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Increases Plasma Concentrations of the Neuroactive Steroid 3A,5A Tetrahydrodeoxycorticosterone (3A,5A-THDOC) in Healthy Volunteers

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Increases Plasma Concentrations of the Neuroactive Steroid 3A,5A Tetrahydrodeoxycorticosterone (3A,5A-THDOC) in Healthy Volunteers Neuropsychopharmacology (2005) 30, 192–195 & 2005 Nature Publishing Group All rights reserved 0893-133X/05 $30.00 www.neuropsychopharmacology.org Panic Induction with Cholecystokinin-Tetrapeptide (CCK-4) Increases Plasma Concentrations of the Neuroactive Steroid 3a,5a Tetrahydrodeoxycorticosterone (3a,5a-THDOC) in Healthy Volunteers 1 2 1 2 1 1 Daniela Eser , Flavia di Michele , Peter Zwanzger , Augusto Pasini , Thomas C Baghai , Cornelius Schu¨le , ,1 2 Rainer Rupprecht* and Elena Romeo 1 2 Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany; Tor Vergata University, IRCCS Santa Lucia, Rome, Italy 3a-reduced neuroactive steroids such as 3a,5a-tetrahydroprogesterone (3a,5a-THP) and 3a,5a-tetrahydrodeoxycorticosterone (3a, 5a-THDOC) are potent positive allosteric modulators of g-aminobutyric acid type A (GABAA) receptors and display pronounced anxiolytic activity in animal models. Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) and sodium lactate is accompanied by a decrease in 3a,5a-THP concentrations in patients with panic disorder, but not in healthy controls. However, no data are available on 3a,5a-THDOC concentrations during experimental panic induction. Therefore, we quantified 3a,5a-THDOC concentrations in 10 healthy volunteers (nine men, one woman) before and after panic induction with CCK-4 by means of a highly sensitive and specific gas chromatography/mass spectrometry analysis. CCK-4 elicited a strong panic response as assessed by the Acute Panic Inventory. This was accompanied by an increase in 3a,5a-THDOC, ACTH and cortisol concentrations. This increase in 3a,5a- THDOC might be a consequence of hypothalamic–pituitary–adrenal (HPA) axis activation following CCK-4-induced panic, and might contribute to the termination of the anxiety/stress response following challenge with CCK-4 through enhancement of GABA receptor A function. Neuropsychopharmacology (2005) 30, 192–195, advance online publication, 29 September 2004; doi:10.1038/sj.npp.1300572 Keywords: neurosteroids; neuroactive steroids; anxiety; CCK-4; panic INTRODUCTION First investigations in panic disorder patients in the absence of panic attacks have demonstrated increased 3a-reduced neuroactive steroids such as 3a,5a-tetrahydro- plasma concentrations of 3a-reduced neuroactive steroids progesterone (3a,5a-THP), 3a,5b-THP and 3a,5a- (Strohle et al, 2002; Brambilla et al, 2003), while the tetrahydrodeoxycorticosterone (3a,5a-THDOC) (Figure 1) concentrations of 3b,5a-tetrahydroprogesterone (3b,5a- have been identified as potent positive allosteric modulators THP), a stereoisomer of 3a,5a-THP, which may act as an of g-aminobutyric acid type A (GABA ) receptors (Paul and A antagonist for GABA agonistic steroids (Rupprecht and Purdy, 1992; Rupprecht and Holsboer, 1999; Rupprecht, Holsboer, 1999), were decreased (Strohle et al, 2002). 2003; Lambert et al, 1995). In line with their GABA- However, during panic induction with sodium lactate or enhancing potential, a pronounced anxiolytic activity has 25 mg cholecystokinin-tetrapeptide (CCK-4), a marked been shown for 3a-reduced neuroactive steroids in various decrease in plasma levels of the 3a-reduced GABA agonistic animal studies (Paul and Purdy, 1992; Rupprecht and neuroactive steroids 3a,5a-THP and 3a,5b-THP was found, Holsboer, 1999; Rupprecht, 2003). which was accompanied by a pronounced increase in the functional antagonistic isomer 3b,5a-THP in patients with panic disorder (Strohle et al, 2003). *Correspondence: Dr R Rupprecht, Department of Psychiatry, In contrast, no changes in neuroactive steroid concentra- Ludwig-Maximilian-University, Nussbaumstr.7, 80336 Munich, Germany, tions could be observed during experimental panic induc- Tel: þ 49 89 5160 2770, Fax: þ 49 89 5160 5524, E-mail: [email protected] tion with sodium lactate or CCK-4 in healthy controls Received 9 February 2004; revised 22 June 2004; accepted 16 August (Strohle et al, 2003). However, panic induction with 25 mg 2004 CCK-4 was far less pronounced in healthy controls than in Online publication: 18 August 2004 at http://www.acnp.org/citations/ patients with panic disorder (Strohle et al, 2003). To rule Npp08180404061/default.pdf out the possibility that the difference in neuroactive steroid Neuroactive steroid concentrations after panic induction D Eser et al 193 any personal or family history of psychiatric illness. Somatic diseases were ruled out by means of physical examination, electrocardiogram, electroencephalogram, and routine laboratory testing, including hematological screen- ing, blood chemistry with glucose, total protein, total bilirubin, liver enzymes, electrolytes, creatinine, urea, uric acid, cholesterol, triglycerides, semiquantitative urinalysis, and thyroid hormones. Any intake of drugs was ruled out by urine toxicology screening at least 4 weeks prior to baseline screening. The protocol was approved by the local ethical committee. After a complete description of the study, all subjects gave their written informed consent. CCK-4 Challenge Procedure Subjects were studied in a supine position in a soundproof room. At 1000 h, 50 mg CCK-4 (Clinalfa, La¨ufelfingen, Figure 1 Biosynthesis of neuroactive steroids. 5a-DHDOC: 5a- Switzerland) was given as an intravenous bolus injection. dihydrodeoxycorticosterone, 21-hydroxy-5a-pregnane-3,20 dione; 5a- Panic symptoms were assessed with the Acute Panic DHP: 5a-dihydroprogesterone, 5a-pregnane-3,20 dione; 3a,5a-THDOC: Inventory (API) (Dillon et al, 1987) at baseline and 5, 10, 3a,5a-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone, 3a, 21-dihydroxy-5a-pregnan-20-one; 3a,5a-THP: 3a,5a-tetrahydropro- and 20 min after CCK-4 injection. gesterone, allopregnanolone, 3a-hydroxy-5a-pregnan-20-one; 3b,5a-THP: 3b,5a-tetrahydroprogesterone, isopregnanolone, 3b-hydroxy-5a pregnan- 20-one. Quantification of Neuroactive Steroids, Cortisol, and ACTH composition between patients with panic disorder and controls just reflects the level of anxiety, 3a,5a-THP, 3a,5b- Blood samples were taken at baseline and 10 and 20 min THP, and 3b,5a-THP were analyzed in a follow-up study in after CCK-4 injection for quantification of 3a,5a-THDOC, healthy volunteers after panic induction with 50 mg CCK-4, cortisol, and ACTH. Plasma cortisol was measured using a which yields the same level of anxiety as 25 mg CCK-4 commercial radioimmunoassay kit (Cortisol RIA, DPC in patients with panic disorder (Zwanzger et al, 2004). Biermann, Germany) with a lower detection limit of However, these neuroactive steroids were not affected by 8.27 nmol/l. For ACTH determination, a commercial im- panic induction with 50 mg CCK-4 in this study either munoradiometric assay (ACTH 100T Kit, Nichols Institute (Zwanzger et al, 2004). Diagnostics, USA) with a sensitivity of 0.11 pmol/l was Therefore, the observed changes in neuroactive steroid employed. Intra- and interassay coefficients of variation concentrations in patients with panic disorder during were below 5%. experimental panic induction might represent a panic Blood samples were quantified for levels of 3a,5a- associated failure to obtain homoeostasis of endogenous THDOC by means of a highly sensitive and specific neuroactive steroids. combined GC/MS analysis extraction with ethyl acetate as 3a,5a-THDOC is mainly formed in the adrenal gland, but described previously (Strohle et al, 2000, 2003). A Finning- also in the central nervous system (Purdy et al, 1991; Reddy, ham Trace GC/MS equipped with a capillary column was 2003). This peripherally secreted neuroactive steroid (Red- used to analyze the derivatized steroids in the negative ion dy and Rogawski, 2002; Reddy, 2003; Purdy et al, 1991) and chemical ionization mode. The detection limit was approxi- its precursor deoxycorticosterone (DOC) (Barbaccia et al, mately 10 fmol. 1996) increase following acute stress and may counteract the anxiety and neuroendocrine consequences of maternal Statistical Analysis separation (Patchev et al, 1997). While various studies show an increase in ACTH and cortisol secretion following Results are expressed as mean7SEM. For statistical analysis challenge with CCK-4 (Koszycki et al, 1998; Zwanzger of 3a,5a-THDOC, cortisol and ACTH concentrations at et al, 2003), no data are available on 3a,5a-THDOC levels baseline and 10 and 20 min after CCK-4 injection, a during experimentally induced panic in humans. Therefore, multivariate analysis of variance (MANOVA) with time as we quantified plasma 3a,5a-THDOC concentrations before within-subject factor was performed. Alpha ¼ 0.05 was set and after challenge with 50 mg CCK-4 in healthy volunteers, as the nominal level of significance. In case of a significant using a highly sensitive and specific gas chromatography/ time effect, univariate F-tests were used to identify those mass spectrometry (GC/MS) analysis. parameters that contributed significantly to this effect. Post hoc comparisons of multiple time points were made by t- tests for paired samples. To keep the type I error equal to METHODS 0.05, all post hoc tests were performed at a reduced level of Subjects significance (alpha adjusted according to Bonferroni procedure). Correlations between psychopathological para- A total of 10 healthy volunteers (nine males, one female; meters and 3a,5a-THDOC, cortisol, and ACTH concentra- mean age 2972 years) were studied. Subjects were free of tions were estimated by Pearson’s correlation coefficient. Neuropsychopharmacology Neuroactive steroid concentrations after panic induction D Eser
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