranzler H R, Southwick S W, Heninger G R. Serotonergic and noradrenergic dysregulation in alcoholism: m-chlorophenylpiperazine and yohimbine effects in recently detoxified alcoholics and healthy control subjects. Am J Psychiatry. 1996; 153 83-92
36 Laruelle M, Baldwin R M, Malison R T, Zea-Ponce Y, Zoghbi S S, Al-Tikriti M S. SPECT imaging of dopamine and serotonin transporters with [123-I]β-CIT: Pharmacological characterization of brain uptake in non-human primates. Synapse. 1993; 13 295-309
37 Laruelle M, Wallace E, Seibyl J P, Baldwin R M, Zea-Ponce Y, Zoghbi S S. Graphical, kinetic, and equilibrium analyses of in vivo [123-I]β-CIT binding to dopamine transporters in healthy human subjects. J Cereb Blood Flow Metab. 1994; 14 982-994
38 Le Marquand D, Pihl R O, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: clinical evidence. Biol Psychiatry. 1994a ; 36 326-337
39 Le Marquand D, Pihl R O, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: findings of animal studies. Biol Psychiatry. 1994b; 36 395-421
40 Lesch K P, Sohnle K, Poten B, Schoellnhammer G, Rupprecht R, Schukte H M (1990). Corticotropin and cortisol secretion after central 5-hydroxytryptamine-lA (5-HT1A) receptor activation: effects of 5-HT receptor and beta-adrenoreceptor antagonists. J Clin Endocrinol Metab. 1990; 70 670-674
41 Lesch K P, Bengel D, Heils A, Sabol S Z, Greenberg B D, Petri S. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996; 274 1527-1531
42 Malison R T, Price L H, Berman R, van Dyck C H, Pelton G H, Carpenter L. Reduced brain serotonin transporter availability in major depression as measured by [¹²³I]-2β-carboxy-3(3-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry. 1998; 44 1090-1098
43 Meltzer H Y, Macs M. Effect of pindolol on the L-5-HTP-induced increase in plasma prolactin and cortisol concentrations in man. Psychopharmacology (Berl). 1994; 114 635-643
44 Meltzer H Y, Macs M, Elkis H. The biological basis of refractory depression. In: Nolen WA, Zohar J, Roose SP, Amsterdam JD, editors Refractory depression: current strategies and future directions. Chichester: John Wiley and Sons 1994: p. 177-198
45 Mueck A O, Seeger H, Kasspohl-Butz S, Teichmann A T, Lippert T H. Influence of norethisterone acetate and estradiol on the serotonin metabolism of postmenopausal women. Horm Metab Res. 1997; 29 80-83
46 Nishizawa S, Benkelfat C, Young S N, Leyton M, Mzenga S, de Montigny C. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA. 1997; 94 5308-5313
47 Owens M J, Nemeroff C B. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clinical Chemistr. 1994; 40 288-295
48 Oxenstierna G, Edman G, Iselius L, Oreland L, Ross S B, Sedvall G. Concentrations of monoamine metabolism in the cerebrospinal fluid of twins and unrelated individuals - a genetic study. J Psychiatry Res. 1985; 20 19-29
49 Pihoker C, Owens M J, Kuhn C M, Schanberg S M, Nemeroff C B. Maternal separation in neonatal rats elicits activation of the hypothalamic-pituitary-adrenocortical axis: a putative role for corticotropin-releasing factor. Psychoneuroendocrinology. 1993; 18 485-493
50 Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G. β-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo. J Neural Transm. 1995; 100 247-256
51 Pirker W, Asenbaum S, Hauk M, Kandlhofer S, Tauscher J, Willeit M. Imaging serotonin and dopamine transporters with 123I-β-CIT SPECT: binding kinetics and effects of normal aging. J Nucl Med. 2000; 41 36-44
52 Schuckit M A, Tipp J E, Smith T L, Shapiro E, Hesselbrock V M, Buchholz K K. An evaluation of type A and B alcoholics. Addiction. 1995; 90 1189-1203
53 Seeman M V. The role of estrogen in schizophrenia. Psychiat Res. 1996; 21 123-127
54 Seibyl J P, Wallace E, Smith E O, Stabin M, Baldwin R M, Zoghbi S S. Whole-body biodistribution, radiation absorbed dose and brain SPECT imaging with Iodine-123-β-CIT in healthy human subjects. J Nucl Med. 1994; 35 764-770
55 Selzer M L. The Michigan Alcoholism Screening Test: The quest for a new diagnostic instrument. Am J Psychiatry. 1971; 127 1653-1658
56 Skinner H A, Sheu W J. Reliability of alcohol use indices: The Lifetime Drinking History and the MAST. J Stud Alcohol 1. 982; 43 1157-1170
57 Slotkin T A, McCook E C, Ritchie J C, Carroll B J, Seidler F J. Serotonin transporter expression in rat brain regions and blood platelets: aging and glucocorticoid effects. Biol Psychiatry. 1997; 41 172-183
58 Spitzer R, Williams J, Gibbon M, First M. Structured Clinical Interview for DSM-III-R-Patient Edition (with Psychotic Screen) (SCED I, version 1.0). Washington; American Psychiatric Press 1990
59 Spitzer R L, Williams J BW, Gibbon M, First M B (1990b). Structured Clinical Interview for DSM-III-R - Personality Disorders (SCID II, version 1.0). Washington; American Psychiatric Press 1990
60 Staley J K, Basile M, Flynn D D, Mash D C. Visualizing dopamine and serotonin transporters in the human brain with the potent cocaine analogue [¹²⁵I]RTI-55: in vitro binding and autoradiographic characterization. J Neurochem. 1994; 62 549-556
61 Stokes P E, Maas J W, Davis J M, Koslow S H, Casper R C, Stoll P M. Biogenic amine and metabolite levels in depressed patients with high versus normal hypothalamic-pituitary-adrenocortical activity. Am J Psychiatry. 1987; 144 868-872
62 Virkunnen M, Kallio E, Rawlings R, Tokola R, Poland R E, Guidotti A. Personality profiles and state aggressiveness in Finnish alcoholic, violent offenders, fire setters, and healthy volunteers. Arch Gen Psychiatry. 1994; 51 28-33
63 Von Bardeleben U, Heuser I, Holsboer F. Human CRH stimulation during acute withdrawal and after medium-term abstention from alcohol abuse. Psychoneuroendocrinology. 1989; 14 441-449
64 Wagner Glenn S, Parsons O A. Prediction of resumption of drinking in posttreatment alcoholics. Int J Addiction. 1991; 26 237-254
65 Wester P, Bergstrom U, Eriksson A, Gezelius C, Hardy J, Winblad B. Ventricular cerebrospinal fluid monoamine transmitter and metabolite concentrations reflect human brain neurochemistry in autopsy cases. J Neurochem. 1990; 54 1148-1153
66 Willeit M, Praschak-Rieder N, Neumeister A, Pirker W, Asenbaum S, Vitouch O. [123I]-beta-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder. Biol Psychiatry. 2000; 47 482-489

Andreas Heinz,MD

Director and Chair, Dept. of Psychiatry of the Charité

Schumannstr. 20/21

10117 Berlin

Germany

Phone: +49 (30) 450 51 70 01

Fax: +49 (30) 450 51 79 10

Email: andreas.heinz@charite.de