Abstract
Rationale
A causal role of sex hormones in the onset and course of alcohol dependence is well established. We recently demonstrated that the genetics of the androgen receptor and aromatase relate to craving in alcohol addicts during withdrawal. This relationship involves the modulation of leptin, which affects the mesolimbic dopamine reward circuit. The steroid 5-α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and thereby causes increased androgenic potency.
Objectives
In this study, we explored whether functionally relevant genetic polymorphisms in SRD5A2 (V89L, A49T, [TA]n) are linked to alcohol addiction and craving.
Methods and results
We investigated 118 male alcohol-addicted inpatients admitted for withdrawal treatment and compared them to 50 healthy age- and body mass index-matched controls. The two groups did not differ in their allelic distributions. Subsequent analyses revealed an association between the V89L genotype and alcohol craving within the patient group (p < 0.05). Leptin accounted for 55 % of this relationship. Compared to VL and VV carriers, LL carriers had reduced serum leptin levels (p < 0.05) and lower levels of craving (p < 0.01). Furthermore, we observed an interaction between the V89L and the TTTAn aromatase polymorphisms (p < 0.05). No effects were found for A49T or (TA)n.
Conclusions
These findings further support a crucial role of sex hormone biosynthetic genes and signaling in alcohol withdrawal. Craving is an accepted risk factor for alcohol relapse. Hence, these results might be helpful in predicting the outcomes of alcohol addicts after detoxification. With SRD5A2 inhibitors already in clinical use worldwide, this study may also guide future preventive and therapeutic strategies.
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References
Addolorato G, Leggio L, Abenavoli L, Gasbarrini G (2005) Neurobiochemical and clinical aspects of craving in alcohol addiction: a review. Addict Behav 30:1209–1224
Allen NE, Reichardt JKV, Nguyen H, Key TJ (2003) Association between two polymorphisms in the SRD5A2 gene and serum androgen concentrations in British men. Cancer Epidemiol Biomark Prev 12:578–581
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC
Anton RF, Moak DH, Latham PK (1996) The obsessive compulsive drinking scale: a new method of assessing outcome in alcoholism treatment studies. Arch Gen Psychiatry 53:225–231
Apter SJ, Eriksson CJP (2003) The effect of alcohol on testosterone concentrations in alcohol-preferring and non-preferring rat lines. Alcohol Clin Exp Res 27:1190–1193
Behre HM, Simoni M, Nieschlag E (1997) Strong association between serum levels of leptin and testosterone in men. Clin Endocrinol (Oxf) 47:237–240
Belelli D, Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6:565–575
Bleich S, Carl M, Bayerlein K, Reulbach U, Biermann T, Hillemacher T, Bönsch D, Kornhuber J (2005) Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS). Alcohol Clin Exp Res 29:334–336
Bottlender M, Soyka M (2004) Impact of craving on alcohol relapse during, and 12 months following, outpatient treatment. Alcohol Alcohol 39:357–361
Bruchovsky N, Wilson JD (1968) The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro. J Biol Chem 243:2012–2021
Ceylan-Isik AF, McBride SM, Ren J (2010) Sex difference in alcoholism: who is at a greater risk for development of alcoholic complication? Life Sci 87:133–138
Chester JA, Cunningham CL (2002) GABA(A) receptor modulation of the rewarding and aversive effects of ethanol. Alcohol 26:131–143
Davis DL, Russell DW (1993) Unusual length polymorphism in human steroid 5 alpha-reductase type 2 gene (SRD5A2). Hum Mol Genet 2:820
Evren C, Durkaya M, Evren B, Dalbudak E, Cetin R (2012) Relationship of relapse with impulsivity, novelty seeking and craving in male alcohol-dependent inpatients. Drug Alcohol Rev 31:81–90
Faul F, Erdfelder E (1992) GPOWER: a priori, post-hoc, and compromise power analyses for MS-DOS [Computer program]. Bonn University, Dep. of Psychology, Bonn
Ford MM, Nickel JD, Finn DA (2005) Treatment with and withdrawal from finasteride alter ethanol intake patterns in male C57BL/6J mice: potential role of endogenous neurosteroids? Alcohol 37:23–33
Ford MM, Mark GP, Nickel JD, Phillips TJ, Finn DA (2007) Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice. Behav Brain Res 179:265–272
Ford MM, Yoneyama N, Strong MN, Fretwell A, Tanchuck M, Finn DA (2008) Inhibition of 5alpha-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice. Alcohol Clin Exp Res 32:1408–1416
Giwercman YL, Abrahamsson PA, Giwercman A, Gadaleanu V, Ahlgren G (2005) The 5alpha-reductase type II A49T and V89L high-activity allelic variants are more common in men with prostate cancer compared with the general population. Eur Urol 48:679–685
Guardia-Serecigni J, Estorch M, Surkov S, Camacho MDV, García-Ribas G (2011) Multidimensional alcohol craving scale and [123I] lodobenzamide SPECT as predictors of early relapse in alcohol-dependent patients. Adicciones 23:157–164
Han DH, Bolo N, Daniels MA, Lyoo IK, Min KJ, Kim CH, Renshaw PF (2008) Craving for alcohol and food during treatment for alcohol dependence: modulation by T allele of 1519T>C GABAAalpha6. Alcohol Clin Exp Res 32:1593–1599
Higley AE, Crane NA, Spadoni AD, Quello SB, Goodell V, Mason BJ (2011) Craving in response to stress induction in a human laboratory paradigm predicts treatment outcome in alcohol-dependent individuals. Psychopharmacology (Berl) 218:121–129
Hillemacher T, Bleich S, Frieling H, Schanze A, Wilhelm J, Sperling W, Kornhuber J, Kraus T (2007a) Evidence of an association of leptin serum levels and craving in alcohol dependence. Psychoneuroendocrinology 32:87–90
Hillemacher T, Kraus T, Rauh J, Weiß J, Schanze A, Frieling H, Wilhelm J, Heberlein A, Gröschl M, Sperling W, Kornhuber J, Bleich S (2007b) Role of appetite-regulating peptides in alcohol craving: an analysis in respect to subtypes and different consumption patterns in alcoholism. Alcohol Clin Exp Res 31:950–954
Hillemacher T, Weinland C, Heberlein A, Gröschl M, Schanze A, Frieling H, Wilhelm J, Kornhuber J, Bleich S (2009) Increased levels of adiponectin and resistin in alcohol dependence–possible link to craving. Drug Alcohol Depend 99:333–337
Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M, DiLeone RJ (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51:801–810
Hommer DW (2003) Male and female sensitivity to alcohol-induced brain damage. Alcohol Res Health 27:181–185
Janak PH, Michael Gill T (2003) Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose. Alcohol 30:1–7
Kanayama G, Hudson JI, Pope HG Jr (2010) Illicit anabolic-androgenic steroid use. Horm Behav 58:111–121
Kantoff PW, Febbo PG, Giovannucci E, Krithivas K, Dahl DM, Chang G, Hennekens CH, Brown M, Stampfer MJ (1997) A polymorphism of the 5 alpha-reductase gene and its association with prostate cancer: a case-control analysis. Cancer Epidemiol Biomark Prev 6:189–192
Kiefer F, Jahn H, Jaschinski M, Holzbach R, Wolf K, Naber D, Wiedemann K (2001a) Leptin: a modulator of alcohol craving? Biol Psychiatry 49:782–787
Kiefer F, Jahn H, Kellner M, Naber D, Wiedemann K (2001b) Leptin as a possible modulator of craving for alcohol. Arch Gen Psychiatry 58:509–510
Kiefer F, Jahn H, Otte C, Demiralay C, Wolf K, Wiedemann K (2005) Increasing leptin precedes craving and relapse during pharmacological abstinence maintenance treatment of alcoholism. J Psychiatr Res 39:545–551
Kimura M, Higuchi S (2011) Genetics of alcohol dependence. Psychiatry Clin Neurosci 65:213–225
Kornhuber J, Erhard G, Lenz B, Kraus T, Sperling W, Bayerlein K, Biermann T, Stoessel C (2011) Low digit ratio 2D:4D in alcohol dependent patients. PLoS One 6:e19332
Kranzler HR, Edenberg HJ (2010) Pharmacogenetics of alcohol and alcohol dependence treatment. Curr Pharm Des 16:2141–2148
Lakoza GN, Barkov NK (1980) The role of testosterone in the development of experimental alcoholism. Bull Narc 32:41–48
Lamharzi N, Johnson MM, Goodman G, Etzioni R, Weiss NS, Dightman DA, Barnett M, DiTommaso D, Chen C (2003) Polymorphic markers in the 5alpha-reductase type II gene and the incidence of prostate cancer. Int J Cancer 105:480–483
Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang H, Barrera JG, Wilson H, Opland DM, Faouzi MA, Gong Y, Jones JC, Rhodes CJ, Chua S Jr, Diano S, Horvath TL, Seeley RJ, Becker JB, Münzberg H, Myers MG Jr (2009) Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab 10:89–98
Lenz B, Jacob C, Frieling H, Jacobi A, Hillemacher T, Muschler M, Watson K, Kornhuber J, Bleich S (2009) Polymorphism of the long polyglutamine tract in the human androgen receptor influences craving of men in alcohol withdrawal. Psychoneuroendocrinology 34:968–971
Lenz B, Frieling H, Jacob C, Heberlein A, Kornhuber J, Bleich S, Hillemacher T (2010) The modulating effect of the androgen receptor on craving in alcohol withdrawal of men is partially mediated by leptin. Pharmacogenomics J 10:226–231
Lenz B, Heberlein A, Bayerlein K, Frieling H, Kornhuber J, Bleich S, Hillemacher T (2011) The TTTAn aromatase (CYP19A1) polymorphism is associated with compulsive craving of male patients during alcohol withdrawal. Psychoneuroendocrinology 36:1261–1264
Lenz B, Müller CP, Stoessel C, Sperling W, Biermann T, Hillemacher T, Bleich S, Kornhuber J (2012) Sex hormone activity in alcohol addiction: integrating organizational and activational effects. Prog Neurobiol 96:136–163
Li Z, Habuchi T, Mitsumori K, Kamoto T, Kinoshitu H, Segawa T, Ogawa O, Kato T (2003) Association of V89L SRD5A2 polymorphism with prostate cancer development in a Japanese population. J Urol 169:2378–2381
Li X, Huang Y, Fu X, Chen C, Zhang D, Yan L, Xie Y, Mao Y, Li Y (2011) Meta-analysis of three polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and risk of prostate cancer. Mutagenesis 26:371–383
Makridakis N, Ross RK, Pike MC, Chang L, Stanczyk FZ, Kolonel LN, Shi CY, Yu MC, Henderson BE, Reichardt JKV (1997) A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Res 57:1020–1022
Makridakis N, Akalu A, Reichardt JKV (2004) Identification and characterization of somatic steroid 5alpha-reductase (SRD5A2) mutations in human prostate cancer tissue. Oncogene 23:7399–7405
Mellon SH, Griffin LD, Compagnone NA (2001) Biosynthesis and action of neurosteroids. Brain Res Brain Res Rev 37:3–12
Milivojevic V, Kranzler HR, Gelernter J, Burian L, Covault J (2011) Variation in genes encoding the neuroactive steroid synthetic enzymes 5alpha-reductase type 1 and 3alpha-reductase type 2 is associated with alcohol dependence. Alcohol Clin Exp Res 35:946–952
Miller MA, Weafer J, Fillmore MT (2009) Gender differences in alcohol impairment of simulated driving performance and driving-related skills. Alcohol Alcohol 44:586–593
Normington K, Russell DW (1992) Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions. J Biol Chem 267:19548–19554
Paba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M (2011) Steroid 5alpha-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders. Curr Pharm Des 17:151–167
Patte-Mensah C, Kibaly C, Mensah-Nyagan AG (2005) Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: a potential component of nociception. Proc Natl Acad Sci U S A 102:9044–9049
Paz-y-Miño C, Witte T, Robles P, Llumipanta W, Díaz M, Arévalo M (2009) Association among polymorphisms in the steroid 5alpha-reductase type II (SRD5A2) gene, prostate cancer risk, and pathologic characteristics of prostate tumors in an Ecuadorian population. Cancer Genet Cytogenet 189:71–76
Pierucci-Lagha A, Covault J, Feinn R, Nellissery M, Hernandez-Avila C, Oncken C, Morrow AL, Kranzler HR (2005) GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride. Neuropsychopharmacology 30:1193–1203
Pluchino N, Ninni F, Casarosa E, Giannini A, Merlini S, Cubeddu A, Luisi M, Cela V, Genazzani AR (2009) Sex differences in brain and plasma beta-endorphin content following testosterone, dihydrotestosterone and estradiol administration to gonadectomized rats. Neuroendocrinology 89:411–423
Poletti A, Coscarella A, Negri-Cesi P, Colciago A, Celotti F, Martini L (1998a) 5 Alpha-reductase isozymes in the central nervous system. Steroids 63:246–251
Poletti A, Negri-Cesi P, Rabuffetti M, Colciago A, Celotti F, Martini L (1998b) Transient expression of the 5alpha-reductase type 2 isozyme in the rat brain in late fetal and early postnatal life. Endocrinology 139:2171–2178
Prendergast MA (2004) Do women possess a unique susceptibility to the neurotoxic effects of alcohol? J Am Med Womens Assoc 59:225–227
Rajender S, Vijayalakshmi K, Pooja S, Madhavi S, Paul SFD, Vettriselvi V, Shroff S, Singh L, Thangaraj K (2009) Longer (TA)n repeat but not A49T and V89L polymorphisms in SRD5A2 gene may confer prostate cancer risk in South Indian men. J Androl 30:703–710
Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291
Robinson TE, Berridge KC (2000) The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 95(Suppl 2):S91–S117
Rupprecht R, Holsboer F (1999) Neuropsychopharmacological properties of neuroactive steroids. Steroids 64:83–91
Scariano JK, Treat E, Alba F, Nelson H, Ness SA, Smith AY (2008) The SRD5A2 V89L polymorphism is associated with severity of disease in men with early onset prostate cancer. Prostate 68:1798–1805
Schmidt P, Helten C, Soyka M (2011) Predictive value of obsessive-compulsive drinking scale (OCDS) for outcome in alcohol-dependent inpatients: results of a 24-month follow-up study. Subst Abuse Treat Prev Policy 6:14
Schulz KM, Molenda-Figueira HA, Sisk CL (2009a) Back to the future: the organizational-activational hypothesis adapted to puberty and adolescence. Horm Behav 55:597–604
Schulz KM, Zehr JL, Salas-Ramirez KY, Sisk CL (2009b) Testosterone programs adult social behavior before and during, but not after, adolescence. Endocrinology 150:3690–3698
Sinha R, Fox HC, Hong KA, Hansen J, Tuit K, Kreek MJ (2011) Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes. Arch Gen Psychiatry 68:942–952
Sinnott RS, Mark GP, Finn DA (2002a) Reinforcing effects of the neurosteroid allopregnanolone in rats. Pharmacol Biochem Behav 72:923–929
Sinnott RS, Phillips TJ, Finn DA (2002b) Alteration of voluntary ethanol and saccharin consumption by the neurosteroid allopregnanolone in mice. Psychopharmacology (Berl) 162:438–447
Spurdle AB, Hopper JL, Chen X, Dite GS, McCredie MRE, Giles GG, Venter DJ, Southey MC, Purdie DM, Chenevix-Trench G (2001) The steroid 5alpha-reductase type II TA repeat polymorphism is not associated with risk of breast or ovarian cancer in Australian women. Cancer Epidemiol Biomarkers Prev 10:1287–1293
Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW (1993) Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest 92:903–910
Torres JM, Ortega E (2006) Steroid 5alpha-reductase isozymes in the adult female rat brain: central role of dihydrotestosterone. J Mol Endocrinol 36:239–245
Treutlein J, Cichon S, Ridinger M, Wodarz N, Soyka M, Zill P, Maier W, Moessner R, Gaebel W, Dahmen N, Fehr C, Scherbaum N, Steffens M, Ludwig KU, Frank J, Wichmann HE, Schreiber S, Dragano N, Sommer WH, Leonardi-Essmann F, Lourdusamy A, Gebicke-Haerter P, Wienker TF, Sullivan PF, Nöthen MM, Kiefer F, Spanagel R, Mann K, Rietschel M (2009) Genome-wide association study of alcohol dependence. Arch Gen Psychiatry 66:773–784
Trigo JM, Martin-García E, Berrendero F, Robledo P, Maldonado R (2010) The endogenous opioid system: a common substrate in drug addiction. Drug Alcohol Depend 108:183–194
van den Wildenberg E, Wiers RW, Dessers J, Janssen RGJH, Lambrichs EH, Smeets HJM, van Breukelen GJP (2007) A functional polymorphism of the mu-opioid receptor gene (OPRM1) influences cue-induced craving for alcohol in male heavy drinkers. Alcohol Clin Exp Res 31:1–10
Wilbert DM, Griffin JE, Wilson JD (1983) Characterization of the cytosol androgen receptor of the human prostate. J Clin Endocrinol Metab 56:113–120
Yang C, Hamajima N, Iwata H, Saito T, Matsuo K, Hirose K, Inoue M, Takezaki T, Tajima K (2002) A49T, V89L and TA repeat polymorphisms of steroid 5alpha-reductase type II and breast cancer risk in Japanese women. Breast Cancer Res 4:R8
Zhou L, Hammer RP Jr (1995) Gonadal steroid hormones upregulate medial preoptic mu-opioid receptors in the rat. Eur J Pharmacol 278:271–274
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We thank the reviewers for constructive suggestions.
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None of the authors had a financial or personal conflict of interest.
Funding
This work was supported by intramural grants of the University Hospital of the Friedrich-Alexander-University of Erlangen-Nuremberg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Lenz, B., Schöpp, E., Müller, C.P. et al. Association of V89L SRD5A2 polymorphism with craving and serum leptin levels in male alcohol addicts. Psychopharmacology 224, 421–429 (2012). https://doi.org/10.1007/s00213-012-2770-5
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DOI: https://doi.org/10.1007/s00213-012-2770-5