1 Department of Pharmacology, Institute of Psychiatry and Neurology, Sobieskiego 9 St., PL-02957 Warszawa,
2 Medagro International, Warszawa and
3 Department of Experimental and Clinical Pharmacology, Warsaw Medical Academy, Warszawa, Poland
Received 4 November 2002; in revised form 15 January 2003; accepted 10 February 2003
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ABSTRACT |
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INTRODUCTION |
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Both animals and humans demonstrate marked individual differences in their propensity to ethanol self-administration (e.g. Cloninger et al., 1988; Piazza et al., 1989
; Kampov-Polevoy et al., 1999
). Several preclinical and clinical studies aimed to identify trait markers for excessive alcohol intake (Bisaga and Kostowski, 1993
; Salimov, 1999
; Scinska et al., 2001
; Bienkowski et al., 2001
; for a review see Farren and Tipton, 1999
). In this respect, D2 receptors received much attention, since it has been reported that the TaqI A minor allele of the DRD2 gene (A1 allele) may be associated with alcohol dependence (Blum et al., 1991
; Noble, 2000
). Binding studies have revealed that the A1 allele predicts low D2 receptor availability in the human brain (Thompson et al., 1997
; Pohjalainen et al., 1998
). Animal studies have also provided some support for the relationship between D2 receptor function and alcohol drinking behaviour. Cools and co-workers have shown that rats genetically selected for low susceptibility to a non-selective D1/D2 receptor agonist, apomorphine, consumed more alcohol in a two-bottle choice procedure than rats selected towards high susceptibility to apomorphine (Cools and Gingras, 1998
; Sluyter et al., 2000
). In contrast, no relationship between apomorphine-induced stereotypy and subsequent ethanol drinking in another non-operant two-bottle choice procedure was found by Bisaga and Kostowski (1993)
.
The relationship between non-operant ethanol drinking and operant ethanol self-administration is still unclear. For example, it has been reported that rats avoiding alcohol in the two-bottle choice test may be successfully initiated to lever press for an alcohol solution in an operant oral self-administration procedure (George and Ritz, 1993; Koros et al., 1999b
). Given the above, we aimed to further characterize the relationship between D2 receptor-associated responses and ethanol self-administration. For this purpose, apomorphine-induced sniffing and raclopride (a D2 receptor antagonist)-induced catalepsy were assessed in male Wistar rats. It has been shown that both apomorphine-induced sniffing and raclopride-induced catalepsy are mediated by dopamine D2 receptors (Köhler et al., 1985
; Ögren et al., 1986
; De Keyser et al., 1995
; Rajakumar et al., 1997
; Germeyer et al., 2002
). Subsequently, lever pressing for ethanol was initiated in a procedure where increasing concentrations of ethanol were introduced in the presence of sucrose (Samson, 1986
; Bienkowski et al., 1999
, 2001
). A factor analysis was used to characterize relationships between these behavioural parameters.
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MATERIALS AND METHODS |
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Treatment of the rats in the present study was in full accordance with the ethical standards laid down in respective Polish and European (directive No. 86/609/EEC) regulations. All procedures were reviewed and approved by an ethics committee on animal studies.
Raclopride-induced catalepsy
Before the evaluation of the D2 receptor-associated responses, the rats were repeatedly familiarized with a horizontal wooden bar and an observational cage used for measurement of raclopride-induced catalepsy and apomorphine-induced sniffing, respectively. Raclopride-induced catalepsy was assessed first. Four days later, apomorphine-induced sniffing was evaluated in the same rats.
Catalepsy was observed 30, 60 and 90 min after administration of 1 mg/kg raclopride (Ögren et al., 1986; Wadenberg and Ahlenius, 1991
). Cataleptic responses were determined by a modification of the bar method (Undie and Friedman, 1988
). Each rat was placed on a clean, smooth table with the wooden bar suspended 10 cm above the working surface. The animals front paws were gently placed over the bar. The length of time (in seconds) the animal touched the bar with both front paws was measured up to a pre-set cut-off time of 180 s. Cataleptic responses were averaged across the three observation times.
Apomorphine-induced stereotypy
Apomorphine-induce sniffing was assessed in the rectangular cage (height x width x length: 25 x 25 x 42 cm) with wooden chip bedding on the floor. Twenty minutes after administration of 0.5 mg/kg apomorphine, each rat was placed in the observational cage and its sniffing behaviour was recorded for 30 min using a video camera (Ögren et al., 1986; Kostowski and Krzascik, 1989
).
Operant oral ethanol self-administration
Ethanol-reinforced behaviour was studied in eight standard operant chambers (Coulbourn Instruments, Inc., Allentown, PA, USA). The chambers consisted of modular test cages placed inside sound-attenuating cubicles with ventilation fans and background white noise (for details see Bienkowski et al., 1999). A white house light was centred near the top of the front of the cage. The start of test sessions was signalled by turning the house light on. The cage was also equipped with two response levers, separated by a liquid delivery system (a liquid dipper; Coulbourn Instruments, Inc.). Only one lever (an active lever) activated the liquid dipper. Presses on the other lever (an inactive lever) were recorded but not reinforced. The liquid delivery system presented a respective fluid in a 0.1 ml portion for 5 s. The availability of reinforcer was signalled by a brief audible click and a white light (4 W) located inside the liquid dipper hole. The programming of each session as well as data recording were based on the L2T2 Software package (Coulbourn Instruments, Inc.) running on an IBM-compatible PC.
The self-administration procedure started 10 days after the assessment of apomorphine-induced sniffing. The rats were trained to respond for 8% v/v ethanol according to the sucrose-fading procedure (Samson, 1986) with some modifications (Bienkowski et al., 1999
, 2001
). All sessions were 30 min long and there was only one session daily (Monday to Friday).
The whole procedure consisted of four phases. During the first 4 days of training, the animals were deprived of water for 22 h a day and shaped to lever press for water according to a fixed ratio 1 (FR1) schedule of reinforcement (Phase 1). As soon as the lever pressing was established (≥100 presses on the active lever/30 min), tap water became freely available in the home cages.
During days 56, the animals received 8% w/v sucrose (Phase 2). Then, over the next 14 sessions (sucrose fading; Phase 3), ethanol concentrations were gradually increased from 0 to 8%, and sucrose concentrations were decreased from 8 to 0%. The rats were given the following combinations of ethanol and sucrose solutions: 2.5% ethanol/8% sucrose (1 day); 5% ethanol/8% sucrose (2 days); 6.5% ethanol/8% sucrose (2 days); 8% ethanol/6% sucrose (2 days); 8% ethanol/4% sucrose (2 days); 8% ethanol/2% sucrose (2 days); and 8% ethanol/1% sucrose (3 days).
The subjects were then allowed to make their 8% ethanol consumption stable during the next 20 days (8% ethanol self-administration; Phase 4).
Drugs
Raclopride and apomorphine (both from Sigma, Poznan, Poland) were dissolved in sterile distilled water and administered intraperitoneally in a volume of 1 ml/kg. Raclopride and apomorphine solutions were prepared immediately prior to use and protected from light. Sucrose and ethanol (95% rectified spirit; Polmos, Zielona Gora, Poland) used in the self-administration procedure were dissolved in tap water. The solutions were prepared daily and stored at room temperature.
Data analysis
The active lever responding (lever presses/30 min) was averaged across the 2 days of 8% sucrose availability (Phase 2) and across days 15, 610, 1115 and 1620 of 8% ethanol self-administration (Phase 4). Sucrose (ml/kg/30 min; Phase 2) and ethanol (g/kg/30 min; Phase 4) intakes were estimated by measuring the amount of solution remaining in the dipper after the self-administration session.
A principal components factor analysis with varimax rotation (Salimov, 1999) was run for 12 variables, i.e. raclopride-induced catalepsy, apomorphine-induced sniffing, responding for and intake of 8% sucrose, and responding for and intake of 8% ethanol in the four successive weeks of Phase 4. All variables included in the factor analysis were independent and normally distributed. The Statistica software package for Windows (StatSoft, Tulsa, OK, USA) was used to analyse all data.
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RESULTS |
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DISCUSSION |
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The results of factor analysis were at variance with the reports of Cools and co-workers (Cools and Gingras, 1998; Sluyter et al., 2000
; see Introduction); however, one should bear in mind that a non-operant ethanol drinking procedure was used in these latter studies. In another study on this topic, Behnert et al.(1987)
analysed the relationship between ethanol drinking and subsequent behavioural reactivity to apomorphine. The authors have reported that apomorphine-induced stereotypy did not differ between alcohol-preferring and alcohol-naive rats. More recently, Samson and Chappell (1995)
have reported no correlation between amphetamine-induced locomotion and non-operant ethanol intake. As mentioned in the Introduction, clinical studies have suggested some association between the A1 allele of DRD2 gene and alcohol dependence (e.g. Blum et al., 1991
). However, the most recent large family-based study (the COGA project) was negative (Edenberg et al., 1998
). Taken together, the present and previous studies suggest that D2-associated responses may not serve as predictors of ethanol self-administration.
It can be argued that the behavioural responses assessed in the present study were associated with D2 receptors located in the dorsal striatum (Arnt, 1985; Klockgether et al., 1988
), while it is dopamine transmission in the nucleus accumbens that plays a specific role in drug reinforcement (Wise, 1998
). However, D2 receptors in the nucleus accumbens may also contribute to cataleptic responses induced by dopamine antagonists (Al-Khatib et al., 1989
; Ossowska et al., 1990
). Similarly, various stereotypical responses, including apomorphine-induced sniffing, may depend on both striatal and accumbal dopamine transmission (Arnt, 1985
; Bradberry et al., 1991
). On the other hand, selective lesions of mesolimbic dopaminergic neurones with 6-hydroxydopamine (6-OHDA) failed to alter either free-choice ethanol drinking or operant responding for ethanol (Lyness and Smith, 1992
; Rassnick et al., 1993
; Ikemoto et al., 1997
; Koistinen et al., 2001
). Notably, Ikemoto et al.(1997)
have shown that although the 6-OHDA lesion did not alter ethanol consumption in rats that had prior experience with ethanol, it slowed the acquisition of ethanol preference in subjects with no ethanol-drinking history. In two of the above studies, genetically selected alcohol-preferring rats served as subjects (Ikemoto et al., 1997
; Koistinen et al., 2001
).
The results of the present study and the data cited above do not exclude the possibility that other dopamine receptor subtypes play a more prominent role in the regulation of alcohol reinforcement. For example, D1 receptors seem to be related to addictive behaviours in general (Self and Nestler, 1995; Cohen et al., 1999
; Farren and Tipton, 1999
) and D3 receptors may be preferentially involved in operant ethanol self-administration in rats (Cohen et al., 1998
).
The absence of a consistent relationship between operant responding for 8% sucrose and 8% ethanol was not surprising. Contrary to previous suggestions (for a review see Kampov-Polevoy et al., 1999), sweets preference predicted neither long-term two-bottle choice alcohol intake in Wistar rats (Koros et al., 1998
, 1999a
) nor the risk of alcohol dependence in humans (Bogucka-Bonikowska et al., 2001
; Scinska et al., 2001
). In a more recent study, Rogowski et al.(2002)
assessed correlations between parameters of operant sucrose and ethanol self-administration in the sucrose-fading procedure. As in the present study, the factor analysis did not show any relationship between sucrose- and ethanol-reinforced behaviour.
The present experiment and other studies of correlations between drug-induced responses and ethanol self-administration may be confounded by carry-over effect(s). One may hypothesize that even a single exposure to a test drug (apomorphine and raclopride in the present study) may alter subsequent initiation of ethanol self-administration. Although the risk of such carry-over effects cannot be fully avoided, one may address this problem by including in future studies an additional control group pre-treated with respective drug vehicles.
A highly significant correlation between responding on the active lever and ethanol consumption (in g/kg) was found in the present and previous studies from our laboratory. Although it has been shown that these measures may predict alcohol concentration in the animals body, correlations between lever pressing, alcohol intake and blood alcohol levels are not perfect (Suzuki et al., 1988; Czachowski et al., 1999
). Thus, assessment of blood alcohol levels could increase the validity of future experiments on the relationship between receptor-mediated behavioural responses and ethanol self-administration.
In conclusion, there is no consistent relationship between apomorphine-induced sniffing, raclopride-induced catalepsy and operant responding for ethanol in Wistar rats. Our results, combined with previous reports, suggest that D2 receptors are not primarily involved in the regulation of ethanol reinforcement.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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