Alcohol & Alcoholism. Vol. 31, No. 2. pp. 175-181. 1996 ADRENALECTOMY PROTECTS ETHANOL-WITHDRAWN RATS FROM HARMINE-INDUCED TREMOR F. LAMBLIN, T. F. MEERT 1 and PH. DE WITTE* Universite de Louvain. Laboratoire de Psychobiologie. Place Croix du Sud. 1348 Louvain-la-Neuve. Belgium and 'Janssen Research Foundation. Beerse. Belgium (Received 26 May 1995: in revised form 2 October 1995. accepted 2 November 1995) Abstract — A growing number of studies have implicated the hypothalamic-pituitary-adrenal (HPA) axis in acute and chronic alcoholization and in ethanol withdrawal. In order to study the ethanol/HPA axis interaction during alcohol withdrawal, we performed experiments using adrenalectomized (ADX) male rats alcoholized by a chronic pulmonary alcoholization procedure. Eight hours after the 3 weeks of the alcoholization procedure, the rats were evaluated for a tremor activity In order to reduce the great variability of the withdrawal tremors, we estimated the supersensitivity of the withdrawn rats to the tremorogenic compound harmine. We also studied the effect of a hydrocortisone treatment given in the drinking bottle during the alcoholization procedure on the harmine-induccd tremors of ADX and sham rats. Alcohol withdrawal resulted in increased tremor response to 10 mg/kg harmine, and a protective effect of adrenalectomy on this effect was observed. Hydrocortisone administration to ADX or sham rats did not affect the tremor profile of the alcohol withdrawn rats. Downloaded from alcalc.oxfordjournals.org by guest on October 10, 2011 INTRODUCTION (Koranyi et al., 1987). Some studies underline the persistence of an enlarged HPA axis activity Acute or chronic ethanol administration to exper- (Ellis, 1966; Tabakoff et al., 1978; Wilkins et al., imental animals and man alters the activity of the 1992) while other studies show a tolerance devel- hypothalamic-pituitary-adrenocortical (HPA) opment of the corticosterone response to ethanol axis. Thus acute exposure to alcohol produces a (Knych and Prohaska, 1981; Spencer and potent activation of the HPA axis marked by an McEwen, 1990). Alcohol intoxication also led to increased plasma glucocorticoid level in rodents disturbance of the normal diurnal variation of (Ellis. 1966; Kakihana et al., 1971: Tabakoff et plasma glucocorticoids in rodents (Kakihana and al., 1978; Pohorecky et al., 1980) and in man Moore, 1976) and humans (Adinoff et al., 1991) (Jenkins and Connolly, 1968; Thiagarajan et al., during chronic alcoholization and during alcohol 1989). This adrenal response is dependent upon an withdrawal. The corticosterone (rodent) or cor- increased pituitary adrenocorticotropic hormone tisol (man) concentration perturbations consisted (ACTH) secretion (Ellis, 1966) which is stimu- of a shortening in the length of the cyclic secre- lated by the corticotropin-releasing factor (CRF) tions. Also an increased adrenal weight of up to from the hypothalamus (Rivier et al., 1984). In 25% and a thymus involution are observed after vitro, a direct stimulatory effect of acute ethanol chronic alcohol intoxication (Spencer and was also evaluated on the hypothalamus, the pitu- McEwen, 1990). itary gland and the adrenal ccrtex but the outcome Alcohol abstinence is accompanied by of the studies varied depending on the experi- increased plasma glucocorticoids in rodents ments used (Wand, 1993). (Tabakoff et al., 1978; Roberts et al., 1992; The effects of chronic alcoholization on the Wilkins et al., 1992) and man (Adinoff et al., HPA axis seem to be controversial. The plasma 1991). The glucocorticoids reach peak values on corticosterone concentration changes vary accord- the first day of alcohol withdrawal when ethanol ing to the alcoholization procedure, even if a is no longer detectable in the blood. This increased similar blood ethanol concentration is reached HPA axis activity coincides with the behavioural and physiological symptoms of the withdrawal syndrome (Tabakoff et al., 1978; Adinoff et al., 'Author to whom correspondence should be addressed. 1991). 175 1996 Medical Council on Alcoholism 176 F LAMBLIN el al. Corticosterone administration was demonstra- alcoholized sham + hydrocortisone, and the non- ted to increase ethanol withdrawal symptoms alcoholized sham group. (Roberts et al., 1991). Adrenalectomy decreased Hydrocortisone (Solu-cortef, Upjohn) was the incidence of withdrawal seizures in animals. given per os in the drinking bottle (85 mg/1) during In mice the functional protective effect of adren- the whole alcoholization procedure at a daily dose alectomy was present in terms of a reduced sen- of 2.5 mg/rat. The hydrocortisone solution was sitivity to audiogenic seizures during ethanol replaced every 2 days and the drinking bottle was withdrawal (Sze et al., 1974; Sze, 1977). sheltered from light. The rats' intake was assessed In the present study, adrenalectomized (ADX) to ensure a constant drug administration. The rats were used to examine the involvement of hydrocortisone treatment was stopped at the end the HPA axis in the alcohol withdrawal-induced of the alcoholization period. tremors. More precisely, following chronic etha- nol inhalation, we analysed the sensitivity of the Chronic alcohol administration animals to alcohol withdrawal-induced tremors in For alcoholization, rats were individually adrenalectomized rats and in adrenalectomized housed in standard rodent living cages, placed in rats treated with hydrocortisone. Because with- an isolated plastic chamber (160 x 60 x 60 cm). drawal-induced tremor is very variable between The chamber was equipped with a mixing system animals over time (Meert and Huysmans, 1994), able to pulse alcohol and air mixtures into the we decided to characterize the supersensitivity of chamber. The quantity of alcohol was gradually withdrawal by injecting subthreshold doses of the increased every 2 days during the whole exper- Downloaded from alcalc.oxfordjournals.org by guest on October 10, 2011 tremorogenic agent harmine, a beta-carboline imental procedure from 0 to 25 mg/1 (Le Bourhis, (Gothoni, 1985; Meert et al., 1992). Alcohol-with- 1975). The rats were kept for a total of 20 days in drawn rats have been demonstrated to be super- the alcoholization chamber. sensitive to the tremorogenic efficacy of this compound at low doses (Meert, 1994). Blood ethanol determination The blood alcohol levels of control and treated MATERIALS AND METHODS rats were regularly determined (between 08:00 and 10:00) during the alcoholization procedure. Animals To do so, samples of plasma (0.1ml) obtained Male Wistar rats weighing 150 g at the start of from blood sampling in the caudal portion of the experiments were used. The rats were separated tail were analysed by an alcohol dehydrogenase- into two groups: an ADX group and a sham group. based method (Boehringer Mannheim kit). For the operation, the rats were anaesthetized with chloral hydrate (400mg/l00g body weight). Tremor measurement Bilateral adrenalectomy was performed by means The apparatus used has been described in detail of two dorsal incisions. Sham surgery consisted of by Meert et al. (1992). Briefly the apparatus bilateral incisions, and localization of the adrenal consisted of four test cages in plexiglass glands without extraction. Following surgery, all (25 x 24 x 25 cm). The floor consisted of a flex- animals were supplied with a 1% (w/v) saline ible plexiglass plate (45 x 23 x 0.6 cm) upon four solution as drinking fluid. Completeness of ADX corners so that it could bend freely. Underneath was verified at the end of the experiment by the middle of the plate, two pieces of piezo-film radioimmunoassay (RIA, Becton Dickinson (200 x 100 x 0.025 mm, polymeric PVF2) were Immunodiagnostics: Cortisol Solid Phase Radio- glued and connected with an amplifier, so that the immunoassay [I25I]. deformations of the cage floor result in a piezo- electric response of each of the piezo-films. These Experimental treatment electric signals are first summed by one differential The ADX and sham groups were subdivided so amplifier and the output of the signal is then as to obtain six experimental groups: the chronic filtered by a bandpass filter between 6 and 12 Hz alcoholized ADX. the chronic alcoholized (18 db/oct slope). This end signal is sent to a ADX + hydrocortisone, the non-alcoholized 4-channel Mac Lab connected to a Macintosh II ADX, the chronic alcoholized sham, the chronic computer. A chart file enables quantification of ADRENALECTOMY AND ETHANOL WITHDRAWAL TREMORS 177 the amplitude and frequencies of the pulses. Two pulses were judged comparable if: (1) the ampli- Statistical analysis tude of both pulses was 3=1 V; (2) the difference The Mann-Whitney IMest (two-tailed) was between the two pulses was <50%; (3) the inter- used to evaluate differences between experi- pulse interval was between 6 and 12 Hz. The selec- mental groups. tion of these parameters was based on the assumption that bursts of tremor activity produce RESULTS a relatively constant bending of the cage floor, resulting in relatively constant output signals. A The ADX rats were more sensitive to chronic series of five comparable pulses resulted in one alcohol intoxication than the corresponding sham tremor count. Data are presented in terms of the controls. Indeed, eleven out of eighteen ADX mean (±SEM) number of tremor counts. animals died during the alcoholization and one The test procedure used to assess the super- during the withdrawal. In the sham group sensitivity to harmine-induced tremor consisted of (n = 9), only one rat died during the alcohol a subcutaneous injection of 5 mg/kg of harmine intoxication. The sensitivity of the ADX rats for (1 ml/100 g body wt) to individually-housed rats. alcoholization was also reflected in the average Five minutes later, the rats were placed into a test body weight at the end of the experiments. The cage and activity was measured for 5 min. Directly mean (±SEM) body wt of the ADX and sham after this session, the same animals received a groups were respectively 213 ± 8 and 307 ± 12 g. second injection of 5 mg/kg harmine (resulting in Compared to the preoperative starting level, this Downloaded from alcalc.oxfordjournals.org by guest on October 10, 2011 a cumulative dose of 10 mg/kg, as referred to in represents an increase of 63 and 157 g respect- the results). After 5 min, a second 5 min recording ively. In the hydrocortisone-treated ADX group was performed. After each measurement, the test (n = 10), one ADX died during the alcoholization cages were cleaned. Based on earlier studies, an and two during the withdrawal. No death was alcohol withdrawal period of 8 h was used to assess observed in the hydrocortisone alcoholized sham the supersensitivity to harmine-induced tremor group (n = 9), nor in both the unalcoholized (Meert et a/., 1992; Meert and Huysmans, 1994). groups (n = 5 each). 200 -( O) 150- o 8 TOO- ADX ADX+Hydrocort. 50 - SHAM SHAM+Hydrocort. Days Fig. 1. Blood alcohol levels in sham and adrenalectomized rats. Some sham and adrenalectomized rats were treated with hydrocortisone orally. Blood samples were analysed from day 12 after the start of the chronic alcoholization. 178 F. LAMBLIN et al. Alcoholized AIcoholization+Hydrocort. • Non Alcoholized Downloaded from alcalc.oxfordjournals.org by guest on October 10, 2011 ADX SHAM Group Fig. 2. Effects of adrenalectomy and hydrocortisone treatment on the alcohol withdrawal-induced supersensitivity to lOmg/kg harmine. Data are the means (±SEM) of tremor counts of sham (n = 5) and ADX (n = 5) non-alcoholized (open bars), sham (« = 8) and ADX (n = 6) alcoholized rats (solid bars), and sham (n = 9) and ADX (n = 8) alcoholized and treated with hydrocortisone (hatched bars). Differences were evaluated with the Mann-Whitney l/-test (two tailed * P < 0 05- **P< 0.005; ***P< 0.001). Blood alcohol levels (BAL) were assessed (P < 0.005) and from all the ADX groups (sham/ repeatedly over time in order to quantify the alcoholized ADX P < 0.005; sham/ADX alcohol- alcoholization procedure and to detect differences ized and treated with hydrocortisone P < 0.005; in the BAL between groups (Fig. 1). There were sham/unalcoholized ADX P< 0.001). The no differences in the BAL values between the four tremor level of the hydrocortisone sham rats was alcoholized groups. The within-group variations intermediate between the alcoholized (P > 0.05) were important and are not shown. At the end of and the unalcoholized sham animals (P>0.05). the alcoholization period, mean blood alcohol The ADX groups had the lowest tremor counts. levels of 148 ± 65 mg/dl were reached. There were no significant differences between the The sensitivity of the rats during alcohol with- three ADX groups (for each comparison, drawal to a tremorogenic compound was evalu- P > 0.05). The alcoholized ADX rats did not show ated by the injection of harmine (5 and 10 mg/kg) a greater tremor activity than the corresponding into rats out of the alcoholization chamber for 8 h. unalcoholized group. Therefore, the hydrocor- There were no significant differences between the tisone treatment appears not to modify the sen- various groups after 5 mg/kg harmine (P > 0.05). sitivity to the harmine-induced tremor. However, after 10 mg/kg harmine administration, significant differences were present. Thus, as shown in Fig. 2, the alcoholized sham rats DISCUSSION appeared more sensitive to the harmine-induced A growing number of studies implicated the tremor than all the other groups. Their increased involvement of the HPA axis in acute and chronic tremor activity made this group significantly dif- alcoholization and in ethanol withdrawal. In order ferent from the unalcoholized sham rats to study the alcohol/HPA axis interaction, we ADRENALECTOMY AND ETHANOL WITHDRAWAL TREMORS 179 performed a series of experiments using adren- review, see Walker et al., 1993). Furthermore, alectomized male rats. The adrenalectomy makes chronic alcohol exposure stimulates these animals more sensitive to the chronic pul- glucocorticoid secretion. Based on these obser- monary alcoholization as shown by the severe vations, it could be hypothesized that the in- mortality rate of ADX and body weight changes creased glucocorticoid concentration following during chronic alcohol exposure. chronic alcoholization may be responsible, at least Alcohol withdrawal results in a series of pheno- in part, for the enlarged hippocampal neuronal mena, including some tremorogenic activity. In death, as for instance seen during hippocampal order to decrease the intra-group variability of damage after insults such as by hypoxic-ischaemia. the withdrawal-induced tremor, we quantified the If the neuronal hippocampal damage is implicated tremorogenic state of the animals by injecting low in some ethanol withdrawal symptoms such as doses of the tremorogenic compound harmine. tremors, adrenalectomy may present an effective Gothoni (1985) reported an increased harmine- protection towards ethanol withdrawal-induced induced tremor intensity following alcohol with- tremor. This is, at least in our experiments, con- drawal. Meert et al. (1992) confirmed this potenti- firmed in terms of supersensitivity to tremorogenic ation of the tremorogenic properties of harmine agents. Further experiments are needed to fully after withdrawal of a liquid diet containing alcohol clarify this issue. (10%, v/v). Our results confirm the use of A second explanation may be found in the fact 10 mg/kg harmine during withdrawal as a tool to that adrenalectomy and glucocorticoid adminis- induce tremor in alcoholized sham rats after being tration may act by a direct interaction with Downloaded from alcalc.oxfordjournals.org by guest on October 10, 2011 intoxicated by inhalation of ethanol vapour for 3 harmine, so reducing the tremorogenic activity of weeks. this compound. The variation in concentration of The ADX rats failed to show an increased glucocorticoid hormones induces modifications of tremor activity upon the injection of 10 mg/kg different neuromediators. Adrenalectomy and harmine. ADX thus appears to overcome the glucocorticoid administration in rodents and in supersensitivity to tremorogenic agents during humans modify dopaminergic (DA) and sero- ethanol withdrawal. A protective effect of adren- tonergic (5-HT) functions (Rothschild et al., alectomy has previously been observed against 1984; Biegon etal., 1985; Wolkowitz et al., 1986; audiogenic seizures upon ethanol withdrawal in Bagdy et al., 1989; Faunt and Crocker, 1989; mice (Sze et al., 1974; Sze, 1977). Biron et al., 1992). Because harmine provokes a There are several ways to explain the protective DA/5-HT imbalance, suggesting a direct impli- effects of ADX on alcohol withdrawal. The cation of these neurotransmitter mechanisms in reduction of the ethanol withdrawal symptoms some of the ethanol withdrawal symptoms (Meert after bilateral adrenalectomy might for instance et al., 1992), a direct pharmacological interaction be explained in terms of a protection towards with the activity of harmine cannot be excluded hippocampal neuronal loss induced by chronic as well as alteration of the hepatic metabolism alcoholization. As a result, there can be a of harmine by glucocorticoids. More studies are reduction in alcohol withdrawal-induced tremor. needed to clarify these ethanol/DA/5-HT/ The hippocampus is the principal target for neur- glucocorticoid linkages during alcohol with- onal loss induced by insults such as seizures or drawal. hypoxic ischaemia in man (Zola-Morgan et al., Surprisingly, hydrocortisone given during the 1986; Petitoe/a/., 1987) and in rodents (Ho et al., alcoholization procedure to the ADX rats did not 1975; Kirino, 1982). This hippocampal neuronal affect the harmine-induced tremor. The hydro- death appears to be exacerbated by glucocorticoid cortisone supplement given to rats with an intact over-exposure in rodents (Sapolsky and Pulsinelli, functional HPA axis produced a small, but insig- 1985; Sapolsky, 1990; Morse and Davis, 1990; nificant, decrease in the tremor counts. This lack Packan and Sapolsky, 1990) and ameliorated by of effect of hydrocortisone may be caused by the adrenalectomy (Sapolsky et al., 1985; Sapolsky, incomplete or absent transformation of hydro- 1986; Stein and Sapolsky. 1988). Chronic alcohol- cortisone to corticosterone, the main circulating ization has been demonstrated to result in a pro- glucocorticoid in rats. An alternative explanation found damage of hippocampal neurons (for of the absence of action of hydrocortisone is that 180 F. LAMBLIN el al. it requires the integration of the HPA axis to exert P. (1971) Adrenalocortical response to ethanol in mice. its action. This latter proposition, however, seems Ada Endocrinologia 67, 653-664. Kirino. T. (1982) Delayed neuronal death in the gerbil unlikely taking the results of Sze et al. (1974) and hippocampus following ischemia. Brain Research 239. Sze (1977) into account. These authors observed 57-69. that the susceptibility to audiogenic seizures of Knych. 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