Alcohol & Alcoholism. Vol. 31, No. 2. pp. 175-181. 1996

                           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           great variability of the withdrawal tremors, we estimated the supersensitivity of the withdrawn rats to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           or sham rats did not affect the tremor profile of the alcohol withdrawn rats.

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                 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).


                                                                                  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-

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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

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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 -(



     8 TOO-

          50 -


                      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.


                                                                       •   Non Alcoholized

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                                 ADX                                             SHAM
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

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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. E T. and Prohaska, J. R. (1981) Effect of chronic
ethanol-withdrawn adrenalectomized mice was                          intoxication and naloxone on the ethanol induced
reinstated by a corticosterone treatment. More-                      increase in plasma corticosterone. Life Sciences 28,
over the hydrocortisone treatment of our sham                     Koranyi. L., Endroczi, E., Tal. E. and Levay, G. (1987)
rats did not produce any significant changes in the                  The effect of acute and chronic ethanol administration
harmine-induced tremor.                                              on serum corticosterone concentration in rats. Ada
                                                                     Physiologica Hungarica 69. 123-128.
Acknowledgements — This study was supported by the FNRS           Le Bourhis. B. (1975) Alcoohsation du rat par voie pul-
(FRSM-LN 9.4552.93). the FDS 94 and groupe Lipha. We are             monaire. Comptes rendus des seances de la Societe de
grateful to Dr R. Broechse and H. Huysmans for their technical       Biologie 169, 898-904.
assistance. Many thanks are also due to the Steroids Laboratory   Meert, T. F. (1994) Pharmacological evaluation of alcohol
of Cliniques Umversitaires Saint-Luc. Bruxelles, for their           withdrawal-induced inhibition of exploratory behaviour
advice on steroid dosages.                                           and supersensitivity to harmine-induced tremor. Al-
                                                                     cohol and Alcoholism 29, 91-102.
                                                                  Meert. T. F. and Huysmans, H. (1994) Repeated charac-
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