Psychopharmacology (1997) 129:277-284

9 Springer-Verlag 1997

P e t e r J. P i e r r e . P a u l V e z i n a

Predisposition to self-administer amphetamine: the contribution of response to novelty and prior exposure to the drug

Received: 6 July 1996/Final version: 5 October 1996

The-present experiment examined the contribution of locomotor response to novelty and prior exposure to amphetamine to rats' predisposition to self-administer a low dose of the drug. Rats were screened for their locomotor response to a novel environment and divided into high (HR) or tow (LR) responders based on whether their locomotor scores were above or below the median activity level of the subject sample. Animals were then pre-exposed to nine daily injections of either saline (1 ml/kg, IP) or amphetamine (1.5 mg/kg. IP). Starting 1 week after pre-exposure, animals in the four different groups (HR pre-exposed to saline or amphetamine; LR pre-exposed to saline or amphetamine) were given the opportunity, in each of ten daily sessions, to lever press for a low dose of amphetamine (10 ~ag/kg per infusion) in a two lever (active versus inactive) continuous reinforcement operant task. Initial lever press performance revealed no difference in active versus inactive lever pressing between amphetamine and saline pre-exposed animals. However, in agreement with previous reports, with successive test sessions amphetamine pre-exposed rats maintained higher levels of active versus inactive lever pressing for drug while saline pre-exposed rats showed a progressive decrease in the pressing of either lever. Interestingly, this enhanced active lever pressing was observed in HR but not LR rats pre-exposed to amphetamine. In addition, HR saline pre-exposed animals showed initial active versus inactive lever pressing equivalent to that of HR amphetamine pretreated rats but this enhanced responding for drug diminished over days and by the last day of self-administration was indistinguishable from that of LR animals having been pre-exposed either to amphetamine or saline. These findings confirm that prior exposure to amphetamine promotes the subsequent self-administration of the drug and suggest that response to novelty may be a predictor more closely linked to an animal's propensity to become sensitized to the facilitatory effects of the drug rather than to Abstract

EJ. Pierre 9 R Vezina ( ~ ) Department of Psychiatry, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA

an animal's current sensitization state and predisposition to self-administer the drug. Key words Amphetamine 9 Pre-exposure - Locomotor activity 9 Sensitization - Response to novelty Self-administration- Predisposition

Introduction Pre-exposure to psychomotor stimulant drugs, like amphetamine, is known to lead to sensitized behavioral responding to subsequent administrations of these drugs (for review, see Kalivas and Stewart 1991). More particularly, there have now been several demonstrations that animals pre-exposed to a sensitizing regimen of amphetamine injections will subsequently be more predisposed to lever press for the intravenous injection of a small dose of amphetamine or cocaine than saline pre-exposed animals (Woolverton et al. 1984; Piazza et al. 1989, 1991a; Horger et al. 1990, 1992), As with the locomotor and biochemical enhancements characteristic of sensitization to amphetamine (Paulson et al. 1991; Paulson and Robinson 1995), such facilitation of subsequent drug self-administration probably reflects a long lasting phenomenon, having been demonstrated 45 days following pre-exposure to amphetamine (Valadez and Schenk 1994). The finding that prior exposure to a drug may influence later responding to it as well as to other drugs has led to investigations of subjects' past histories in an attempt to isolate aspects of behavior that are predictive of future drug taking. Both stress and social isolation, for example, have been shown to produce cross-sensitization to the locomotor activating effects of psychomotor stimulant drugs as well as to increase the propensity to selfadminister these drugs (Schenk et al. 1987; Piazza et al. 1990; Deminiere et al. 1992; Ahmed et al. 1995; Haney et al. 1995; Henry et al. 1995). Recently, Piazza et al. (1989) suggested that an animal's locomotor response to a novel environment may serve as a predictor of its pre-

278 disposition subsequently to respond for drug. In a series of experiments, they found that animals with a higher response to novelty (HR: high responders) displayed apparently sensitized responding to amphetamine indicated by a higher locomotor response to the drug and higher overall levels of self-administration of the drug compared to animals with a lower response to novelty (LR: low responders). The additional finding that LR animals could be made to self-administer amphetamine, like HR animals, by exposing them to a sensitizing drug regimen suggested that the latter may already be sensitized and because of this be more predisposed to self-administer the drug (Piazza et al. 1989, 1991a). Indeed, it has been reported that, in addition to enhanced behavioral responding, HR animals also exhibit, relative to LR animals, higher dopaminergic activity in the nucleus accumbens in response to novelty (Piazza et al. 1991b), tailpinch stress (Rouge-Pont et al. 1993), amphetamine (Bradberry et al. 1991) and cocaine (Hooks et al. 1991c). HR animals have also been reported to exhibit higher basal dopaminergic activity in this nucleus (Piazza et al. 1991b; Hooks et al. 1992a) although this has not been observed in animals sensitized to amphetamine (Crippens et al. 1993). Considerable evidence links nucleus accumbens dopamine to the locomotor activity produced and self-administration supported by psychomotor stimulant drugs (Deminiere et al. 1989; Bozarth 1991; Robinson and Berridge 1993). The above relationships between an animal's locomotor response to novelty and its locomotor response to acute and repeated injections of psychomotor stimulants have not always been observed, however. It is not clear, for example, whether the enhanced biochemical and behavioral responding described above in HR rats reflects prior sensitization in these animals or enhanced sensitivity or reactivity to the unconditioned drug stimulus. Some have reported that HR animals show maximal locomotor responding to drug challenge and no further sensitization of this response with repeated injections, while LR animals show lower initial locomotor responding but progressive sensitization of this response with repeated injections (Piazza et al. 1989). Others have similarly found higher acute locomotor responding to amphetamine in HR compared to LR animals but equal development of locomotor sensitization with repeated injections in these two groups (Ahmed et al. 1993; Exner and Clark 1993). Alternatively, it has also been reported that HR animals are more predisposed to develop locomotor sensitization and conditioning of drug effects than LR animals and that, at least for sensitization, this effect need not necessarily be related to animals' initial response to the drug (Hooks et al. 1991a,b, 1992b, 1994; Ahmed et al. 1993; Jodogne et al. 1994). Interestingly, in one of the latter experiments, exposing LR animals to a higher dose of the sensitizing drug than that used with HR animals produced similar levels of locomotor sensitization and conditioning in both groups (Ahmed et al. 1993). These results suggest that individual differences in responding to novelty may be associated more with animals" differen-

tial sensitivities or reactivities to the unconditioned drug stimulus or with their susceptibility to develop sensitization rather than with an animal's current sensitization state and predisposition to self-administer the drug. The following experiment further investigated these possibilities by assessing the contribution of locomotor response to novelty and prior exposure to amphetamine to animals' predisposition to self-administer a low dose of the drug. This drug self-administration paradigm, in which animals are given the opportunity to self-administer low sub-threshold doses of a drug, has been shown to be sensitive to between-subject differences in predisposition to engage in drug self-administration behaviors (Piazza and Le Moal 1996).

Materials and methods Subjects Thirty-six male Sprague-Dawley rats (Charles River Canada, St Constant, Quebec, Canada), weighing 250-300 g at the beginning of the experiment, were used. They were individually housed and maintained with ad libitum food and water in a reverse light cycle room (12 h light/12 h dark) for the duration of the experiment. Animals were handled daily for 2-3 days prior to any testing and were always tested during the dark period of the light cycle. Apparatus Twelve test chambers were used. Each chamber (22x43x33 cm) was constructed of opaque plastic (rear and two side walls), a Plexiglas front-hinged door and a tubular stainless-steel ceiling and floor. Each chamber was enclosed in a plastic box that shielded animals from extraneous disturbances. White noise was supplied in each box by a ventilating fan. The test chambers were used for both the pre-exposure and drug self-administration phases of the experiment. Two infrared photo beams positi6ned 3.5 cm above the cage floor and spaced evenly along and perpendicular to the long axis of each chamber were used to record locomotor activity. Separate interruptions of the two photo beams were summed to provide an estimate of horizontal locomotor activity. Photo beam interruptions with a duration of less than 0.5 s were not recorded in order to filter out rapid and repetitive movements in one place. A removable response lever (5 cm above the floor) and a stimulus light (13.5 cm above the lever) were positioned on each of the side walls. The response levers were removed during assessment of rats" locomotor responses to novelty and the systemic injections in the pre-exposure phase. They were reintroduced into the chambers for the amphetamine self-administration phase. The test chambers were equipped with a liquid swivel system to allow for the self-administration of drug upon depression of the active lever. The liquid swivel system was composed of a steelspring tether, a liquid swivel, and an infusion pump (Razel Scientific Inc., Model, A.E). The tether was connected to the animal by screwing its captive collar onto the threaded portion of a custom designed L-shaped Plastics One cannula (20 gauge) secured to the animal's skull. Separate interruptions of photo beams, lever presses and drug infusions were detected, recorded and controlled via an electrical interface by a computer using locally developed software for locomotion and software developed by Roberts and Richardson (1992) tbr drug self-administration.

279 Procedures The experiment consisted of four phases: response to novelty screen, pre-exposure, surgery, and amphetamine self-administration.

Response to novelty screen Rats' locomotor responses to a novel test environment were assessed on two tests. In the first, rats were simply placed in the chamber for 2 h. In the second, 3 days later, rats were injected with sterile saline prior to being placed in the chamber for 2 h. The activity counts from the two tests were averaged and this mean was subjected to a median-split procedure. Rats with locomotor activity scores above the sample median were designated high responders (HR) and rats with locomotor activity scores below the sample median were designated low responders (LR). High and low responders were then equally divided into two groups receiving amphetamine or saline during pre-exposure. Four groups were therefore tested: HR animals pre-exposed to amphetamine (AMPH-HR) or saline (SAL-HR) and LR animals pre-exposed to amphetamine (AMPH-LR) or saline (SAL-LR).

Pre-exposure In this phase, beginning on the day following the second response to novelty test, animals were administered nine injections of amphetamine (1.5 mg/kg, IP) or saline (1.0 ml/kg, IP). Injections were made once a day for 4 days and, following 2 days (intervening weekend) without injection, for another 5 consecutive days. Each day, immediately following their respective injection, rats were placed in the chambers where locomotor activity was recorded for 2 h.

SurgeIT During the 9 days between pre-exposure and amphetamine selfadministration, animals were not tested but were surgically prepared for intravenous self-administration of the drug. The intravenous catheter used was made of silastic tubing (Dow Corning, Inc.) on which two small bulbs of silicon were fashioned to secure it in the external jugular vein. Catheters were surgically implanted under sterile conditions and performed with the animal under deep anesthesia (sodium pentobarbital, 55 mg/kg, IP) according to an approved IACUC protocol. The catheterization procedure began with an incision on the ventral surface above the rat's right external jugular vein. Tissue was carefully pushed aside to expose a 1- to 2-cm length of the vein. Small lengths of suture were passed under the vein on either side of the point of insertion of the catheter. The vein was pierced with a 26 gauge needle and dilated with a vessel dilator. A catheter filled with a flushing solution (30 IU heparin/per ml, ampicillin 250 mg/ml, and 8333 IU/ml streptokinase diluted in 0.9% saline solution) was inserted until the second of its two silicone bulbs was flush with the incision in the vein. The catheter was then sutured onto the vein with the silicone bulbs serving as anchoring points. The inserted portion of the catheter measured 3.1 cm, placing its tip approximately at the top of the auricle. An incision was then made on top of the rat's head and the catheter passed subcutaneously to this point where it was connected to the 20 gauge stainless steel L-shaped Plastics One cannula. The cannula was secured to the animal's skull with stainless steel screws and dental cement. Catheter patency was then confirmed, an obturator screwed into the cannula, and rats returned to their home cages for a 2- to 5-day recovery period.

Amphetamine self-administration As indicated above, this phase began 9 days following the last preexposure injection for all animals. As with the sensitization of 1o-

comotion by amphetamine, enhanced drug self-administration has been observed soon (I day) or long (45 days) following pre-exposure to the drug (see Paulson et al. 1991; Valadez and Shenk 1994). Daily self-administration sessions were preceded by an assessment of animals' overall fitness, weight, visual examination of the sutures and cap, and verification of catheter patency. Patency was assessed twice daily, before and immediately after an experimental session, by infusing approximately 0.15 ml of the flushing solution both into (flow) and out (draw) of the catheter. Following connection to the tether, rats were placed in the chambers and lever pressing was measured over the course of a 3h test session. No priming infusions were given at any time. Locomotor activity was not measured during drug self-administration. For all animals, presses on the Active lever delivered an infusion of amphetamine through the catheter (10 pg/kg per infusion) under a schedule of continuous reinforcement. Amphetamine was injected in volumes of 0.10-0.13 ml/infusion at a rate of 1.6 ml/min. Different injection volumes were necessitated by the different and changing body weights of the animals. At no time were there significant differences in mean body weight between the different groups. For 10 s immediately following depression of the Active lever, the stimulus light located above the lever was lit. During this 10-s period, presses on the Active lever were recorded but did not lead to further infusions. Presses on the other Inactive lever were also recorded but were without consequence. Self-administration sessions were given daily for 5 days on each of 2 consecutive weeks for a total of ten sessions. Following each session, rats were returned to their individual home cages. Animals found to be without catheter flow were immediately excluded from the experiment, Following the tenth session, each rat's terminal patency was determined by injecting a lethal dose of Nembutal into the catheter. Rats that did not lose muscle tone within 2-3 s and expire readily were judged to be non-patent and were excluded from the experiment. Four rats (three from the amphetamine and one from the saline pre-exposure groups) were thus excluded. Data from the remaining 32 rats (17 in the amphetamine and 15 in the saline pre-exposure groups) are presented below.

Data analysis Data were analyzed with analyses of variance (ANOVA) followed by post-hoc Scheff6 comparisons according to Kirk (t968). The locomotor activity data obtained in the response to novelty screen were analyzed with one-between, one-within ANOVA with response to novelty (HR/LR) as the between factor and time (12 10rain bins) as the within factor as well as with a two-way between ANOVA with response to novelty (HR/LR) as one factor and subsequent pre-exposure (amphetamine/saline) as the second factor. The locomotor activity data obtained in the pre-exposure phase were analyzed with two-between, one-within ANOVA with response to novelty (HR/LR) and subsequent pre-exposure (amphetamine/saline) as the between factors and time (twelve 10-rain bins) or days (9) as the within factor. The amphetamine self-administration data (number of active versus inactive lever presses) were analyzed with separate two-way within ANOVA with lever (active/inactive) and days (10) as the two factors. The number of active lever presses emitted by the different groups on day I of amphetamine self-administration were also compared with a t-test and a two-way between ANOVA.

Results R e s p o n s e to n o v e l t y s c r e e n F i g u r e 1 s h o w s that H R a n i m a l s , as e x p e c t e d , e x h i b i t e d s i g n i f i c a n t l y m o r e l o c o m o t i o n in r e s p o n s e to n o v e l t y

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Fig. 1 Locomotor activity counts obtained on the response to novelty screen. Data (group means_+SEM) are shown for each of the two constituent tests (top). The 2-h total counts obtained for each animal in the two tests were averaged and the means subjected to a median-split procedure (bottom left). Rats with locomotor activity

scores above the sample median were designated high responders (HR) and those with scores below the median were designated low responders (LR). Each of the HR and LR groups was then randomly divided into two groups (n=6-10/group) designated to receive either amphetamine (AMPH-HR and AMPH-LR) or saline (SALHR and SAL-LR) during pre-exposure (bottom right)

than LR animals. This was the case in each of the constituent novelty screen tests (Fig. 1, top). The ANOVA conducted on counts obtained in the first test revealed significant effects of group [F(1, 30)=6.16, P<0.02] and time [F(11, 330)=149.32, P<0.001] as well as a significant groupxtime interaction [F(11,330)=2.65, P<0.0051. On the second test, significant effects of group [F(1, 30)=15.86, P<0.001] and time [ F ( l l , 330)=35.50, P<0.001] were obtained. The ANOVA conducted on the locomotor activity counts exhibited by the AMPH-HR, SAL-HR, A M P H - L R and S A L - L R groups (Fig. 1, bottom right) revealed a significant response to novelty effect [F(1, 28)=17.98, P<0.001] and post hoc comparisons showed that this effect was significant (P<0.05-0.005) for each of the pre-exposure conditions. Neither the two H R groups nor the two LR groups differed significantly from one another.

The locomotor activity exhibited by these four groups on the first and last of the 9 pre-exposure days is shown in Fig. 2. As expected, amphetamine produced significant increases in locomotion on both days [F(1, 28)2151.53 and 158.50, P<0.001, for days 1 and 9, respectively]. Both ANOVA also revealed a significant effect of time [ F ( l l , 308)=18.47 and 8.03, P<0.001] and a pre-exposurextime interaction [ F ( l l , 308)=15.67 and 10.96, P<0.001], findings indicative of the different effects of amphetamine and saline over time on each day. No other significant effects were found. H R and LR animals did not, therefore, differ significantly in their locomotor response to amphetamine. In addition, the significant difference observed between HR and LR animals in responding to novelty was no longer evident by the first saline pre-exposure injection. This pattern of results was observed throughout pre-exposure. An ANOVA conducted on the locomotor activity counts obtained on all 9 days revealed only a significant effect of pre-exposure [F(1, 28)=212.35, P<0.001].

Amphetamine self-administration: effects of individual differences in prior exposure to the drug When subsequently given the opportunity to lever press for amphetamine, both amphetamine and saline pre-exposed animals initially showed significantly more pressing of the active compared to the inactive lever. However, with successive test sessions, amphetamine pre-exposed animals maintained higher levels of active versus inactive lever pressing while saline pre-exposed animals showed a progressive decrease in the pressing of either lever (Fig. 2). In amphetamine pre-exposed animals, the

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self-administration testing in animals having been pre-exposed either to amphetamine (top) or saline (bottom), Presses on the active lever delivered a l0 pg/kg IV infusion of amphetamine Qilled circles). With successive test sessions, amphetamine pre-exposed animals (n=17) maintained significantly higher levels of active versus inactive lever pressing for drug while saline pre-exposed animals (n=l 5) showed a progressive decrease in the pressing of either lever ANOVA revealed a significant effect of lever [F(1, 16)----10.14, P<0.006] while, in saline pre-exposed animals, significant effects of lever IF(l, 14)=7.47, P<0.02] and days IF(9, 126)---2.63, P<0.01] were obtained. Posthoc comparisons showed that while amphetamine preexposed animals showed significantly higher active versus inactive lever pressing from day 2 through day 10 (P<0.05-0.001), this effect was no longer significant for saline pre-exposed animals on days 9 and 10. The latter animals also pressed significantly less on either lever on these last 2 days compared to day 1 of self-administration (P<0.001). The two groups did not differ significantly in level of contact with the active lever on day 1 of self-administration It(30)=0.16, NS].

Amphetamine self-administration: effects of individual differences in response to novelty When subjects' response to novelty was taken count, it was found that enhanced active versus lever pressing was shown by HR but not LR pre-exposed to amphetamine. In addition, while

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Fig. 4 The contribution of response to novelty to amphetamine self-administration. Data are shown as group mean (+SEM) presses on the active and inactive levers on the 10 days of self-administration testing in animals designated HR (left) or LR (right) and pre-exposed either to amphetamine (AMPH; top) or saline (SAL; bottom). Note that the self-administration of amphetamine was promoted only in HR animals having been pre-exposed to amphetamine (n=6-10/group)

mals pre-exposed to saline also initially exhibited higher active versus inactive lever pressing, pressing for either lever decreased progressively with successive sessions in these animals. LR animals pre-exposed to saline showed low levels of pressing for either lever throughout self-administration (Fig. 3). The ANOVA conducted on these data revealed a significant effect of lever I F ( l , 6)=6.45, P<0.05] for A M P H - H R animals and significant effects of lever IF(l, 8)=6.29, P<0.05] and days [F(9, 72)=3.22, P<0.003] for S A L - H R animals. The ANOVA revealed no other significant effects. Post-hoc comparisons showed that while A M P H - H R animals showed significantly higher active versus inactive lever pressing from day 3 through day 10 (P<0.05-0.001), this effect was no longer significant for S A L - H R animals on days 8 through 10. S A L - H R animals also pressed significantly less on either lever on these last 3 days compared to the first day of self-administration (P<0.001). Regardless of pre-exposure condition, H R animals exhibited significantly more contact with the active lever than LR animals on day 1 of self-administration I F ( l , 28)=5.43, P<0.03]. However, neither the A M P H - H R and S A L - H R nor the A M P H - L R and S A L - L R groups differed significantly from one another in level of contact with the active lever on this day.

282

Discussion The present results indicate, in agreement with previous reports, that prior exposure to amphetamine promotes the subsequent self-administration of a low dose of the drug. Taking into account subjects' locomotor response to novelty, however, revealed that this effect, observed in amphetamine compared to saline pre-exposed rats, was due to enhanced drug self-administration in amphetamine pre-exposed HR animals only. Prior exposure to amphetamine in LR animals did not produce enhanced levels of drug self-administration. In addition, while HR animals pre-exposed to saline showed levels of amphetamine self-administration initially similar to those of HR amphetamine pre-exposed animals, enhanced responding for drug in these animals decreased progressively with successive sessions and by the last day of self-administration was indistinguishable from that of LR animals pre-exposed to either amphetamine or saline. These results suggest that response to novelty may be a predictor more closely linked to an animal's propensity to become sensitized to those effects of the drug that promote its self-administration rather than reflective of an animal's current sensitization state and predisposition to self-administer the drug. It has been known for some time that humans as well as experimental animals exhibit considerable individual variation in the behavioral sensitization produced by repeated amphetamine. Some individuals appear to be very sensitive and others quite resistant to the sensitizing effects of this drug (for review, see Robinson 1988). The present results suggest, in agreement with Hooks et al. (1991a,b, 1992b), that response to novelty may provide an effective behavioral screen for distinguishing between these two groups. Thus, prior exposure to a sensitizing regimen of amphetamine injections was found to induce sensitization in HR but not LR animals as indicated by the enhanced predisposition of the former to self-administer a low dose of the drug. LR animals appeared to be protected against this sensitizing effect of amphetamine. Piazza et al. (1989) have reported that HR animals display enhanced levels of amphetamine self-administration compared to LR animals and that the latter could be made to self-administer the drug like HR animals by exposing them to a sensitizing regimen of amphetamine injections. As indicated above, this is not what was observed in the present experiment. Interestingly. in a way similar to that reported by Piazza et al. (1989), saline pre-exposed HR animals in the present experiment did initially show enhanced active versus inactive lever pressing. However, with continued self-administration testing for up to ten successive sessions (Piazza et al. tested their animals for only 5 consecutive days), responding for drug decreased progressively in these animals. These results indicate that while high responding to novelty may be associated with initially enhanced active versus inactive lever pressing, it does not appear to be associated with maintained responding for a low dose of amphetamine. Rather, this type of maintained re-

sponding was observed only in HR animals having been pre-exposed (sensitized) to amphetamine. Greater initial contact with the active lever, associated with high responding to novelty but not with amphetamine pre-exposure, was insufficient, therefore, to lead in and of itself to maintained self-administration of a low dose of the drug. While there is no doubt that animals can differ in their locomotor response to novelty, different results have supported different views of the relationship between an animal's response on this screen and its subsequent locomotor response to acute and repeated injections of psychomotor stimulants (see Introduction). The present results showing similar acute locomotor responding to amphetamine in HR and LR animals, for example, are in agreement with those of some (Hooks et al. 1991a,b) but not others (Piazza et al. 1989; Exner and Clark 1993). Similarly, the patterns of lever pressing for drug exhibited by HR and LR animals in the present experiment are consistent with a view of response to novelty supported by some but not other locomotor data (see above) and, more importantly, are not in complete agreement with those patterns of self-administration behavior reported by others (Piazza et al. 1989). It is difficult to account for these discrepancies. It is possible that such inconsistencies in the data reflect the limited predictive resolution afforded by the response to novelty screen. It is noteworthy, for example, that, the above discrepancies notwithstanding, most reports, including the present, describe some form of enhanced predisposition in locomotor responding to or self-administration of psychomotor stimulant drugs in HR compared to LR animals. Difficulties in formulating more consistent detailed predictions of animals' behavioral responses to drugs may also be related to the use of different experimental procedures in different laboratories. Several variables may be pertinent in this context, including the drug close used to sensitize and test animals as well as the possibility afforded for conditioning to occur (see Hooks et al. 1991a; Ahmed et al. 1993; Jodogne et al. 1994), the presence or absence of priming stimuli (cf Piazza et al. 1989; Horger et al. 1990), the type, dimensions and response requirements of the apparatuses used to test locomotion and drug self-administration (cf Deminiere et al. 1989; Piazza et al. 1989; Horger et al. 1990; Hooks et al. t991a) and the strain of rat used (cf Piazza et al. 1989; Hooks et al. 1991a; see Shoaib et al. 1995). The simplicity of the response to novelty screen (a single 1- to 2-h session) may also render it vulnerable to extraneous factors present on the test day. For this reason, two novelty tests (spaced 3 days apart, the second preceded by a saline injection) were administered in the present experiment. While the majority of animals performed similarly on both, some animals showing locomotor scores close to their sample median performed differently on the two tests (above the sample median on one and below on the other). Interestingly, the differential designation of these subjects as HR or LR and the different subgroups produced by the two screens did not lead to appreciable differences in the locomotor and self-

283 a d m i n i s t r a t i o n results o b t a i n e d , suggesting, as e x p e c t e d , that the r e s p o n s e to novelty screen m a y be m o r e sensitive to those subjects s h o w i n g l o c o m o t o r scores m o r e rem o v e d from the m e d i a n (such as the u p p e r and l o w e r 25% o f the subject sample; see P i a z z a et al. 199 lb, 1993; H o o k s et al. 1992a). T h e present results indicate that p r e - e x p o s i n g H R animals to a m p h e t a m i n e p r o m o t e s the subsequent self-adm i n i s t r a t i o n o f the drug by these animals. This finding is c o n s i s t e n t with the view that such animals are m o r e pred i s p o s e d than L R a n i m a l s to b e c o m i n g sensitized to those effects o f the drug that p r o m o t e its s e l f - a d m i n i s t r a tion. Similarly, p r i o r e x p o s u r e to morphine, a m p h e t a m i n e and c o c a i n e has also been shown to enhance the r e w a r d i n g or incentive m o t i v a t i o n a l effects o f these drugs as m e a s u r e d by the c o n d i t i o n e d place p r e f e r e n c e p r o c e d u r e (Lett 1989; G a i a r d i et a l 1991; S h i p p e n b e r g and H e i d b r e d e r 1995). Interestingly, recent reports indicating that H R and L R a n i m a l s do not differ in the extent to which they d e v e l o p p l a c e p r e f e r e n c e c o n d i t i o n i n g (Erb and Parker 1994; G o n g et al. 1996) have led to the c o n c l u s i o n that separate n e u r o n a l m e c h a n i s m s underlie c o n d i t i o n e d place p r e f e r e n c e and drug s e l f - a d m i n i s t r a tion or that the f o r m e r is not well suited to m e a s u r e differences in drug p r e f e r e n c e intensity (Piazza and L e M o a l 1996). Alternatively, and consistent with the present findings, differences in p l a c e preference c o n d i t i o n i n g b e t w e e n H R and L R a n i m a l s m a y be apparent o n l y in animals having been p r e - e x p o s e d to the d r u g This possibility is p r e s e n t l y being a s s e s s e d in this l a b o r a t o r y 9 Acknowledgements This study was supported by USPHS grant # DA-09397 to P. V. Part of this work was conducted at the Loeb Medical Research Institute (Ottawa, Canada) and supported by a Medical Research Council of Canada grant to P. V. Technical assistance was supplied at the Loeb Medical Research Institute by Jason Rush. P. J. P. is a postdoctoral fellow supported by USPHS grant # T32-DA-07255.

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