Department of Psychology, Göteborg University, Box 500, SE-405 30 Göteborg, Sweden
Received 11 May 2001; in revised form 8 August 2001; accepted 21 September 2001
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ABSTRACT |
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INTRODUCTION |
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Type 2 alcoholism is more likely to occur in individuals with a particular temperamental configuration, in that their level of novelty seeking is typically above average, while harm avoidance is generally below (Virkkunen and Linnoila, 1990; Cloninger et al., 1996
). Against this clinical background, we recently studied these temperamental dimensions in rats with axon-sparing basal forebrain lesions known to increase ethanol intake (Johansson and Hansen, 2001
). Novelty seeking, as tapped by the frequency of nose poking in a novel hole-board, was significantly increased by the lesion. By contrast, the same rats' risk assessment behaviours (stretched attend posturing) when in danger were significantly reduced. This was interpreted to mean that the level of harm avoidance was lower than average following the brain damage. Not unlike the prototypical Type 2 alcoholic, then, rats with basal forebrain neuronal loss appear to be non-anxious novelty seekers (Johansson and Hansen, 2001
).
The present work addressed two issues raised by our previous research. The first concerns the well-established fact that normal rats differ markedly in their voluntary intake of alcohol. For instance, in our strain of Wistar rats there is at least a 20-fold difference between low- and high-preferring animals in the amount of home-cage alcohol ingested (Hansen et al., 1995). Considering our finding that a brain intervention which enhances home-cage alcohol intake also affects the responsiveness to novelty and potential threats, we wished to know whether alcohol-preferring normal animals are higher than the average rat on novelty seeking and lower than usual on harm avoidance. More specifically, our hypothesis was that rats drinking much alcohol are more prone than others to explore novel surroundings (nose poking) and less wary when in potential danger (stretched attend posturing). This was not the first attempt to relate alcohol drinking to behavioural or somatic traits, earlier studies having suggested links between ethanol drinking and high anxiety (Spanagel et al., 1995
), low anxiety (Möller et al., 1997b
), preference for sweet tastes (Hansen et al., 1994
), impulsivity (Poulos et al., 1995
), increased reactivity in an open-field (Nowak et al., 2000
), decreased reactivity in an open-field (Gingras and Cools, 1995
), increased amphetamine responsiveness (Fahlke et al., 1995
) and increased sensitivity to the dopamine-releasing actions of ethanol (Engel et al., 1992
) or elevated basal corticosterone levels (Prasad and Prasad, 1995
).
The second issue concerned the neuro-anatomical substrate for the changes in alcohol drinking, novelty seeking and harm avoidance observed in previous studies. The anatomical location of our previous brain lesions was mostly guided by functional behavioural, rather than structuralanatomical, considerations. That is, the studies did not aim to injure as specifically as possible a particular anatomical system; rather, their point of departure was the classic septal rage syndrome' literature showing that lesions to the septum, importantly in combination with damage to adjacent structures, induce a syndrome of hyper-defensiveness which in its extreme form is expressed as vicious and indiscriminate aggressiveness (Brady and Nauta, 1953; Albert and Richmond, 1975
; Blanchard et al., 1979
). In terms of Alheid and Heimer's (1996) recent neuro-anatomical parcellation of the basal forebrain, it is now clear that the septal rage syndrome' derives from partial damage to three emotional motor systems: the septal system, the ventral striato-pallidal system and the extended amygdala. The purpose of the second part of the experiment was to examine the relative contributions of the two latter networks to the alterations in alcohol drinking, novelty seeking and harm avoidance following basal forebrain damage. Thus, we compared the effect of axon-sparing lesions to the temporal part of the amygdala with similarly sized lesions in the ventral striatum on ethanol ingestion, nose poking and stretched attend posturing.
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MATERIALS AND METHODS |
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Subjects
Male Wistar rats weighing 180220 g and ~60 days old were purchased from Möllegaard Breeding Laboratories (Vejle, Denmark). They were housed in groups of four to five per cage (52 x 30 x 18 cm) in an air-conditioned colony room (lights-off 10.0022.00) with free access to food (R70, Labfor) and water. The animals were allowed 2 weeks to adapt to the novel laboratory conditions before the experiment began.
Alcohol consumption
Two weeks after arrival, the rats were given access to a second bottle containing an ethanol solution in addition to the water bottle. The ethanol concentration was gradually increased (246%, v/v) over this period. The animals were subsequently housed individually in clear plastic Macrolon 3 cages (45 x 30 x 16 cm), while having continued access to two bottles (plastic 300 ml bottles with ballvalve spouts; ALAB, Södertälje, Sweden) containing tap water (right) or ethanol solution (left). Fluid intake during this pre-experimental phase was measured three times per week (Mondays, Wednesdays, and Fridays at 09.0010.00). The intake of 6% alcohol and water was monitored by weighing the bottles to the nearest 0.1 g, three times a week. The animals were weighed at weekly intervals.
Harm avoidance
The anxiety test apparatus (Grewal et al., 1997) comprised a circular (104 cm diameter), deep green platform elevated to 73 cm above the ground level. A clear red perspex circular canopy (70 cm diameter) was supported 10 cm directly above the platform by a central pillar. This divided the apparatus in a covered closed zone, and an outer open zone. Eight white lines were drawn radially from the centre of the platform. The arena was illuminated by normal fluorescence room lighting, yielding a level of illumination of ~165 lux in the covered zone and 560 lux in the open zone.
The 10-min test started by placing the animal under the canopy. The number of stretched attend postures, the number of lines crossed and the time spent in the outer exposed zone of the arena were recorded by two observers sitting on opposite sides of the platform. A stretched attend posture was defined as flexed hindlimbs and a flattened lower back position with extended forelimbs; usually the response was accompanied by either a lack of movement or a very slow gait. The apparatus was cleaned with soap and water between the two tests.
Novelty seeking
The exploration test apparatus (File and Wardill, 1975) was a wooden, brown-painted hole-board (78 x 78 cm; walls 29 cm high). The floor was divided into 16 squares by white lines. Each square contained a hole, 4 cm in diameter and 2.5 cm deep. The rat was placed in the middle of the arena and allowed to habituate to the test environment for 5 min. During the next 5 min, the number and cumulative duration of nose pokes (both eyes disappearing in the hole) into the holes was recorded together with the number of squares crossed. The tests were conducted when the rats were 117124 days old and during the dark phase of the lightdark cycle in a darkened room (9 lux). The apparatus was cleaned with soap and water between the two tests. The brief habituation period prior to recording, plus the dim testing condition, allowed us to obtain a reasonably pure measure of exploration, relatively unaffected by other motivational forces.
Surgery
Brain lesions were made under pentobarbital anaesthesia (30 mg/kg intraperitoneally) while the animal was fixed in a Kopf stereotaxic instrument. Bilateral excitotoxic lesions were created by infusing ibotenic acid (10 µg/µl; Sigma) at the following stereotaxic coordinates (incisor bar: 3.3 mm): amygdala: 2.2 mm behind bregma, 4.3 mm lateral to midline, 9.0 mm below the skull (n = 20); ventral striatum: 1.6 mm in front of bregma, 1.5 mm lateral to midline, 8.3 mm below the skull (n = 20). The infusions (3.5 µg/0.35 µl over 30 s in each hemisphere) were made through a stainless steel cannula (outer diameter: 0.25 mm) using a CMA 100 (Stockholm, Sweden) microinjection pump. The cannula remained in place for 3.5 min after the end of the infusion. The animals regained consciousness in a warm incubator.
Histology
On the day after the last alcohol measurement day, the rats were given an overdose of pentobarbital. The brains were removed and placed in 10% formalin for several weeks. They were cut through the lesioned area in 35 µm sections, every 10th of which was placed on gelatine-subbed glass slides and stained with thionine (Swanson, 1992). The extent of the lesions was determined microscopically with the aid of Swanson's (1992) brain atlas.
Statistical analysis
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). Non-parametric tests (Wilcoxon matched-pairs signed-ranks test, MannWhitney U-test, Spearman rank correlation) were used to assess the results (StatView, Abacus, Cary, NC). All P-levels are two-tailed. The choice of non-parametric tests was based on the fact that the distribution of alcohol drinking is skewed in our strain of rats (Hansen et al., 1994), and the prudence in regarding the scores derived from animal experimental tests for harm avoidance and novelty seeking as being inherently in ranks (Siegel and Castellan, 1988
). Configurational frequency analysis (Lienert, 1978
) was used in the investigation of possible response patterns in alcohol drinking and temperamental traits.
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RESULTS |
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Correlational analyses revealed no significant relationship between the number of stretched attend postures (or any other parameters derived from the risk assessment test) and alcohol intake. However, nose-poking frequency (r = 0.33, P < 0.01) and duration (r = 0.42, P < 0.001) were significantly correlated to alcohol drinking. To explore this relationship further, the rats were split into two groups with respect to nose poking, below and above the median. Figure 1 shows that there was a significant difference between animals low (3.0 ± 1.0 responses) or high (10.0 ± 3.0 responses) on nose poking, such that the former group drank less alcohol than the latter (U = 252.5, P < 0.004). In contrast, there was no relationship between exploratory activity and the drinking of water (r = 0.03, not significant), nor between locomotor activity and ethanol ingestion (r = 0.18, not significant).
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DISCUSSION |
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Intact animals
It has long been suspected that certain temperamental features make individuals more vulnerable to alcohol addiction (Babor, 1996). For example, considering alcohol's well-known anti-anxiety actions (Chutuape and de Wit, 1995
), there is considerable intuitive appeal in the notion that anxious individuals are unusually prone to develop a persisting drinking habit (Cappell and Greeley, 1987
) and trait anxiety plays a major role in the development of Cloninger's Type 1 form of alcoholism (Cloninger et al., 1996
). However, although the rate of alcohol problems is elevated in people suffering from anxiety disorders (Otto et al., 1992
), it has been difficult to demonstrate an unequivocal relationship between pre-existing anxiety traits and susceptibility to alcohol misuse (Schuckit and Hesselbrock, 1994
). In rats, higher levels of harm avoidance, as measured by the reluctance to enter the open arms in the elevated plus-maze test, have been reported in alcohol-preferring lines in comparison to their alcohol-non-preferring counterparts (Stewart et al., 1993
; Colombo et al., 1995
). A positive association between anxiety-related measures in the plus-maze and ethanol intake has also been observed in genetically heterogeneous rats (Spanagel et al., 1995
). However, there are also reports showing that an alcohol-preferring rat line shows less anxiety-related behaviour (Tuominen et al., 1990
; Baldwin et al., 1991
; Möller et al., 1997b
). Moreover, Viglinskaya et al. (1995) demonstrated that, across a range of alcohol-preferring and alcohol-non-preferring rat lines, there was no consistent relationship between anxiety-related behaviours in the elevated plus-maze and alcohol intake. In the present study, we assessed harm avoidance using the canopy test' developed by Grewal et al. (1997). This test is designed to elicit high levels of stretched attend postures, an important risk assessment behaviour by which the rat gathers information about potential dangers (Blanchard and Blanchard, 1994
). The behaviour pattern is sensitive to a variety of anxiolytic agents (Blanchard and Blanchard, 1994
; Molewijk et al., 1995
; Grewal et al., 1997
). We found that the individual variation in the frequency of stretched attend postures did not vary with home-cage alcohol consumption. We tentatively conclude, then, that in our strain of Wistar rats, the level of anxiety is unrelated to the propensity to drink ethanol.
Numerous clinical studies show that novelty-seekers have an enhanced risk for developing drug misuse, including alcoholism (Cloninger et al., 1988, 1996
; Galen et al., 1997
; Masse and Tremblay, 1997
). An influential series of papers showed that the responsiveness to novelty is linked to drug-taking also in rats (Piazza et al., 1996
). Rats showing heightened locomotor responses in a novel environment were more prone than low-reactive rats to self-administer psychostimulants (Deminière et al., 1989
), and Dellu et al. (1993) demonstrated that animals defined as high-reactive in this manner also prefer novelty to familiarity in a Y-maze procedure and are quicker to enter an illuminated area in a darklight emergence test. Attempts to extend these findings to include alcohol drinking have met with mixed success. Nowak et al. (2000) did find that alcohol-preferring P rats showed heightened locomotor responses in a novel environment, whereas Gingras and Cools (1995) reported that alcohol-preferring rats actually showed less locomotor activation to novelty. Most studies have found no association whatsoever (Bisaga and Kostowski, 1993
; Fahlke et al., 1995
; Samson and Chapelle, 1995
; Koros et al., 1998
, 1999
). Likewise, in the present study, measures of novelty-induced locomotor activity in two different situations were unrelated to alcohol drinking.
Enhanced locomotor activity is but one of several behaviours that are elicited by exposure to novelty, and not all of them reflect its incentive, approach-instigating features (Exner and Clark, 1993; Burns et al., 1996
). That novelty stimulates several conflicting response tendencies is not astonishing in view of the intense and widespread brain activity brought about by simply placing a rat in an unfamiliar environment (Badiani et al., 1998
; Emmert and Herman, 1999
; Day et al., 2001
). In the present study, we used the rat's natural tendency to use the nose to explore aspects of its physical environment, such as holes. We also attempted to minimize the aversiveness of the test procedure by allowing the animal to adapt briefly to the apparatus and by conducting the test in almost total darkness during the active part of its daily activity cycle. Previous research has shown that nose poking is a valid measure of novelty seeking and is governed by factors partly different from those regulating novelty-induced locomotor activity (File and Wardill, 1975
; Abel, 1995
). For example, Piazza et al. (1990) found that rats with the greater locomotor response to novelty did not show higher levels of nose poking in a hole exploration test. Using this reflection of novelty seeking we found a significant relationship between exploration and ethanol ingestion, such that higher levels of nose poking were associated with increased home-cage alcohol consumption. In our strain of rats, then, the degree of novelty seeking may predict the propensity to drink ethanol. Our finding is in apparent contrast to that of Nowak et al. (2000), who reported that rats of the alcohol-preferring P line were no more prone than NP rats to nose poke in response to novel odours. This discrepancy may be due to the numerous methodological differences between the two studies; alternatively, it is possible that rats with a different genetic background drink alcohol for different reasons.
The same level of a given trait may be expressed in different ways, depending on other temperamental qualities. For example, the behaviour of individuals similar in novelty seeking but different in harm avoidance, may be quite separate, and vice versa (Cloninger, 1987). This point led us to analyse whether level of harm avoidance, which when considered separately was unrelated to alcohol consumption, would emerge as a significant factor when considered in combination with degree of novelty seeking. However, configurational frequency analysis failed to support an interaction between the two traits with respect to alcohol drinking. Hence, it appears as if novelty seeking alone is the dominant temperamental factor regulating ethanol intake in our strain of rats.
Because the animals in this part of the study had had access to alcohol for several weeks before testing, we cannot exclude the possibility that individual variations in drug intake caused the behavioural differences. That is, a high intake of alcohol may affect the brain permanently in such a way that exploratory behaviour is enhanced. While this certainly remains a possibility, we are not aware of any study showing that alcohol has enduring neurotoxic effects at the doses ingested by the present animals.
Behaviour following brain lesions
The amygdaloid lesions encompassed major portions of the central and basolateral nuclei. The localization of neuronal damage should be expected to obliterate much of the functioning of the amygdala, since the central nucleus receives cortical and subcortical input via the basolateral divisions, and constitutes the major output pathway of the amygdala (Pitkänen et al., 1997; Swanson and Petrovich, 1998
). An interesting behavioural effect of the amygdaloid damage was the instantaneous drop in home-cage ethanol intake. This finding would seem to suggest that the amygdala is involved in the neural circuitry regulating voluntary ethanol intake. A similar effect has been reported by Möller et al. (1997a) following axon-sparing lesions in the central, but not basolateral, amygdala. However, in our study post-operative water drinking was also depressed, raising the distinct possibility that the decrease in ethanol intake observed in our rats was secondary to a global deficit in fluid intake. Möller et al.'s study (1997a) showed, however, that smaller damage to the central amygdala can bring about a selective decrease in ethanol ingestion.
Current accounts of the amygdaloid complex highlight its role in a wide range of defensive and attentional responses (Woods, 1956; Blanchard and Blanchard, 1972
; LeDoux, 1996
; Kilcross et al., 1997
; Rosen and Schulkin, 1998
). In the present study, we found no consistent effect of amygdaloid damage on risk assessment in a novel arena, the post-operative trend of a suppression of stretched attend posturing just missing conventional levels of statistical significance. However, when taking into account the pre-operative level of risk assessment behaviour, a more robust effect was obtained. That is, animals with the higher level of pre-operative anxiety were significantly more sensitive to amygdaloid damage than were rats initially showing fewer stretched attend postures.
Yet, the effects of amygdaloid lesions on risk assessment were relatively marginal. For example, the average number of stretched attend postures in rats with lesions was still higher than that observed pre-operatively in low-anxious individuals. This suggests that the amygdala, as classically defined, may not constitute the major neuro-anatomical substrate for risk assessment behaviour. Non-existent to weak effects of amygdaloid lesions have also been observed in the elevated plus-maze paradigm (Möller et al., 1997a), and trait anxiety (in contrast to acute fear responses) remains unaffected by extensive amygdaloid lesions in the rhesus monkey (Shelton et al., 2000
). One possible resolution of this problem is the distinction between contextual and phasic fear-eliciting stimuli (Sparks and LeDoux, 1995
; Davis and Shi, 1999
). That is, amygdaloid mechanisms located in the temporal area appear to be involved in defensive responses to phasic, highly explicit and discrete cues, whereas fear responses elicited by more diffuse, long-term cues, such as being exposed to a threatening environment, do not. Recent work (Davis et al., 1997
; Davis and Shi, 1999
) on fear-potentiated acoustic startle suggests that the bed nucleus of the stria terminalis, i.e. the rostro-medial end of the extended amygdala (Alheid and Heimer, 1996
; De Olmos and Heimer, 1999
), mediates contextual generalized fear. On the basis of these considerations, one might hypothesize that lesions in the anterior limb of the extended amygdala would yield clearer decreases in risk assessment behaviour in the canopy test'. This hypothesis receives some support from a recent study of ours showing that basal forebrain lesions involving rostral parts of the extended amygdala depress stretched attend posturing in the rat (Johansson and Hansen, 2001
).
In contrast to the amygdaloid lesions, which attenuated information gathering (stretched attend posturing) in an aversive setting, ventral striatal lesions enhanced information gathering (nose poking) in an appetitive, or at least less frightening, situation. This increase was particularly marked in rats with a lower-than-average pre-operative level of novelty seeking. One reason for this behavioural change might be that dysfunction in ventral striato-pallidal circuits, in the form of faulty switching among behavioural alternatives (Redgrave et al., 1999; Parkinson et al., 2000
), increases the apparent perceptual curiosity' (Berlyne, 1955
) of the rat by enhancing the reward value intrinsic to novelty (Hughes, 1968
; Bardo et al., 1990
). This interpretation is in broad agreement with reports that rats with ventral striatal lesions eat more of novel tasty foods (Burns et al., 1996
), find the reward efficacy of certain stimuli greater than usual (Johnson et al., 1996
) and are less behaviourally inhibited by aversive events (Johansson and Hansen, 2000
). In accordance with several previous studies (Lorens et al., 1970
; Kafetzopoulos, 1986
; Maldonado-Irizarry and Kelley, 1995
; Burns et al., 1996
; Johansson et al., 1999
; Johansson and Hansen, 2000
, 2001
), we also observed enhanced locomotor activity which might reflect yet another form of altered responsiveness to a novel environment in this group of animals. Coupled with the increase in novelty seeking, there was, in rats with moderate pre-operative drinking habits, a significant enhancement of ethanol ingestion following ventral striatal lesions. This confirms a previous observation of ours (Johansson and Hansen, 2000
).
Basal forebrain lesions in rats stimulate alcohol drinking, increase novelty seeking and reduce harm avoidance (Johansson and Hansen, 2001). When the damage is extensive, extreme hyper-defensiveness appears along with other behavioural changes (Brady and Nauta, 1953
; Albert and Richmond, 1975
; Blanchard et al., 1979
; Hansen et al., 1995
; Bergvall et al., 1996
; Johansson et al., 1999
; Johansson and Hansen, 2000
). In the light of contemporary knowledge of the organization of the basal forebrain, it appears as if this syndrome is due to damage to both the ventral striatum and the anterior part of the extended amygdala (Alheid and Heimer, 1996
). For example, destruction of the area under the anterior septum', which seems so central for the emergence of aggressive hyper-defensiveness (Albert and Richmond, 1975
; Blanchard et al., 1979
), would today be regarded as damaging the caudo-medial part of the nucleus accumbens and the anterior bed nucleus of the stria terminalis. Although not all leading workers in the field concur (Swanson and Petrovich, 1998
; De Olmos and Heimer, 1999
), this area is composed of both striatal and amygdaloid tissue (Alheid and Heimer, 1996
). Building on this neuro-anatomical framework, we made a crude attempt to identify which behavioural changes stemmed from amygdaloid and striatal damage, respectively. Our results tentatively indicate that dysfunction in striatal circuits is responsible for the increases in novelty seeking and alcohol intake, whereas malfunctioning in amygdaloid networks reduces harm avoidance. Moreover, we suspect that, when the neural damage is extensive, and perhaps includes other systems, the resultant temperamental configuration leads to the vicious hyper-defensiveness (Brady and Nauta, 1953
; Albert and Richmond, 1975
; Blanchard et al., 1979
) and impulsivity (McCleary, 1961
; Kaada et al., 1962
) characterstic of animals with large basal forebrain lesions.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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