PERSISTENCE OF DEFECTIVE SEROTONERGIC AND GABAERGIC CONTROLS OF GROWTH HORMONE SECRETION IN LONG-TERM ABSTINENT ALCOHOLICS

Alcohol & Alcoholism Vol. 32, No. 1, pp. 85-90, 1997 PERSISTENCE OF DEFECTIVE SEROTONERGIC AND GABAERGIC CONTROLS OF GROWTH HORMONE SECRETION IN LONG-TERM ABSTINENT ALCOHOLICS P. P. VESCOVI and V. COIRO* Centre for Alcohology, Institute of Internal Medicine, University of Parma, Parma, Italy (Received 22 April 1996; in revised form 29 August 19%; accepted 3 September 1996) Abstract — In order to establish whether long-term abstinence from alcohol reverses the defective serotonergic and GABAergic controls of growth hormone (GH) secretion affecting alcoholic patients, the 5-HT1D serotonergic receptor agonist sumatriptan and the GABAergic agent gamma-hydroxybutyric acid (GHB) were administered to 12 normal men (32-49 years) and 22 non-depressed male alcoholic subjects (38-52 years) after 1-2 years of abstinence from alcohol. All subjects were also tested with placebos. Furthermore, tests with GH-releasing hormone (GHRH) and L-arginine (which releases GH from somatostatin inhibition) were performed to determine whether GH secretion in response to its major determinants is preserved in alcoholics. Administration of placebo did not change plasma GH levels in any subject. Similar GH responses were observed in normal controls and alcoholic subjects when GHRH or arginine were administered. A significant GH increase was observed in normal controls after sumatriptan or GHB injection; in contrast, GH secretion was not modified by sumatriptan or GHB administration in alcoholic patients. These data show a persistent selective loss of 5-HT1D receptor and GHB-mediated neurotransmissions in alcoholics that a long-term abstinence from alcohol is unable to restore. in such studies. We have recently identified defective serotonergic and GABAergic controls of GH secretion in alcoholics during the first 4 weeks of abstinence by using the sumatriptan test and the GHB test as biological indices of abnormal neurotransmission at the hypothalamic pituitary level (Coiro and Vescovi, 1995; Vescovi and Coiro, 1995). Various neurological and neuroendocrine alterations have been observed in alcoholics studied during the first month of alcohol withdrawal. However, many changes appeared to be at least in part reversible after a long period of abstinence. In fact, alterations of hypothalamicpituitary—adrenal axis function and various neuropsychological tests improve after long-term abstinence (Adinoff et al, 1990; Marchesi et al, 1994). In the present study, in order to establish whether alterations in serotonergic and GABAergic control of GH secretion persist in alcoholics after a long period of abstinence, we tested the GH responses to sumatriptan and GHB in 12—24 months abstinent patients. In addition, the same subjects were tested with growth-hormone-releasing hormone (GHRH) and arginine [an inhibitor of INTRODUCTION A variety of studies suggest alterations of serotonergic and gamma-aminobutyric acid (GABA)-ergic function in alcoholism (Sellers et al, 1992; Mhatre and Ticku, 1992); however, the precise mechanisms of these neuroendocrine disorders are still unclear. There are various serotonergic receptor subtypes, which are involved in different ways in mediation of serotonergic neurotransmission (Bloom, 1990). The recent availability of the specific serotonergic 5-HT1D receptor agonist sumatriptan, which selectively stimulates growth hormone (GH) secretion in humans (Rolandi et al., 1992; Herdman et al., 1994), provided the possibility of gaining a better insight into this matter. In addition, the GABAergic agent gammahydroxybutyric acid (GHB), which has been found capable of stimulating growth hormone (GH) secretion in normal human subjects (Takahara et al, 1911; Gerra et al., 1994), could also be utilized 'Author to whom correspondence should be addressed at: Istituto di Oinka Mcdica Generate e Terapia Medica, Via A. Gramsci 14-43100 Parma, Italy. 85 © 1997 Medical Council on Alcoholism 86 P. P. VESCOV1 and V. COIRO somatostatin (Alba-Roth et al, 1988)] to control the activity of the major regulators of GH secretion. MATERIALS AND METHODS Subjects Twenty-two male chronic alcoholics aged 3852 years with a previous history of continuous ethanol consumption of 10.2 + 2.9 years (mean ± SEM), who had been abstinent from alcohol for 12 years as members of a multifamily group, were informed of the purpose of the study and gave their informed consent. The study was in accordance with the Helsinki II Declaration. Clinical assessment All patients were assessed with the Hamilton Rating Scale for Anxiety (HRSA) (Hamilton, 1959) and the Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960). HRSA and HRSD scores (mean + SEM of 22 patients) were 8.0 ±1.0 and 7.0 ± 0.5, respectively. All subjects had normal body weight [body mass index (mean + SEM), 23.0 ± 0.8]. Two physicians performed clinical examination of the patients. Only subjects with normal or slightly altered liver function were included in the study. Particularly, the presence of hepatic abnormalities was assessed with laboratory tests (plasma levels of aspartate transaminase, 43 ± 15 [mean ± SD of 22 patients] UIK; alanine transaminase, 35 ± 14 UIK; gamma-glutamyl transpeptidase, 107 ± 32 U/l) and with liver, spleen, and portal vessel echography. Ultrasound examination and, in unclear cases, biopsy, excluded the presence of cirrhosis. Twelve normal men (aged 32—49 years; body mass index 23.2 ± 1.3) participated in the study as controls. Control and alcoholic subjects showed normal plasma levels of free fatty acids (controls, 0.8 ± 0.075 mmol/1; alcoholics, 0.77 ± 0.08), measured with a colorimetric method using kits provided by Boehringer (Mannheim, Germany). Each subject was tested five times within 4 weeks (sumatriptan, GHB, GHRH, arginine, and placebo tests). Tests were performed in random order at weekly intervals. Experimental procedures The experimental procedure was similar for all tests. At 09:00 on the day of the experiment, i.v. indwelling needles were inserted into antecubital veins of overnight fasting subjects in the recumbent position. The needles were kept patent with a slow infusion of normal saline (NaCl, 0.9% w/v); one needle was used for blood sampling and the other for GHRH, arginine, or saline administration. Sumatriptan was given s.c, whereas GHB was given p.o. In all tests, a basal blood sample was withdrawn 30 min after needle insertion, just before drug administration (time 0). Further blood sampling was performed at 15, 30, 45, 60, 75, 90, 105 and 120 min. The tests were performed as follows. Sumatriptan test: 6mg sumatriptan (Imigran; Glaxo, Verona, Italy) diluted in 0.5 ml distilled water was injected subcutaneously at time 0; GHRH test: 1 ug/kg body weight GHRH (1-29; Geref, Serono, Rome, Italy) diluted in 1 ml normal saline was injected as an i.v. bolus at time 0; arginine test: 30 g arginine monohydrochloride diluted in 50 ml normal saline was infused i.v. over a 30 min period from time 0; GHB test: 25 (...truncated)