EFFECT OF LOCAL INTRACEREBRAL CORTICOSTERONE IMPLANTS ON ALCOHOL INTAKE IN THE RAT

Claudia Fahlke and Stefan Hansen*

Department of Psychology, Göteborg University, Box 500, SE-405 30 Göteborg, Sweden

Received 8 February 1999; in revised form 23 March 1999; accepted 21 May 1999


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Corticosterone acts within the brain to stimulate alcohol consumption in the rat. The experiments reported here were aimed at identifying where in the brain corticosterone acts to facilitate ethanol drinking. The daily fluid intake of male Wistar rats with simultaneous access to 6% ethanol and water was determined during a 1-week pre-operative baseline period and following implantation of corticosterone in various brain areas. Animals bearing unilateral or bilateral implants of corticosterone in the ventral striatum showed increased ethanol consumption compared to cholesterol-treated controls. Ethanol intake was not affected when corticosterone was implanted into septum, hippocampus, or thalamus. Neither were changes in fluid intake detected in animals bearing ventral striatal implants of two related steroid hormones, aldosterone and testosterone. These results indicate that corticosterone partly acts within the ventral striatopallidal system to facilitate alcohol consumption in the rat.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
A number of animal experimental studies have shown that the adrenosteroidal glucocorticoid hormone corticosterone participates in the control of voluntary alcohol intake (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., 1995aGo) adrenalectomy attenuates voluntary ethanol intake in Wistar rats 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). 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).

Another line of evidence indicates that individual differences in the pattern of endogenous corticosterone secretion predicts individual differences in ethanol intake. Thus, it has been found that rats with basal hypercorticosteronaemia together with an attenuated rise in corticosterone output during stress are predisposed to consume more alcohol in a two-bottle choice test (Prasad and Prasad, 1995Go). In a similar vein, it has been shown that adult non-human primates consume more alcohol than usual in stressful settings and that plasma cortisol concentrations are positively correlated with alcohol consumption rate (Higley and Linnoila, 1997Go). Furthermore, individual differences in plasma cortisol during social separation in 6-month-old macaques predicts adult alcohol consumption 4 years later (C. Fahlke et al., submitted).

The stimulatory effects of systemic corticosterone administration on ethanol intake in intact and adrenalectomized animals (Fahlke et al., 1994aGo,bGo, 1995Go) was recently duplicated by exposing the brain alone to corticosterone. More specifically, Fahlke et al. (1996) found that intracerebroventricular (i.c.v.) infusions of a small amount corticosterone (100 µg) restored voluntary ethanol drinking to pre-operative baseline levels in adrenalectomized rats, whereas s.c. injections of corticosterone, at the same dose, were without a significant effect. Finally, adrenally intact low-drinking animals tripled their daily ethanol consumption with i.c.v. infusions of corticosterone (Fahlke et al., 1996Go). These findings suggest that corticosterone facilitates alcohol drinking by acting in the brain.

The present experiments aimed at identifying where in the brain corticosterone acts to stimulate ethanol intake. This question was addressed by monitoring alcohol drinking in rats bearing implants of corticosterone in various brain regions. The first experiment focused on the ventral striatum. This choice was made because it is well known that neurotransmission in this part of the basal ganglia is responsive to both corticosterone (Piazza et al., 1991Go, 1996Go; Piazza and Le Moal, 1996Go) and alcohol (Imperato and Di Chiara, 1986Go; Engel et al., 1992Go). Moreover, many studies implicate the striatum, and particularly its ventral division, in drug-seeking behaviour (reviewed by Wise and Bozarth, 1987; Robinson and Berridge, 1993; Altman et al., 1996; Koob and Le Moal, 1997). As our initial experiment showed that striatal corticosterone implants elevated voluntary alcohol drinking, the subsequent experiments were designed to assess the neuroanatomical and hormonal specificity of the effect. Thus, alcohol intake was examined in rats bearing corticosterone implants in neighbouring brain sites (septum, hippocampus, thalamus), and in animals with striatal implants of other steroid hormones (aldosterone, testosterone). Within the limits of the present study our results indicate that striatal corticosterone exposure may be uniquely effective in enhancing alcohol consumption in the rat.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Animals and familiarization with alcohol
Male Wistar rats, purchased from Möllegard Breeding Laboratories (Denmark) were used. They were 120–150 days of age and weighed 300–350 g at the beginning of the experiments. Animals were housed in an air-conditioned colony room (lights off 10:00–22:00) at a temperature of 23°C and a relative humidity of 50–60%. The rats had free access to water and R34 food pellets (Labfor, Lactamin, Vadstena, Sweden).

The animals were initially housed in groups of four/cage for 1 week to adapt to the novel laboratory conditions. During the following 2-week period, the rats had continuous access to a second bottle containing an ethanol solution in addition to the water bottle. The ethanol concentration was gradually increased (2–4–6% v/v) over this period. Subsequently the animals were housed individually in clear plastic cages (45 x 30 x 16 cm), while having continued access to two bottles (plastic 300-ml bottles with ballvalve spouts; ALAB, Sweden) containing tap water or 6% ethanol solution for the remainder of the experiment. This particular ethanol concentration stimulates peak levels of consumption in this strain of rats (Hansen et al., 1994Go). Fluid intake was measured twice a week when the bottles were cleaned and refilled with fresh liquids. The experiments began 3 weeks later, when the rats showed stable levels of ethanol intake (expressed as g/kg/day of absolute ethanol) and preference (i.e. percentage of ethanol solution intake relative to total fluid consumption). On the basis of their ethanol intake during this period, the animals were assigned to the various experimental groups. The experiments were approved by the local ethical committee of the Swedish National Board for Laboratory Animals.

Stereotaxic surgery and brain cannulation
Following induction of anaesthesia (Brietal, Lilly; 100 mg/kg, i.p.) the rats were positioned in a stereotaxic instrument (incisor bar: –3.3 mm). Animals were implanted unilaterally with 2.5- or 5-mm long guide cannulae (22G; Plastic Products) aimed at one of four brain sites. Brain sites and stereotaxic coordinates (Paxinos and Watson, 1986Go) were: ventral striatum (AP: +1.6 mm, L: –1.5 to –3.0, V: –8.3, guide cannula: 5 mm), septum (AP: +0.7 mm, L: –0.7 mm, V: –7.0, guide cannula: 2.5 mm), hippocampus (AP: –3.3 mm, L: –1.8 mm, V: –4.5, guide cannula: 2.5 mm), or thalamus (AP: –3.0 mm, L: –2.5 mm, V: –7.0, guide cannula: 2.5 mm). Acrylic dental cement (Svedia) was used to secure the guide cannulae to the skull. Hormone-filled internal cannulae (28G) were inserted through the guides and were secured with a plastic crystal applicator cover.

Steroid hormone implants
The following steroids (purchased from Sigma) were used: corticosterone, d-aldosterone, testosterone, and cholesterol. An internal cannula was filled with steroid by gently tapping it on to a thin layer of steroid crystals spread out on a glass dish. A small wire was inserted into the cannula to ensure that steroid had entered the tip of the cannula. The cannula was then wiped clean with a napkin to remove any steroid adhering to the outside of the cannula. By weighing the cannulae before and after filling, we estimate that each tube contained 200–300 µg of the various steroids. Corticosterone and aldosterone, at these dose levels, stimulate food intake when placed in the hypothalamic paraventricular nucleus (Tempel et al., 1993aGo,bGo). Medial pre-optic area testosterone implants activate sexual behaviour in castrated male rats (Christensen and Clemens, 1974Go). The internal cannula was left in place throughout the test period, but at the end of the behavioural observations, it was removed and inspected for steroid content. It was found that the tip of the internal cannula was devoid of steroid, indicating that the crystals had diffused out of the internal cannula over the test period.

Histological analysis
At the end of the behavioural observations, animals received an overdose of Mebumal (Aco). The brains were removed and placed in 10% formalin–saline for several weeks. The brains were cut into 35-µm frozen sections, placed on gelatine-coated glass slides and stained with thionine (Swanson, 1992Go). Cannula placements were determined microscopically with the aid of a brain atlas (Swanson, 1992Go). Rats with off-target placements were eliminated from the study.

Procedure
Experiment 1. The intakes of 6% ethanol and water were determined daily (at 09:00) over a 1-week baseline period in 29 rats which were then divided into two groups, matched with respect to ethanol intake. Animals were cannulated and received implants of corticosterone (n = 21) or cholesterol (CHOL) (n = 8) in the ventral striatum. Following a 1-day rest, the intake of fluids was recorded daily (at 09:00) for 1 week following implantation.

Experiment 2. Three groups of rats were implanted with corticosterone-containing cannulae in either the septum (n = 9 after exclusion of one rat with an off-target cannula), hippocampus (n = 8 after exclusion of two rats with off-target cannulae) or the thalamus (n = 16). Two other groups were implanted with cholesterol in either the septum (n = 5) or the hippocampus (n = 5 after exclusion of two rats with off-target cannulae); since the results from these groups were similar, they were combined to form a single septo-hippocampal cholesterol control group (n = 10). For all groups, fluid intakes were recorded daily (at 09:00) for 1 week before implantation and 1 week after implantation.

Experiment 3. Following a 1-week pre-operative baseline period, one group of animals received aldosterone (n = 4 after exclusion of one rat with an off-target cannula) or testosterone (n = 6 after exclusion of four rats with off-target cannulae) implantation in the striatum. A second batch of animals was divided into two matching groups, one group was implanted bilaterally with corticosterone (n = 8 after exclusion of two rats with off-target cannulae) and the other with CHOL (n = 8 after exclusion of one rat with an off-target cannula) in the striatum. The procedure for measurement of fluid intake was the same as in the previous experiments.

Statistical assessment
Because the distribution of ethanol intake is positively skewed (Hansen et al., 1994Go), non-parametric methods were used in the statistical treatment of the data (StatView; Abacus software) and the results are presented as median ± median absolute deviation (MAD; i.e. the median of the set of differences between each data point and the median of the data). The Page test for ordered alternatives (Siegel and Castellan, 1988Go) was used to assess the effect of the various intracerebral hormone implants on fluid intake. In these computations, the median value for each rat during the pre-operative testing phase was entered as the start point, together with each ensuing treatment day's intake. In the text and tables, the test statistic for the Page test is represented as L for small group sizes and as zL for large sample sizes (n >= 20). Within-group changes in body weight were analysed with the Wilcoxon matched-pairs signed-ranks test. Between-group comparisons were made with the Mann–Whitney U-test. The P-values for the latter two tests are two-tailed.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Experiment 1
The purpose of the first experiment was to document the effect on voluntary alcohol consumption of unilateral corticosterone implants in the ventral striatum.

Fluid intake. Table 1Go and Fig. 1AGo show that the two groups were comparable with regard to fluid intake during the pre-operative baseline period. As shown in Fig. 1AGo, animals in the corticosterone group showed an increase in ethanol intake compared to the pre-operative period (ZL = 5.5, P < 0.0001). This trend was not present among the cholesterol rats (L = 1367, n.s.). A between-groups analysis confirmed that corticosterone rats drank more ethanol than cholesterol rats during treatment (U = 41, P < 0.04).


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Table 1. Effects of corticosterone and cholesterol implants on body weight and intake of ethanol, water, and total fluid
 


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Fig. 1. Effects of unilateral corticosterone and cholesterol implants on ethanol intake by rats.

Data are given as median ± MAD ethanol intake (expressed as g/kg/day of absolute ethanol) in animals during a 1-week pre-operative baseline period and following 1 week of bearing (A) unilateral implants of corticosterone (CORT; n = 21) or cholesterol (CHOL; n = 8) in the ventral striatum, and (B) unilateral CORT implants in the septum (n = 9), hippocampus (n = 8), or thalamus (n = 15).

Control rats that received CHOL in the dorsal hippocampus (n = 5) and septum (n = 5) were combined into one group.

***P < 0.0001 Page's test for ordered alternatives.

 
Along with the increase in ethanol consumption, the corticosterone rats also displayed a significantly enhanced ethanol preference and a decreased water intake (Table 1Go). These significant effects were absent in cholesterol rats (Table 1Go). The body weights of both groups decreased during the course of treatment (Table 1Go), but to similar extents (U = 52, n.s.).

Histology. Figure 2Go illustrates the location of the striatal corticosterone (Fig. 2AGo) and cholesterol (Fig. 2BGo) implants. In the majority of cases, the cannula tips were placed in the ventral division of the striatum, particularly in the vicinity of the anterior commissure in the nucleus accumbens. In this and the subsequent experiments, there was no evidence of non-specific brain damage (gliosis, cavitation) around the cannula tip, except for the inevitable cannula track.



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Fig. 2. Location of unilateral hormone implants. Location was in the region of the ventral striatum in Experiment 1 (A, B) and Experiment 3 (C, D). Sections were taken from Swanson (1992).

 
Experiment 2
Having established that corticosterone implants placed in the ventral striatum stimulated ethanol consumption, the next experiment set out to determine the neuroanatomical specificity of the effect.

Fluid intake. Figure 1BGo shows that there was no statistically significant difference in ethanol intake before and during treatment in rats with corticosterone implants in either the septum (L = 1521, n.s.), hippocampus (L = 1295, n.s.), or thalamus (ZL = 1.42, n.s.), or in rats bearing septohippocampal cholesterol implants (L = 1667, n.s.). As shown in Table 2Go no drinking parameter was altered as a consequence of treatment. However, the body weight of animals with thalamic corticosterone implants was significantly lower at the end of the experiment than at the beginning (Table 2Go).


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Table 2. Effects of corticosterone implants on body weight and intakes of ethanol, water, and total fluid
 
Histology. Figure 3Go (top section) illustrates the location of the septal corticosterone and cholesterol implants. The cannula tips were generally positioned in the lateral septal nucleus. The hippocampal hormone implants (Fig. 3Go, middle section) were situated in the CA1 field and the dentate gyrus of the dorsal hippocampus. The corticosterone implants placed in the thalamus were restricted to its ventrolateral portion, involving the reticular nucleus and the ventral posterolateral– posteromedial nuclei (Fig. 3Go, lower section). As before, there was little evidence of non-specific brain damage around the cannula tips.



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Fig. 3. Location of unilateral hormone implants. Location was studied in Experiment 2 in the septum (top), hippocampus (middle), and thalamus (bottom). Sections were taken from Swanson (1992).

 
Experiment 3
The previous observations suggested that corticosterone implants placed in the ventral striatum, but not in the septum, hippocampus, or thalamus, stimulated the drinking of ethanol. Focusing on the ventral striatum, the present experiment investigated, first, the effect of unilateral striatal implants of two related steroid hormones, aldosterone and testosterone. Second, we determined the effect of bilateral corticosterone implants positioned in the striatum.

Fluid intake. Table 3Go shows that there was no alteration in the fluid intake of rats implanted with either aldosterone or testosterone in the ventral striatum when compared to the pre-operative baseline period.


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Table 3. Effects of steroid hormone implants on body weight and intakes of ethanol, water, and fluid
 
Figure 4Go and Table 4Go show fluid intake before and during treatment with bilateral corticosterone implants in the ventral striatum. The corticosterone group drank more ethanol (L = 1010, P < 0.001) and showed a greater alcohol preference (Table 4Go) during the course of hormone exposure, whereas no significant trend was discernible in the chol-esterol group (L =782, n.s.). A between-groups comparison confirmed that corticosterone, but not cholesterol, stimulated ethanol consumption (U = 13, P < 0.05).



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Fig. 4. Effects of bilateral corticosterone and cholesterol implants in ethanol intake by rats.

Data are given as median ± MAD ethanol intake (expressed as g/kg/day of absolute ethanol) in animals during a 1-week pre-operative baseline period and following 1 week of bearing bilateral CORT implants (n = 8) or cholesterol (n = 8) in the ventral striatum.

***P < 0.001 Page's test for ordered alternatives.

 

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Table 4. Effects of bilateral corticosterone and cholesterol implants on body weight and intakes of ethanol, water, and fluid
 
Histology. Figures 2C and 2DGo show the unilateral aldosterone and testosterone implant sites, and Fig. 5Go shows the location of the bilateral corti-costerone implants. In all cases, the cannula tips were located in the ventral striatum, and tended to aggregate in tissue around the anterior commissure. The bilateral corticosterone implants were fairly symmetrical.



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Fig. 5. Location of bilateral hormone implants. Location was studied in the region of the ventral striatum in Experiment 3. Sections were taken from Swanson (1992).

 

    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
A previous study of ours indicated that multiple i.c.v. corticosterone infusions facilitate alcohol intake, thereby implicating the brain in the stimulatory actions of corticosterone on ethanol consumption (Fahlke et al., 1996Go). The aim of the present study was to identify at a rudimentary level the place in the brain at which corticosterone stimulates ethanol intake. Out of the four basal forebrain structures tested, the ventral striatum was identified as a potential candidate. Thus, we found that rats bearing unilateral (Experiment 1) or bilateral (Experiment 3) corticosterone implants in the ventral striatum showed a significant and selective increase in voluntary ethanol consumption. This effect was accompanied by a significant increase in ethanol preference in both experiments. The effect on water intake was somewhat less consistent: in Experiment 1, it was significantly lowered, whereas in Experiment 3, it was not. The important point is that water intake did not increase along with ethanol consumption during the course of corticosterone exposure. This means that corticosterone does not increase ethanol consumption by enhancing fluid intake generally. CHOL implants in the ventral striatum were ineffective in stimulating ethanol ingestion. Furthermore, no reliable changes in alcohol intake were observed following placement of aldosterone and testosterone implants in this region. The absence of an effect of these steroid hormones is consistent with previous observations that aldosterone fails to restore alcohol consumption in adrenalectomized rats (Fahlke et al., 1994aGo) and that castration-induced testosterone deficiency has minimal consequences for ethanol drinking in the male rat (Fahlke et al., 1989Go).

Further evidence for a certain degree of specificity of ventral striatal corticosterone stimulation of ethanol drinking was provided by the demonstration that corticosterone-filled cannulae placed in the lateral septum, dorsal hippocampus, or ventrolateral thalamus left ethanol intake unaffected (Experiment 2). These observations indicate that similarly sized hormone implants exert differential behavioural effects depending on their neuroanatomical localization, and provide some evidence against the idea that the ventral striatal corticosterone effect is due to hormone diffusion to brain site(s) very distant to the implant. Note, however, that the septal-corticosterone group consisted of animals showing a somewhat higher baseline level of ethanol intake than the other groups. Consequently, a ceiling effect might have prevented the detection of a stimulatory action of the steroid on alcohol drinking in this part of the brain. A ceiling effect might also explain why bilateral corticosterone implants placed in the ventral striatum seemed no more effective than unilateral ones in raising ethanol drinking: the former group drank more than the latter during the baseline measurement period (cf. Figs 1 and 4GoGo). Indeed, we have previously found that i.c.v. corticosterone infusions facilitate alcohol intake only in animals showing low ethanol intake (Fahlke et al., 1996Go). These questions should be re-examined in animals with lower baseline ethanol intakes. It should also be pointed out that the increment in ethanol intake observed following striatal corticosterone implantation was quite modest, compared to the increases seen following chronic systemic administration (Fahlke et al., 1995Go) or following i.c.v. corticosterone infusions (Fahlke et al., 1996Go). We suspect, therefore, that corticosterone supports alcohol ingestion by acting not solely in the ventral striatum, but also elsewhere in the brain.

These caveats notwithstanding, our observations are consistent with the hypothesis that corticosterone stimulates ethanol intake by acting at least in part within the ventral striatum. Many of our ventral striatal corticosterone implants were located in the nucleus accumbens, a structure now being partitioned on anatomical (e.g. Alheid and Heimer, 1996) and functional (e.g. Moldanodo-Irizarry and Kelley, 1995) grounds into ‘shell’ and ‘core’ zones. Because the present experiments were not designed to distinguish the relative effectiveness of these two zones with regard to corticosterone stimulation of alcohol intake, it would be unwise at present to speculate whether the shell or core contributes differentially to the effects reported here. That corticosterone acts partly within the ventral striatopallidal system to facilitate alcohol self-administration is consistent with many previous studies implicating this particular system in the neurobiology of drug abuse (reviewed by Wise and Bozarth, 1987; Robinson and Berridge, 1993; Altman et al., 1996; Koob and Le Moal, 1997). Through the work of Imperato et al. (1989) and Piazza et al. (1996) we know that corticosterone, directly or indirectly, affects neurotransmission in this system by increasing the extracellular concentrations of dopamine in the nucleus accumbens. These observations are invaluable for the understanding of the way in which corticosterone promotes the self-administration of psychostimulants, but their relevance for corticosterone facilitation of ethanol drinking is less certain. First, unlike psychostimulant self-administration (reviewed by Altman et al., 1996), the maintenance of alcohol drinking is resistant to large accumbens dopamine depletions in our rats (Fahlke et al., 1994cGo; Fahlke and Hansen, 1999Go) and in several other strains of rats (Kiianmaa et al., 1979Go; Rassnick et al., 1993Go; Ikemoto et al., 1997Go). Second, corticosterone apparently interacts with intracellular glucocorticoid receptors to facilitate the behavioural effects of psychostimulants (Marinelli et al., 1994Go, 1997Go). Alcohol drinking, on the other hand, is not diminished by systemic (Fahlke et al., 1995Go) or i.c.v. (Fahlke et al., 1996Go) administration of type 1 and/or type 2 corticosterone receptor antagonists, suggesting a different, perhaps non-genomic, mechanism of action for corticosterone stimulatory effect on ethanol drinking.

Other lines of evidence, however, do implicate (non-dopaminergic) ventral striatopallidal mechanisms in the maintenance of ethanol drinking in the rat. We have repeatedly found that extensive axon-sparing lesions involving most of the nucleus accumbens and neighbouring basal forebrain systems are associated with a dramatic and long-lasting increase in home-cage alcohol intake (Hansen et al., 1995aGo,bGo; Bergvall et al., 1996Go; Johansson et al., 1999Go). In a recent study, Å. K. Johansson and S. Hansen (submitted) found that neuronal loss largely restricted to the part of the accumbens surrounding the anterior commissure was sufficient to elevate voluntary alcohol consumption in the rat. The present ethanol-promoting ventral striatal corticosterone implants also tended to aggregate within this general area. This suggests that the corticosterone implants increased alcohol consumption by creating a structural lesion in the accumbens. We consider this possibility less likely because: (a) there was minimal tissue damage at the implant site; (b) similarly sized cholesterol control implants left ethanol drinking unaffected. Another, more interesting, possibility is that there are resemblances in the way the nucleus accumbens operates during intense corticosterone exposure and following loss of intrinsic neurons. In general, non-genomic effects of corticosteroids (which probably underlie the corticosterone potentiation of ethanol intake) involve suppression of neuronal activity in various brain regions (reviewed by Joëls, 1997). Although to our knowledge the effect of corticosterone on accumbens neuronal activity has not been investigated, it is tempting to speculate that local corticosterone implants in the accumbens increase alcohol drinking by suppressing some aspect of its functioning.


    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), the Swedish Council for Research in the Humanities and the Social Science, Fredrik och Ingrid Thurings Stiftelse, and Magn Bergvalls Stiftelse. We should like to thank Mrs B. Linder for excellent technical assistance and Miss L. Werme for animal maintenance.


    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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