ETHANOL-REINFORCED BEHAVIOUR PREDICTS ACQUISITION BUT NOT EXTINCTION OF COCAINE SELF-ADMINISTRATION IN THE RAT

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1 Alcohol & Alcoholism Vol. 38, No. 6, pp , 2003 doi: /alcalc/agg114, available online at ETHANOL-REINFORCED BEHAVIOUR PREDICTS ACQUISITION BUT NOT EXTINCTION OF COCAINE SELF-ADMINISTRATION IN THE RAT PAWEL MIERZEJEWSKI 1,2, ARTUR ROGOWSKI 1, ROMAN STEFANSKI 1,2, STEVEN GOLDBERG 3, WOJCIECH KOSTOWSKI 1,2 and PRZEMYSLAW BIENKOWSKI 1 * 1 Department of Pharmacology, Institute of Psychiatry and Neurology, 2 Department of Experimental and Clinical Pharmacology, Warsaw Medical Academy, Warsaw, Poland and 3 Preclinical Pharmacology Section, Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA (Received 11 March 2003; first review notified 7 May 2003; in revised form 28 May 2003; accepted 10 June 2003) Abstract Aims: The aim of the present study was to evaluate the relationship between operant oral ethanol self-administration and intravenous (i.v.) cocaine self-administration in male Wistar rats. Methods: Twenty-four rats were trained to lever press for 8% v/v ethanol in the sucrose-fading procedure. The subjects with the highest (high ethanol responders [HER], n =7) and lowest (low ethanol responders [LER], n=7) ethanol intakes were selected for further experiments. After a wash-out period, during which i.v. catheters were implanted, the HER and LER were trained to nose-poke for cocaine infusions (0.33 mg/kg/infusion, a FR1 schedule) for nine daily sessions. Results: The HER emitted more active nose-pokes and obtained more cocaine infusions during sessions 2 4. Drug-seeking behaviour in the absence of cocaine reinforcement was then assessed for three consecutive extinction sessions. No between-group differences were found in terms of extinction of cocaine seeking. Locomotor responses to a novel environment were also similar in both groups. Conclusions: The present results suggest that a propensity to self-administer ethanol predicts more rapid acquisition of cocaine self-administration behaviour but does not influence subsequent behaviour during extinction. INTRODUCTION Both laboratory animals and humans demonstrate marked individual differences in their propensity to acquire alcoholand drug-taking behaviour (Piazza et al., 1989; George and Ritz, 1991; Koros et al., 1998; Merikangas et al., 1998). An interesting aspect of the above findings is the degree to which consumption of legally available substances (e.g. alcohol) might predict self-administration of illicit drugs (e.g. cocaine). Several epidemiological studies have indicated that cocaine and alcohol misuse go together. For example, subjects with the diagnosis of alcohol dependence are more likely to become cocaine misusers and experience more adverse consequences of cocaine use (Heil et al., 2001; Staines et al., 2001). On the other hand, alcohol abuse is a common problem among cocaine-dependent patients (Miller et al., 1989). In line with the clinical data, Gahtan et al. (1996) have reported that rates of intravenous (i.v.) cocaine self-administration predicted subsequent ethanol intake in Wistar rats. The exact nature (genetic vs environmental) of the above findings remains to be established. It has been reported that pre-treatment with amphetamine (Horger et al., 1992; Valadez and Schenk, 1994), nicotine (Horger et al., 1992), and 3,4-methylenedioxy-methamphetamine (Fletcher et al., 2001) enhanced the positive reinforcing effects of cocaine in the rat. Thus, one could hypothesize that also ethanol pre-treatment may facilitate cocaine self-administration. Notably, all data cited above support theories linking reinforcing properties of different drugs with a common neurochemical mechanism (e.g. activation of dopaminergic transmission in the limbic system) (George, 1991; Wise, 1998; Di Chiara, 1999). *Author to whom correspondence should be addressed at: Department of Pharmacology, Institute of Psychiatry and Neurology, 9 Sobieskiego St., PL-02957, Warsaw, Poland. Tel.: ; Fax: ; pbienko@yahoo.com In the present study, we aimed to test a hypothesis that individual differences in ethanol self-administration might predict acquisition of cocaine self-administration in the rat. The present study was not designed to answer a question of whether or not any associations between ethanol and cocaine self-administration were environmental (effects of ethanol pre-treatment) or genetic in nature. A group of Wistar rats was trained to lever press for oral ethanol in the sucrose-fading procedure (Samson, 1986; Bienkowski et al., 1999a,b). Rats with the highest (high ethanol responders [HER]) and lowest (low ethanol responders [LER]) ethanol intakes were subsequently trained to nose-poke for i.v. cocaine infusions. MATERIALS AND METHODS General design Studies of correlations between operant responses for different reinforcing events should take into account possible carry-over effects. Rats trained to respond for one drug may be prone to maintain self-administration of another substance in the same test environment. Thus, in the present study, ethanol and cocaine self-administration was initiated in different sets of operant test cages located in different experimental rooms. Different operanda were mounted in the ethanol (levers) and cocaine test cages (nose-poke holes ). For a given rat, a socalled active hole and active lever were always located on the opposite sides of the test cages (e.g. if a left lever was active in the ethanol cage, a right hole was active in the cocaine cage). Table 1 presents a general design of the study. Animals Twenty-four male Wistar rats (Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland) weighing g at the beginning of the study were kept in a room with constant environmental conditions (temperature 22 ± 1 C; ~60% humidity; 12-h light dark cycle: light on at 06:00 hours). 543 Alcohol & Alcoholism 38 Medical Council on Alcohol 2003; all rights reserved

2 544 P. MIERZEJEWSKI et al. Table 1. Order of experimental procedures lever pressing for oral ethanol (n =24 rats) shaping of operant behavior, 4 sessions sucrose-fading, 16 sessions maintenance phase, 20 sessions selection of LER (n =7) and HER (n =7)* two-week wash-out period surgical procedures measurement of spontaneous locomotor activity nose-poking for i.v. cocaine, 9 sessions extinction of cocaine-seeking behaviour, 3 sessions *Only low ethanol responders (LER) and high ethanol responders (HER) were run in further experiments. A fixed ratio 1 (FR1) schedule of reinforcement was used in both self-administration procedures. The rats were tested between 14:00 hours and 16:00 hours. Food (Labofeed H; WPiK, Kcynia, Poland) was available ad libitum. Tap water was available ad libitum except as noted below. Treatment of the rats in the present study was in full accordance with the ethical standards laid down in respective European (directive no. 86/609) and Polish regulations. All procedures were reviewed and approved by a local Ethics Committee on Animal Studies. Apparatus Ethanol- and cocaine-reinforced behaviour was studied in eight standard operant chambers (Coulbourn Instruments, Allentown, PA, USA). The ethanol and cocaine chambers were located in the rooms with controlled environmental conditions. The rooms differed in size, colour and illumination details. The chambers consisted of the test cages (E10-18TC; Coulbourn) enclosed within sound-attenuating cubicles with fans for ventilation and background white noise. A white house light was centred near the top of the back wall of the chamber. The start of each session was signalled by turning the house light on. The ethanol cages (for details, see Bienkowski and Kostowski, 1998; Bienkowski et al., 1999a,b) were equipped with two response levers ( active and inactive ), separated by a liquid delivery system (a liquid dipper, E14-05; Coulbourn). Only the active levers activated the liquid dippers. Presses on the inactive levers were recorded but had no programmed consequences. The liquid delivery system presented a respective solution (see below) in a 0.1-ml portion for 5 s. The availability of liquid was signalled by a brief audible click and a small white light (4 W) located inside the dipper. The cocaine cages were equipped with two nose-poke holes and an i.v. injector system (for details, see Stefanski et al., 1999, 2002). Nose-pokes in the active holes resulted in delivery of cocaine solution (0.1 ml within 2 s), whereas nose pokes in the inactive holes were recorded but had no programmed consequences. Each nose-poke response produced a brief feedback tone. Following each cocaine infusion there was a 30-s time-out (TO 30 s) period during which responding was recorded but had no programmed consequences. The house light was on during drug availability but was turned off during the entire infusion and TO period. The injector system contained a fluid swivel (A73-51; Coulbourn) mounted on top of the cage. One end of the swivel was connected via polyethylene tubing encased in a protective stainless steel spring tether to the animal s catheter, while the other end of the swivel was connected via polyethylene tubing to an infusion pump (Razel, Stamford, CT, USA). The rat harness (A71-21R-350/500; Coulbourn) protected the catheter from being pulled out while the rat was in the operant cage. Programming of all sessions as well as data recording made use of L2T2 (the ethanol cages) or WinLinc (the cocaine cages) Coulbourn software and IBM-compatible computers. Ethanol self-administration and selection of experimental groups Twenty-four rats were trained to respond for 8% v/v ethanol according to the procedure described by Samson (1986) and modified by Bienkowski et al. (1999a,b). All training sessions were 30 min long and there was one session each day, Monday to Friday. The rats were deprived of water for 22 h/day during the first 4 days of training and shaped to lever press for water on a fixed ratio 1 schedule of reinforcement (FR1; each lever press produced 5-s access to a dipper of water or ethanol solution). As soon as lever pressing was established, water was made freely available in the home cages. On days 5 and 6, the animals self-administered 8% w/v sucrose solution (8% sucrose/0% ethanol). Then, over the next 14 sessions, ethanol concentrations were gradually increased from 0 to 8%, and sucrose concentrations were decreased from 8 to 0%. Finally, testing was continued for another 20 days (a maintenance phase) to allow 8% ethanol consumption to stabilize. The seven rats with the highest ethanol intakes (HER; 30% of the whole group) and the seven rats with the lowest ethanol intakes (LER) during the last 5 days of the maintenance phase were selected for further experiments. The selection of the HER and LER was thought to maximize the difference between the two experimental groups. There was a 2-week wash-out period after the maintenance phase, during which rats were surgically prepared with i.v. catheters and were tested for locomotor activity in a novel open field arena (Table 1). Surgery Chronic i.v. catheters were implanted into the right jugular vein under ketamine anaesthesia [75 mg/kg intraperitoneally (i.p.)]. A small incision was made to the right of the midline of the neck and the external jugular vein was isolated and opened. A silastic catheter (for details, see Stefanski et al., 1999, 2002) was inserted into the vein and anchored into the neck muscles by sutures. The other end of the catheter was threaded subcutaneously (s.c.) around the animal s back and exited the skin through a small opening near the midscapular region. An obturator was inserted into the distal end of the catheter to prevent its clogging and maintain a closed system. One week of recovery was allowed before the start of further experiments. The catheters were flushed each day with a 0.1-ml sterile saline containing heparin (1.25 U/ml) and gentamicin (0.16 mg/kg). Catheter patency was tested periodically with methohexital (10 mg/kg i.v.) for loss of consciousness within 5 s. In addition, the patency of all catheters was verified at the end of the study. Assessment of spontaneous exploratory activity One week after the completion of the surgical procedures, open-field activity was measured, as described by Koros et al. (1998). The open-field apparatus consisted of four identical

3 ETHANOL AND COCAINE SELF-ADMINISTRATION IN THE RAT 545 computer-controlled cages ( cm; COTM, Bialystok, Poland) located in a dimly lit room with a background white noise of 60 db. Each cage was transected by two perpendicular, coplanar arrays of 16 infra-red photocells (located 3 cm above floor level) which were intended to measure horizontal activity (in cm) by determining the rat s position every 100 ms. Another set of photocells located 15 cm above the cage floor measured the number of rearings. After initial habituation for 20 min to the test room, each rat was placed in the open field arena for another 20 min. The cages were carefully cleaned between the recordings. The latency to the first active nose-poke during the first self-administration session (i.e. before any cocaine infusion was obtained) was used as another measure of exploratory behaviour in the HER and LER. Acquisition and extinction of cocaine self-administration The HER and LER were allowed to nose-poke for cocaine infusions (0.33 mg/kg) on a FR1, TO 30 s schedule of reinforcement. When the house light was on, each nose poke in an active hole produced a cocaine infusion. During the 30-s TO that followed each infusion, the house light was off and nose pokes in the active hole had no programmed consequences. Self-administration sessions were 2 h in duration and there was one session each day, Monday to Friday. At the beginning of each session, a cocaine injection was automatically delivered to fill the dead space of the catheter. After nine self-administration sessions (i.e. when operant responding reached plateau), three 1-h extinction sessions were given. During the extinction sessions, nose pokes in the active hole produced infusion of saline instead of cocaine according to the FR1 schedule of reinforcement. Drugs Ethanol solutions were prepared daily from a 96% stock solution (Polmos, Zielona Gora, Poland) and tap water. Cocaine hydrochloride (Pharma Cosmetics, Krakow, Poland) was dissolved in sterile physiological saline (Polfa, Lublin, Poland). The cocaine dose (0.33 mg/kg) refers to the salt form. All solutions were prepared immediately prior to use. Statistics The Statistical software package (StatSoft, Tulsa, OK, USA) was used to analyse all data. Data are presented as group means with standard errors of the means (SEM). Student s t-test was used to locate differences between the HER and LER in terms of body weights, sucrose and ethanol intakes and spontaneous exploratory activities. A two-way (group day) or a three-way (group hole day) ANOVA with repeated measures on a day factor was employed to analyse the parameters of cocaine self-administration (infusions and nose-poke responding, respectively). The threeway ANOVA (group hole day) was also used to analyse extinction of cocaine-seeking. Newman Keuls test was chosen for post-hoc comparisons. A probability level (P) <0.05 was considered significant. Pearson product moment correlation test was used to search for correlations between cocaine self-administration and extinction of cocaine-seeking behaviour. In addition to control for baseline, between-group differences in cocaine self-administration, responding in the active hole during the first extinction session, was expressed as a percentage of responding in the active hole during the last selfadministration session [100 active responses during the first extinction session / active responses during the last selfadministration session]. Mann Whitney U-test was used to compare extinction scores calculated for the HER and LER. RESULTS Ethanol self-administration in HER and LER The HER and LER did not differ in terms of their body weights at the time of selection or at any other stage of the study (t-values <1.65; d.f. = 12; P-values >0.12, Student s t-test; Table 2). The HER emitted significantly more responses on the active lever and consumed significantly more ethanol than the LER in the last week of the maintenance phase. Ethanol consumption averaged across the whole 20-day maintenance phase was also significantly higher in the HER group (Table 2). In the ethanol self-administration procedure, the mean number of inactive lever presses never exceeded 0.7 responses/ session (data not shown). Table 2. Behavioural characteristics of high ethanol responders (HER) and low ethanol responders (LER) before initiation of cocaine self-administration Parameter (mean ± SEM) LER (n =7) HER (n =7) Student s t-test Body weight (g)* 425 ± ± 18 t = 1.32, P = 0.21 Lever pressing for 8% w/v sucrose (responses/30 min) 101 ± ± 29 t = 0.29, P = % w/v sucrose consumption (ml/kg/30 min) 29.5 ± ± 9 t = 0.22, P = 0.89 Lever pressing for 8% v/v ethanol (responses/30 min) days ± 2 46 ± 4 t = 9.18, P < Absolute alcohol consumption (g/kg/30 min) days ± ± 0.07 t = 7.56, P < Lever pressing for 8% v/v ethanol (responses/30 min) days ± 2 56 ± 4 t = 10.11, P < Absolute alcohol consumption (g/kg/30 min) days ± ± 0.08 t = 7.76, P < Open-field activity Horizontal (cm/20 min) 6248 ± ± 239 t = 0.36, P = 0.71 Number of rearings 38 ± 9 44 ± 10 t = 0.46, P =0.65 Latency to the first active nose-poke** 430 ± ± 42 t = 0.79, P = 0.44 *Measured at the time of the group selection. Averaged across the 2 days of 8% sucrose availability. Averaged across the final 5 days of the maintenance phase. Averaged across the whole maintenance phase. Measured during the wash-out period. **Measured during the first session of cocaine self-administration.

4 546 P. MIERZEJEWSKI et al. Spontaneous exploratory activity in HER and LER before initiation of cocaine self-administration The HER and LER did not differ in terms of horizontal or vertical locomotor activity in the open field arena. Similarly, latencies to the first active nose-poke did not differ significantly between the groups (Table 2). Cocaine self-administration in HER and LER Nose-poke responding. Both groups acquired cocaine-selfadministration as confirmed by significant hole [F(1,24) = 13.84; P < 0.01] and day [F(8,192) = 2.29; P < 0.05] effects, and a significant hole day interaction [F(8,192) = 3.93; P <0.01] (Fig. 1a). The ANOVA indicated that the HER emitted more active and inactive responses during the self-administration sessions [a significant group effect: F(1,24) = 5.11; P < 0.05]. Although a group hole interaction did not reach significance [F(1,24) = 2.67; P = 0.11], the post-hoc analysis revealed that the above difference was significant only for active hole responding during sessions 2, 3, 4, 7 and 9 (Fig. 1a). Cocaine infusions The ANOVA revealed that the HER consumed more cocaine than the LER [a significant group effect: F(1,40) = 5.43; P < 0.05]. The difference reached significance in sessions 2 4 and decreased with time as confirmed by a significant group day interaction [F(8,320) = 2.93; P < 0.01] (Fig. 1b). Extinction of cocaine-seeking behaviour Both groups extinguished their cocaine-seeking behaviour as revealed by a significant day effect [F(2,48) = 13.83; P < 0.001] and a significant hole day interaction [F(2,48) = 9.04; P < 0.01] (Fig. 1a, right-hand panel). However, no between-group differences were found as a group effect and all interactions were non-significant (F-values <1). The percentage extinction score [100 active responses during the first extinction session / active responses during the last self-administration session] did not differ between the HER (96 ± 42%) and LER (126 ± 36%; P = 0.33; Mann Whitney test). There were no correlations between the parameters of cocaine self-administration in the nine self-administration sessions and nose-poking in the three extinction sessions (n =14 rats; r-values <0.46; P-values >0.1; Pearson test). DISCUSSION The rats consuming the highest amounts of ethanol in the operant self-administration procedure (the HER) acquired cocaine self-administration more readily than the subjects with the lowest ethanol intakes (the LER). In this respect, our results are consistent with previous clinical observations that a positive relationship exists between ethanol and cocaine consumption in humans (e.g. Miller et al., 1989; Heil et al., 2001; see Introduction). Several basic hypotheses could explain our findings. First, it is possible that the same gene(s) control both ethanol and cocaine self-administration in Wistar rats. In line with this hypothesis, Hyytiä and Sinclair (1993) have reported that genetically-selected alcohol preferring AA rats consumed Fig. 1. (a) Total numbers (means ± SEM, bars) of active (AC; squares) and inactive (IN; circles) nose-pokes emitted by low ethanol responders (LER; closed symbols) and high ethanol responders (HER; open symbols) during nine cocaine 2-h self-administration sessions (SA1 SA9) and three 1-h extinction sessions (E1 E3). (b) Total numbers (means ± SEM, bars) of cocaine infusions (0.33 mg/kg/infusion) obtained by the two groups. *P < 0.05,**P < 0.01 vs the LER, Newman Keuls test; n = seven rats per group. more cocaine solution than their alcohol non-preferring ANA counterparts in the two-bottle choice procedure. The AA rats were more sensitive to chronic cocaine in terms of dopamine release in the nucleus accumbens (Mikkola et al., 2001), and sensitization of locomotor activity (Honkanen et al., 1999). Similar results were obtained when behavioural responses to opioid agents were compared in the AA and ANA subjects (Hyytiä and Sinclair, 1993; Hyytiä et al., 1996; Honkanen et al., 1999). Secondly, it is possible that chronic alcohol consumption alters subsequent initiation of cocaine self-administration. Although the rewarding effects of cocaine measured with a conditioned place preference procedure remained unaffected after chronic ethanol drinking (Le Pen et al., 1998), cocaineinduced conditioned taste aversion was diminished after chronic ethanol pre-exposure (Kunin et al., 1999). Ethanol and cocaine exert their central effects through interactions with common neurotransmitter systems, including dopaminergic,

5 ETHANOL AND COCAINE SELF-ADMINISTRATION IN THE RAT 547 opioidergic, serotonergic, noradrenergic and others (Koob and Weiss, 1992; Fadda and Rosetti, 1998; Faingold et al., 1998; Turchan et al., 1999). Chronic ethanol intake in rats decreases binding densities of dopamine D 1 and D 2 receptors (Lucchi et al., 1988) and suppresses dopamine synthesis and release (Diamond and Gordon, 1997; Fadda and Rosetti, 1998). Accordingly, in the present study, chronic ethanol selfadministration might affect some basic dopamine-related mechanisms involved in the acquisition of cocaine-taking behaviour (Koob and Weiss, 1992; Wise, 1998). It has been reported that dopamine receptor antagonists enhance selfadministration of higher cocaine doses. This effect is consistent with an attenuation of cocaine reward (e.g. Bergman et al., 1990; Caine et al., 1995). Similarly, in the present study, presumed hypofunction of dopaminergic transmission induced by ethanol might have led to compensatory increases in cocaine self-administration in the HER. In fact, it seems that it was more the level of cocaine consumption than the speed of acquisition of self-administration behaviour that really differentiated the two experimental groups in the present study. On the other hand, Katner and Weiss (2001) have reported that elevated extracellular dopamine levels in the nucleus accumbens predicted high ethanol preference in rats. Thus, it is possible that it was rather elevated dopaminergic transmission which enhanced cocaine self-administration in the HER. Finally, chronic alcohol intake could modify subsequent cocaine responses through alterations in its pharmacokinetics. Vadlamani et al. (1984) have found that ethanol pre-treatment (2.5 g/kg, twice daily for 16 days) produced significantly higher brain-to-plasma cocaine concentration ratios. More recently, Pan and Hedaya (1999) have reported that chronic pre-exposure to 10% ethanol in the drinking water led to increases in cocaine plasma concentration, which correlated with heightened central and peripheral responses to cocaine. In contrast, no changes in cocaine plasma concentrations after acute ethanol administration have been shown by Briscoe et al. (1999). It should be stressed that forced administration of relatively high ethanol doses ( 4 g/kg/day) was used in the above studies. In the present study, acute pharmacokinetic interactions between ethanol and cocaine were unlikely as the 2-week wash-out period was introduced between the last ethanol and the first cocaine self-administration session. On the other hand, chronic effects of ethanol pre-exposure on cocaine pharmacokinetics may not be excluded as blood cocaine levels were not assessed in the HER and LER. Further experiments will be needed to resolve this issue. The hypotheses discussed above may not be exclusive. Several human studies have indicated that both genetic and environmental factors determine initiation of regular drug use (Bierut et al., 1998; Merikangas et al., 1998; Uhl, 1998). Regardless of its genetic and/or environmental nature, a general propensity to drug self-administration (Hyytiä and Sinclair, 1993; Gahtan et al., 1996; Tsuang et al., 1998; the present study) may result from a specific drug-prone behavioural profile including alterations in incentive learning and reward processing (Wise, 1998; Di Chiara, 1999; Koob and Le Moal, 2000). Less specific behavioural traits could also increase probability of drug self-administration. For example, heightened impulsivity has been reported in various populations of drug misusers (Moeller et al., 2001; Petry, 2001), as well as in alcohol preferring-rats (Poulos et al., 1995) and this could facilitate initiation of drug-taking behaviour. One may argue that rats successfully trained to work for one drug will be more prone to acquire self-administration of another substance in the same environment ( carry-over effects). As mentioned in the Materials and methods section, care was taken to differentiate the two self-administration procedures. The HER and LER did not differ in terms of lever pressing for sucrose, locomotor activity in the open field or latencies to the first active nose-poke. Lastly, the groups emitted similar numbers of both active and inactive nose pokes during the first cocaine self-administration session. Thus, although we may not completely rule out this hypothesis, it seems that it cannot fully account for the present findings. Lack of differences between the HER and LER in their spontaneous locomotor behaviour measured after the initiation of lever pressing for ethanol was not surprising. We have shown that open-field activity did not predict subsequent 24-h ethanol drinking (Koros et al., 1998) or operant responding for ethanol solution (Bienkowski et al., 2001). On the other hand, our findings do not agree with previous reports showing that locomotor responses to novel environment correlated with self-administration of psychostimulants (Piazza et al., 1989; Bardo et al., 1996). However, one should be aware that the above correlation may only be true for threshold doses of psychostimulants. Several groups found no relationship between locomotor responses to novelty and self-administration of higher (>0.25 mg/kg) doses of cocaine (Kruzich et al., 1999; Sutton et al., 2000; Mantsch et al., 2001). Surprisingly, the two groups emitted almost identical numbers of responses when tested in the extinction sessions. This observation was rather unexpected as the HER earned more cocaine infusions and emitted more active nose-pokes than the LER. Moreover, no overall correlation between cocaine self-administration and nose-poking in extinction was found. In this respect, our results are in line with previous reports showing that drug self-administration and drugseeking behaviour may be regulated by at least partially different neuronal mechanisms (e.g. Meil and See, 1997). Kruzich et al. (1999) have reported that levels of cocaine selfadministration did not predict extinction of cocaine-seeking behaviour, although a trend towards a negative correlation was observed. No relationship between amphetamine selfadministration under a progressive ratio schedule and subsequent extinction of amphetamine-seeking behaviour has been found by Mendrek et al. (1998). Earlier studies on correlations between ethanol self-administration and ethanolseeking behaviour have brought similar results. Ethanol selfadministration did not predict either extinction or cue-induced reinstatement of ethanol-seeking in non-selected rats (Koros et al., 1999; Samson et al., 2001; Bienkowski et al., unpublished observation). In contrast, Vacca et al. (2002) observed a positive correlation between ethanol self-administration and extinction responding in genetically selected Sardinian alcohol-preferring rats. In conclusion, the present findings indicate that propensity to self-administer high amounts of alcohol may predict more rapid acquisition of cocaine self-administration behaviour but not the speed of subsequent extinction of cocaine selfadministration behaviour.

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