EFFECT OF ADRENALECTOMY AND EXPOSURE TO CORTICOSTERONE ON ALCOHOL INTAKE IN ALCOHOL-PREFERRING AND ALCOHOL-AVOIDING RAT LINES

Claudia Fahlke* and C. J. Peter Eriksson1

Department of Psychology, Göteborg University, Box 500 SE - 405 30 Göteborg, Sweden and
1 Department of Mental Health and Alcohol Research, National Public Health Institute, POB 719, FIN-00101, Helsinki, Finland

Received 15 May 1999; in revised form 20 September 1999; accepted 5 October 1999


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
— The daily fluid intake of male rats of the alcohol-preferring (AA) and alcohol-avoiding (ANA) lines with simultaneous access to 10% (v/v) ethanol and water was determined during a baseline period (2 weeks), following adrenalectomy (1 week), and for 2 weeks following corticosterone treatment. The results showed that adrenalectomized AA rats decreased their ethanol intake compared to the sham-operated AA controls and that treatment with corticosterone restored the intake of ethanol to that observed during the baseline period. In contrast to the AA rats, there were no alterations in ethanol intake after adrenalectomy and following corticosterone replacement in the ANA rats. These results suggest that corticosterone stimulates ethanol intake in animals with pronounced high preference for ethanol.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
A number of studies have shown that the adrenal steroid hormone corticosterone plays a significant role in the modulation of alcohol consumption in an unselected population of rats (for review see Hansen et al., 1994). It has been shown that surgical (Morin and Forger, 1982Go; Fahlke et al., 1994aGo; Lamblin and De Witte, 1996Go) or drug-induced (Fahlke et al., 1994bGo; Hansen et al., 1995Go) adrenalectomy attenuate voluntary ethanol intake and that short-term treatment with corticosterone reverses these effects (Fahlke et al., 1994aGo, bGo). Long-term treatment of adrenalectomized animals with daily substitution of corticosterone enhances ethanol intake to levels above those normally observed in intact animals of our strain (Fahlke et al., 1995Go). Furthermore, states associated with enhanced corticosterone secretion, such as food restriction, increase alcohol intake, and this effect is corticosterone dependent (Hansen et al., 1995Go). Fahlke et al. (1996) recently found that corticosterone facilitates alcohol drinking by exposing only the brain to corticosterone. Thus, intracerebroventricular infusions of corticosterone restore ethanol intake in adrenalectomized animals to levels indistinguishable from intact animals. Moreover, in a recent study, we found that corticosterone implants in the ventral striatum increase voluntary ethanol consumption (Fahlke and Hansen, 1999Go). Taken together, these findings suggest that corticosterone facilitates alcohol intake in an unselected population of rats.

By selective breeding for high or low voluntary alcohol intake, two rat lines, alcohol-preferring (AA) and alcohol-avoiding (ANA), have been developed at the Biomedical Research Center of Alko Ltd, Helsinki, Finland (Eriksson, 1968Go, 1971Go; Hilakivi et al., 1984Go). A series of investigations has been devoted to search for physiological differences between the two lines potentially contributing to the differential intake of ethanol. These studies included investigations of neurochemical, metabolic, and behavioural parameters (Sinclair et al., 1989Go; Kiianmaa et al., 1991Go).

In view of the suggested relationship between corticosterone and alcohol intake, the present study examined if genetic lines of rats with high and low ethanol intake respond to manipulations of the hypothalamic–pituitary–adrenal (HPA) axis. Thus, using the AA and ANA rats, we investigated the effects of adrenalectomy and subsequent treatment with corticosterone on voluntary alcohol intake.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects and familiarization with alcohol
Animals were 19 males from the Alco AA rat line, and 19 males from the ANA line of generation F58. The rats were maintained in stainless-steel wire cages (4–5 rats per cage) with free access to food (standard powdered EWOS R3 rat diet, Södertälje, Sweden) from glass jars and tap water in graduated 100-ml Richter tubes. The animal facilities had a room temperature of 22°C, a relative humidity of 55%, and a 12-h light–12-h dark cycle with lights on at 06:00–18:00.

At the time of the experiment, the animals were about 3 months of age and were placed individually in the stainless-steel wire cages. Initially, for a habituation period of 10 days, animals had 10% (v/v) ethanol solution as the sole drinking fluid (Richter tubes). After this habituation, they were given a choice between water and 10% ethanol solution for a further 2-week period. Fluid intake was measured daily and the bottles were cleaned and refilled with fresh beverages twice a week. On the basis of their ethanol intake (expressed as g/kg/day of absolute ethanol) and ethanol preference (i.e. proportion of ethanol solution intake relative to total fluid consumption as a percentage) during this period, the animals were assigned to matching groups and taken for surgery. Body weight and food intake were recorded once a week for all animals throughout the experiment.

Adrenalectomy and corticosterone treatment
The animals were subjected to adrenalectomy (AA, n = 10; ANA, n = 10) or sham surgery (controls; AA, n = 9, ANA, n = 9). Rats were anaesthetized with sodium metohexital (Brietal, Lilly; 100 mg/kg, i.p.) and the adrenal glands were removed through bilateral flank incisions. Control animals underwent the same treatment, except that the adrenal glands were left in situ. The rats regained consciousness in a warm (32°C) incubator, and were then replaced in their home cages, which were equipped with a NaCl pellet fastened to a wire hanging down from the cage top. Intake of fluids was recorded daily for 1 week following surgery.

Corticosterone (purchased from Sigma, Aldrich, Sweden) was administered to the adrenalectomized AA and ANA rats by dissolving corticosterone in equal amounts (25 mg/1000 ml fluid) in each of the drinking fluids presented to the animals (a dose of approximately 2.6 mg/kg/day; for method see Akana et al., 1985 and Fahlke, 1994). The remaining two groups (AA and ANA controls) served as controls for the corticosterone treatment. Intake of fluids was recorded daily for a further 2-week period.

Hormonal assay
To verify the removal of the adrenal glands, assessment of plasma levels of corticosterone was performed. Blood samples were collected from each rat at the end of the three different phases (baseline, adrenalectomy, and corticosterone treatment) of the experiment. Blood samples were taken 3 to 6 h after lights were switched on by tail nicking while the rats were briefly restrained in a wooden box. The blood samples (100–200 µl) were collected in heparinized test tubes and the blood was separated by centrifugation for 5 min at 1500 rpm. The plasma was collected and stored at –70°C until the levels of corticosterone were estimated with radioimmunoassay, using kits supplied by ICN Biomedicals (Carson, CA, USA).

Statistics
Because the distribution of ethanol intake is too skewed to permit statistical testing with parametric tests, non-parametric methods were used in the statistical treatment of the data (StatView, Abacus software) and results are presented as median ± median absolute deviation (MAD). For each individual, the average intakes of fluids (ethanol or water) and food during the different periods (baseline, adrenalectomy, first and second weeks of corticosterone treatment) of the experiment were computed. Differences in average fluids or food consumption between two phases (baseline vs adrenalectomy) and adrenalectomy vs week 1 or week 2 of corticosterone replacement) were calculated for each rat. Groups were compared on the basis of these difference scores by the Mann–Whitney U-test. Within-group comparisons were analysed with the Wilcoxon matched-pairs signed-ranks test. Two-tailed levels of significance were used.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
AA animals
Figure 1Go shows that the two groups were comparable with regard to ethanol intake (upper panel) and ethanol preference (lower panel) during the baseline period. Adrenalectomized rats drank less ethanol (U = 6, P < 0.01; Fig. 1Go, upper panel) and had a lower ethanol preference (U = 0, P < 0.001; Fig. 1Go, lower panel) compared to the control rats. Total fluid intake was enhanced in adrenalectomized rats compared to controls (U = 15, P < 0.05; Table 1Go), due to the greatly enhanced water intake (U = 0, P < 0.001; Table 1Go).



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Fig. 1. Alcohol intake and preference by alcohol-preferring (AA) rats before and after adrenalectomy and subsequent corticosterone supplementation. Data are given as median ± MAD (bars) intake in absolute ethanol, offered as a 10% solution (upper panel), and ethanol preference (% of total fluid intake; lower panel) during a 2-week baseline period (adrenally intact), 1 week following adrenalectomy (ADX; n = 10) or sham surgery (n = 9), andfollowing 2 weeks of exposure to corticosterone (CORT). *P < 0.05; **P < 0.01; ***P < 0.001 (Mann–Whitney U-test).

 

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Table 1. Body weights and food, water, and total fluid intakes by alcohol-preferring rats before and after adrenalectomy and subsequent corticosterone supplementation
 
Ethanol intake in adrenalectomized animals remained low in comparison to control rats during the first week of treatment with corticosterone (U = 20, P < 0.05; Fig. 1Go, upper panel). At week 2, there was an increase in ethanol intake in adrenalectomized animals. Thus, adrenalectomized animals and controls did not differ significantly during week 2 of corticosterone treatment. By the last treatment week, the ethanol intake of adrenalectomized rats was comparable to that observed during the baseline period. The difference in ethanol preference (Fig. 1Go, lower panel) during the first and second week of corticosterone treatment was not statistically significant between the two groups. However, within-group comparisons showed that ethanol preference was significantly lower in week 1 and week 2 compared to baseline in the adrenalectomized group (week 1: Z = 2.80, P = 0.01; week 2: Z = 1.98, P = 0.05). Ethanol intake and ethanol preference did not change significantly during the corresponding period in the control group.

As seen in Table 1Go, there were no statistically significant differences in total fluid intake or water intake between the adrenalectomized and control group during the 2 weeks of corticosterone treatment, probably due to the large distribution seen in the adrenalectomized animals. However, within-group comparisons showed that total fluid intake and water intake by the first and second week of corticosterone treatment was significantly higher than during the baseline period in the adrenalectomized group (total fluid intake: week 1, Z = 2.80, P = 0.01, and week 2, Z = 2.70, P = 0.01; water intake: week 1, Z = 2.80, P = 0.01 and week 2, Z = 2.39, P = 0.02). Total fluid intake and water intake did not change significantly during the corresponding period in the control group.

Adrenalectomy caused a decrease in body weight and food intake, compared to control rats (body weight: U = 21, P < 0.05; food intake: U = 21, P < 0.05; Table 1Go). Treatment of adrenalectomized animals with corticosterone caused an increase in both variables; thus there were no significant differences between adrenalectomized and control animals during the corticosterone treatment period.

ANA animals
In contrast to the AA rats, there were no alterations in ethanol drinking after removing the adrenal glands and following corticosterone replacement in the ANA rats. Thus, adrenalectomized and control rats did not differ significantly in ethanol intake and ethanol preference during any of the three different periods (baseline, adrenalectomy and subsequent treatment with corticosterone) of the experiment (Fig. 2Go).



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Fig. 2. Alcohol intake and preference by alcohol-non-preferring (ANA) rats before and after adrenalectomy and subsequent corticosterone supplementation. Data are given as median ± MAD (bars) intake of absolute ethanol, offered as a 10% solution (upper panel), and ethanol preference (% of total fluid intake; lower panel) during a 2-week baseline period (adrenally intact), 1 week following adrenalectomy (ADX; n = 10) or sham surgery (n = 9), andfollowing 2 weeks of exposure to corticosterone (CORT). The differences between groups are not statistically significant.

 
There were no statistically significant differences between adrenalectomized and control animals in total fluid intake or water intake during the adrenalectomy period (Table 2Go). During the corticosterone treatment period, total fluid intake increased in the adrenalectomized group week 1 (U = 0, P < 0.001) and week 2 (U = 17, P < 0.05), compared to the control animals (Table 2Go). Also water intake was significantly higher week 1 (U = 0, P < 0.001) and week 2 (U = 8.5, P < 0.01) in the adrenalectomized group.


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Table 2. Body weights and food, water, and total fluid intakes by alcohol-non-preferring rats before and after adrenalectomy and subsequent corticosterone supplementation
 
Removal of the adrenal glands caused a decreased body weight (U = 20.5, P < 0.05) and food intake (U = 21, P < 0.05) compared to control animals (Table 2Go). There were no statistically significant differences in body weight or food intake between the adrenalectomized and control groups during the 2 weeks of corticosterone treatment.

Plasma corticosterone
Table 3Go shows plasma levels of corticosterone in blood samples obtained from all adrenalectomized and control animals at the end of the three periods: baseline (adrenally intact), adrenalectomy, and corticosterone replacement. All adrenalectomized rats had lower plasma levels of corticosterone, compared to their respective controls (AA, U = 0, P < 0.001; ANA, U = 0, P < 0.001).


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Table 3. Plasma corticosterone concentration in alcohol-preferring (AA) and -non-preferring (ANA) rats before and after adrenalectomy and subsequent corticosterone supplementation
 
When corticosterone was administered to the adrenalectomized rats by dissolving corticosterone in equal amounts in each of the drinking fluids presented to the animals, levels of plasma corticosterone did not differ significantly between the adrenalectomized and control groups during the corticosterone treatment period (Table 3Go). By the last week of corticosterone treatment, the plasma levels of corticosterone of both adrenalectomized groups (AA and ANA) were comparable to those observed during the baseline period.


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Our previous studies have indicated that adrenalectomy attenuates ethanol intake in an unselected population of rats and that this effect is reversed by treatment with corticosterone (e.g. Fahlke et al., 1994a,b, 1995, 1996). The results of the present study show that rats of the AA, but not ANA, line respond to manipulation of the HPA-axis. Thus, it was found that adrenalectomy decreased ethanol intake in AA animals. When corticosterone was administered to adrenalectomized rats, by dissolving it in equal amounts in each of the drinking fluids presented to the animals, ethanol intake in adrenalectomized AA animals remained low in comparison to control rats during the first week of treatment. By the last treatment week, adrenalectomized AA rats increased their ethanol intake significantly to levels indistinguishable from intact animals. In contrast to the AA rats, there were no alterations in ethanol drinking after adrenalectomy and following corticosterone replacement in the ANA rats.

One possible explanation for the lack of effect of adrenalectomy on ethanol intake in the ANA group is that these animals cannot lower their ethanol intake much more. This is in agreement with previous studies showing that the effect of adrenalectomy as well as short-term treatment with corticosterone on ethanol intake is dependent on the pre-operative levels of ethanol drinking. Thus, it was found that ethanol intake remained entirely unaffected by adrenalectomy and subsequent corticosterone treatment in an unselected group of animals showing spontaneously low preference for ethanol with an average intake of 0.5 g ethanol/kg/day (Fahlke et al., 1994aGo). Furthermore, Fahlke et al. (1994b) found that there were no alterations in voluntary ethanol intake following treatment with the 11ß-hydroxylase inhibitor metyrapone, which blocks the formation of corticosterone (Ganong, 1987Go), in low-preferring animals. Neither did metyrapone and corticosterone, administered in combination, affect ethanol intake in these animals (Fahlke et al., 1994bGo). In contrast to the short-term treatment studies, long-term treatment of adrenalectomized animals with daily substitution of a constant corticosterone signal over several weeks enhances ethanol intake to levels above those normally observed in animals of an unselected strain of rats (Hansen et al., 1994Go; Fahlke et al., 1995Go). In addition, it was also found recently that adrenally intact low-preferring animals triple their daily ethanol intake by intracerebroventricular infusions of corticosterone (Fahlke et al., 1996Go). Furthermore, a recent study employing the taste reactivity test (Berridge, 1996Go) suggested that prolonged exposure to exogenous corticosterone might increase alcohol consumption by enhancing the sensory reward value of ethanol (Söderpalm and Hansen, 1999Go). In the present study, the animals received short-term treatment with the steroid by dissolving corticosterone in equal amounts in each of the drinking fluids. All ANA animals, regardless of whether they were subjected to adrenalectomy or sham surgery, showed a lower total fluid intake than the AA animals (P < 0.001). It is possible that the amount of corticosterone ingested was not sufficient to facilitate ethanol drinking in ANA rats. Further studies are needed to explore whether long-term treatment with corticosterone, e.g. by subcutaneous implantation of corticosterone, or by exposing the brain alone to corticosterone, stimulates ethanol drinking, not only in ANA animals, but also in AA animals.

In line with earlier studies (Fahlke et al., 1994aGo, 1995Go; Hansen et al., 1995Go), the present study found that removal of the adrenal glands caused a decrease in body weight and food intake which was restored with corticosterone administration. In a related area of research, it has been found that corticosterone appears to act in the paraventricular nucleus of the hypothalamus to modulate food intake. For example, Tempel et al. (1992) have shown that corticosterone implants in the hypothalamic nucleus reproduce the effect of peripheral corticosterone injections. Thus, corticosterone can influence many behaviours (McEwen et al., 1986Go) and the brain (McEwen, 1991Go) by affecting the nerve cell surface to alter, for instance, ion permeability or neurotransmitter release (McEwen, 1991Go; Moore and Orchinik, 1991Go; Orchinik et al., 1994Go). In a recent study by Fahlke and Hansen (1999), it was found that corticosterone partly acts within the ventral striatopallidal system to facilitate alcohol intake in rats. Thus, we found that animals bearing unilateral corticosterone implants in the ventral striatum showed a selective increase in voluntary alcohol consumption, whereas ethanol intake was not affected when corticosterone was implanted into the septum, hippocampus or thalamus. Furthermore, manipulation of corticosterone causes an array of changes in several components of the HPA system (McEwen et al., 1986Go; Dallman et al., 1992Go; Joels and De Kloet, 1992Go) such as changed secretion of vasopressin, ß-endorphin, corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH). Some of these components, e.g. CRF (George et al., 1990Go; Ehlers et al., 1992Go), ß-endorphin (Sandi et al., 1989Go; Froehlich et al., 1990Go) and ACTH (Krishnan et al., 1991Go), may be involved in the modulation of ethanol intake. In fact, Gianoulakis et al. (1992) found that there are genetically determined differences in the pituitary and brain ß-endorphin system between ANA and AA rats, with the latter group having higher content of ß-endorphin and pro-opiomelanocortin (POMC; a protein which is subsequently cleaved into ACTH, ß-endorphin and other biologically active peptides; Herbert et al., 1980), which may be important in controlling the differences in voluntary alcohol consumption exhibited by these animals. Further studies are needed to specify the involvement of the HPA system in ethanol drinking in the genetic lines of AAA and ANA rats.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This study was supported by the Swedish Medical Research Council (K98-21P-11842-03A), Nordic Council for Alcohol and Drug Research, Finnish Foundation, Åke Wibergs Stiftelse and Fredrik och Ingrid Thurings Stiftelse. We are indebted to Mrs Hilka Salohalla for technical assistance.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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