Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine

BRAIN RESEARCH ELSEVIER

Brain Research 674 (1995) 291-298

Research report

Influence of novel versus h o m e environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine Aldo Badiani *, Kaitlin E. Browman, Terry E. Robinson Department of Psychology and Neuroscience Program, The University of Michigan, Neuroscience Laboratory Building, 1103 East Huron St., Ann Arbor, MI, 48104-1687, USA Accepted 6 December 1994

Abstract

The acute psychomotor response (rotational behavior in rats with a unilateral 6-OHDA lesion), and the development of sensitization, were studied in rats that received seven consecutive daily injections of amphetamine (Experiment 1) or cocaine (Experiment 2) either at home or in a 'novel' test environment. The home (HOME) and novel (NOVEL) cages were physically identical, but one group lived and was tested in these cages, whereas the rats in the other group were transported from the stainless steel hanging cages where they lived, to these NOVEL test cages, for each test session. In Expt. 1, the acute psychomotor response to 3.0 m g / k g of amphetamine i.p. and the development of sensitization (increase in the rotational response between the first and the seventh test session) were greater in the NOVEL than in the HOME environment. In Expt. 2, there were no significant group differences in the acute response to 20 m g / k g of cocaine i.p., but the animals tested in the NOVEL environment showed greater sensitization than animals tested in the HOME environment. In addition, the animals pretreated with cocaine in the NOVEL environment, but not those pretreated with cocaine in the HOME environment, showed conditioned rotational behavior in response to an injection of saline. These data indicate that: (i) sensitization to the psychomotor activating effects of both amphetamine and cocaine is enhanced in a NOVEL environment; (ii) this phenomenon appears to be independent of the effects of the NOVEL environment on the acute response to these drugs; (iii) a robust conditioned psychomotor response to contextual cues develops only when cocaine treatments are given in the NOVEL test environment.

Keywords: Conditioning; Context-specific sensitization; Environment-specific sensitization; Novelty; Stress; Rotational behavior; Striatum; Dopamine; Rat

1. Introduction

T h e r e p e a t e d administration o f addictive drugs such as a m p h e t a m i n e and cocaine results in a progressive increase (sensitization) in their behavioral activating effects [21,33], and it has b e e n suggested that the neuroplastic adaptations underlying 'behavioral sensitization' m a y be responsible for the d e v e l o p m e n t of compulsive drug-seeking and drug-taking behavior [32,34]. T h e r e is considerable interest, therefore, in identifying the factors, especially environmental factors, that m o d u l a t e the d e v e l o p m e n t and the expression of behavioral sensitization (for a review see [39]).

* Corresponding author. Fax: (1) (313) 936-2690. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0 0 0 6 - 8 9 9 3 ( 9 5 ) 0 0 0 2 8 - 3

W e recently reported, for example, that the environm e n t in which rats receive a m p h e t a m i n e can have a significant effect on the d e v e l o p m e n t of sensitization to the p s y c h o m o t o r stimulant properties of a m p h e t a m i n e [2-4]. Rats that receive a m p h e t a m i n e in a 'novel' ( N O V E L ) test e n v i r o n m e n t show a greater rate of sensitization than rats that receive the drug in the h o m e ( H O M E ) environment, even t h o u g h the H O M E and N O V E L environments are physically identical. This p h e n o m e n o n is of interest because in h u m a n s as well the behavioral and subjective effects of addictive drugs d e p e n d to a large extent on the context in which drugs are administered [9-11]. Sensitization to b o t h a m p h e t a m i n e and cocaine is associated with changes in a c o m m o n neural system, the mesotelencephalic d o p a m i n e system [21,33], alt h o u g h these two drugs have different mechanisms of

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action. It is of interest, therefore, to determine if exposure to the N O V E L environment has a similar effect on the development of sensitization to these two drugs. Thus, the purpose of the present study was two-fold: (i) to replicate our earlier findings on the influence of N O V E L versus H O M E test environments on a m p h e t a m i n e sensitization, and (ii) to assess if N O V E L and H O M E environments have a similar effect on cocaine sensitization.

2. Materials and methods Z l. Subjects

Eighty-seven male S p r a g u e - D a w l e y rats, weighing 175-200 g at the beginning of the experiment, were purchased from Harlan Sprague Dawley Inc. (Indianapolis, IN, USA). They were individually housed in rooms with a 14-h light/10-h dark cycle (lights on from 06.00 to 20.00), and had ad libitum access to food and water. In addition, prior to the experiments all rats received a unilateral 6 - O H D A lesion (see below), so that drug-induced rotational behavior [42] could be used as an index of psychomotor activation. The rationale for using rotational behavior in rats with a unilateral 6 - O H D A lesion as an index of the psychomotor activating effects of a m p h e t a m i n e and cocaine has been discussed previously [2]. Briefly, the quantification of rotational behavior offers two major advantages over the quantification of locomotor activity. (i) The d o s e response curve for rotational behavior in rats with a unilateral 6 - O H D A lesion is linear over a wide range of doses [42], and sensitization is seen as a progressive increase in rotational behavior [31]. In contrast, the d o s e - r e s p o n s e curve for amphetamine-induced locomotor activity in naive rats is very complex [35], and the development of sensitization is not necessarily characterized by a progressive increase in locomotor activity (because of the emergence of stereotyped behaviors). (ii) Exposure to a N O V E L environment by itself produces marked locomotor hyperactivity, whereas it produces negligible effects on rotational behavior [2]. Thus, rotational behavior is more suitable than locomotor activity for studying the interactions between the effects of drugs and a N O V E L environment. 2.2. Surgical and screening procedures

One week after their arrival in the animal colony all rats received a unilateral 6 - O H D A lesion of the mesostriatal dopamine system using procedures described elsewhere [31]. Briefly, the animals were first pretreated with desipramine [6], and anaesthetized with sodium pentobarbital. A 29 gauge stainless steel cannula was then lowered into the medial forebrain bun-

die, and this was used to deliver 8 / x g of 6 - O H D A over an 8-min period. One week after the surgery the rats were tested with 0.05 m g / k g of apomorphine: the appearance of vigorous contraversive rotational behavior ( > 50 r o t a t i o n s / 3 0 min) indicated denervation supersensitivity, which is a good indicator of a 90-95% lesion [16,17]. 2.3. Procedures Experiment 1 Twenty-eight rats passed the apomorphine screen and were used in this experiment. Fourteen of them ( A M P H - H O M E group, n = 14) were housed on the floor of a testing room in plastic cylindrical (25 cm diameter, 36 cm high) cages. The bottoms of these cages were covered with ground corn cob bedding. The other 14 rats ( A M P H - N O V E L group, n = 14) were housed in stainless steel hanging cages located in the main animal colony room. The waste trays below the hanging cages were covered with pine wood shavings. After one week of habituation to these housing conditions, N O V E L rats were transferred every day from their home cages in the animal colony to the testing room, placed in plastic cages identical to those in which H O M E rats lived (including the presence of ground corn cob bedding, food, and water), and immediately given an injection of 3.0 m g / k g of amphetamine i.p.. This procedure was repeated for seven consecutive days. Rats in the H O M E group received an a m p h e t a m i n e injection at the same time. Therefore, the environments in which A M P H - H O M E and A M P H - N O V E L groups received drug treatments were physically identical, but this was a 'novel' environment for one group and the home environment for the other group. Each of the seven daily test sessions lasted 90 min, after which time N O V E L rats were returned to their hanging cages in the animal colony. The behavior of the animals was videotaped during the 1st and 7th test sessions, and rotational behavior was quantified by viewing the videotapes. One rotation was defined as a complete 360 ° turn. Experiment 2 Fifty-nine rats passed the apomorphine screen and were used in this experiment. Twenty-eight of them were housed and tested as group H O M E in Expt. 1. The other 31 rats were housed and tested as group N O V E L in Expt. 1. Both H O M E and N O V E L groups were further subdivided into those groups that received seven consecutive daily i.p. injection of either saline ( S A L - H O M E , n = 11, and S A L - N O V E L , n = 15) or 20.0 m g / k g of cocaine ( C O C - H O M E , n = 17, and C O C - N O V E L ; n = 16). The day after the last injection of cocaine, all groups were challenged with an injection of saline, under the same conditions in which they

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received the chronic treatments, to assess the development of conditioned hyperactivity. Rotational behavior was quantified as in Expt. 1.

2.4. Drugs 6 - O H D A (2,4,5-trihydroxyphenethylamine hydrobromide) was dissolved (2 m g / m l ) in a saline-ascorbate solution. Desipramine hydrochloride was given i.p. (15 m g / k g in 1 m l / k g distilled water). Apomorphine hydrochloride (dissolved in a saline-ascorbate solution, 0.1 m g / m l ) was injected subcutaneously in the neck (0.05 mg/kg). D-amphetamine sulfate was administered i.p. (3.0 m g / k g , weight of the salt, in 1 m l / k g saline). All these drugs were purchased from Sigma Chemical Company (St. Louis, MO). Sodium pentobarbital (The Butler, Company, Columbus, OH) was given i.p. (52 m g / k g in 0.8 m l / k g of a 10% ethanol solution). Cocaine hydrochloride (Mallinckrodt, Hazelwood, MO) administered i.p. (20.0 m g / k g , weight of the salt, in 1 m l / k g saline).

A M P H - H O M E , A M P H - N O V E L , COC-HOME, and C O C - N O V E L group. In addition, overall correlational analyses were performed on the data for H O M E and N O V E L rats, after pooling the data of A M P H - H O M E and C O C - H O M E groups, and A M P H - N O V E L and C O C - N O V E L groups, respectively.

3. Results

3.1. Experiment 1 Fig. 1 shows the effects on rotational behavior of the 1st and the 7th injection of amphetamine given in EFFECT OF NOVEL ENVIRONMENT ON AMPHETAMINE SENSITIZATION O •

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0 Test Session Fig. 1. Left hand panel: the mean ( + S . E . ) number of rotations during the 1st and 7th test sessions for rats that received amphetamine (3.0 m g / k g , i.p.) either in the H O M E ( A M P H - H O M E ) or in the N O V E L (AMPH-NOVEL) environment. The data from the first test session were analyzed with a one-tailed Student's t-test which indicated that the N O V E L group was significantly more active than the H O M E group (t = 1.94, P = 0.033). The data from both test sessions were analyzed with a two way-ANOVA with repeated measures on one factor that resulted in a significant effect of test enuironment (F1,26 = 13.50, P = 0.001), and in a test enuironment x test session interaction (F1.26 = 29.01, P < 0.0001). The simple effect of test session was significant in the N O V E L (F1.26 = 33.91, P < 0.0001), but not in the H O M E (F1.26 = 3.22, P < 0.1) group (although a one-tailed paired t-test resulted in a significant difference between the 1st and 7th test session in the H O M E group, t = 2.39, P = 0 . 0 1 6 ) . Right hand panel: the mean ( ± S . E . ) number of full rotations during the 1st and 7th test sessions in animals given amphetamine (3.0 m g / k g , i.p.), after both groups were divided, on the basis of the group median for the initial response to amphetamine (see Methods), into two subgroups corresponding to the rats with rotational scores below (LOW) and above the median (HIGH). Two statistical analyses of the differences between AMPHH O M E ( H I G H ) group and A M P H - N O V E L (LOW) group indicate that the more robust sensitization in N O V E L rats illustrated in the left hand panel was not a simple function of their higher initial response to amphetamine. A M P H - N O V E L (LOW) rats made fewer rotations than A M P H - H O M E ( H I G H ) rats on the first test session, although this difference was not quite statistically significant (t = 2.07, P = 0.06). Despite their lower initial response to amphetamine A M P H - N O V E L (LOW) rats still showed greater sensitization than A M P H - H O M E ( H I G H ) rats, as indicated by a test environment x test session interaction (two-way A N O V A with repeated measures for one factor: F1,12 = 32.98, P < 0.0001).

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either the H O M E or the N O V E L environment. Two findings are illustrated in Fig. 1: (i) the first injection of amphetamine produced a larger increase in rotational behavior in the A M P H - N O V E L group than in the A M P H - H O M E group; (ii) the degree of amphetamine sensitization was greater in the A M P H - N O V E L group, as indicated by a significant test environment × test session interaction. The group differences in the rate of sensitization were not a simple function of group differences in the initial response to amphetamine. The right hand panel of Fig. 1 compares the rotational behavior of the A M P H - H O M E rats whose response to the first injection of amphetamine was above the median, A M P H H O M E (HIGH), to that of A M P H - N O V E L rats whose response to the first injection of amphetamine was below the median, A M P H - N O V E L (LOW). Although there were no significant group differences on the first test session, the amount of sensitization in the A M P H - N O V E L (LOW) group was higher than in the A M P H - H O M E (HIGH) group, as indicated by a significant test environment × test session interaction. Indeed, the median split analysis shows that the A M P H H O M E (HIGH) group did not sensitize at all, whereas the A M P H - N O V E L (LOW) group did (Fig. 1). Fig. 2 (top panels) shows another analysis indicating that the amount of amphetamine sensitization was not correlated in a positive way to the initial drug response. In the A M P H - H O M E group there was, in fact, a significant negative correlation between the initial response to amphetamine and the delta score, and in the A M P H - N O V E L group the two variables were not significantly correlated at all. 3.2. Experiment 2

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Fig. 3 shows the effects on rotational behavior of repeated injections of saline (SAL) or cocaine (COC) given in either the H O M E or in the N O V E L environment. The following major findings are illustrated in Fig. 3. (i) An injection of saline in either the H O M E or the N O V E L environment produced negligible rotational behavior. (ii) The first injection of cocaine produced an increase in rotational behavior in both the H O M E and the N O V E L groups. (iii) There were no significant group differences in the initial response to cocaine. (iv) The magnitude of cocaine sensitization was significantly greater in the C O C - N O V E L group than in the C O C - H O M E group, as indicated by a simple test environment by test session interaction. Since the two groups did not differ significantly on the first test session, the group difference in the rate of sensitization was clearly not a function of a group difference in the acute response to cocaine. Fig. 2 (middle panels) shows that also for cocaine the initial response to the drug was negatively corre-

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1st Test Session (Number of Rotations) Fig. 2. Top panels: linear correlation of delta scores (rotational score on the 1st test session minus rotational score on the 7th test session) and initial responses to amphetamine. The asterisk indicates that there was a significant negative correlation ( r = 0.76, P < 0.001) in A M P H - H O M E rats, but not in A M P H - N O V E L rats ( r = 0.03, P > 0.90). Middle panels: linear correlation of delta scores and initial responses to cocaine. There was a significant negatiue correlation ( r = 0.54, P = 0.02) in C O C - H O M E rats, but not in C O C - N O V E L rats ( r = 0.34, P > 0.20). Bottom panels: linear correlation of delta scores and initial responses to drug w h e n the amphetamine- and cocaine-treated animals were pooled. There was a significant negative c o r r e l a t i o n ( r = 0.66, P < 0.0001) in H O M E rats, but not in N O V E L rats ( r = 0.02, P > 0.90).

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Fig. 3. T h e m e a n ( + S.E.) n u m b e r of rotations during the 1st and the 7th test session for rats that received saline (SAL) or 20 m g / k g cocaine i.p. (COC) either at H O M E ( S A L - H O M E and C O C - H O M E ) or in a N O V E L environment ( S A L - N O V E L and C O C - N O V E L ) . T h e data from the 1st test session were analyzed with a two-way A N O V A that resulted in a significant effect of t r e a t m e n t (F1.55 = 32.80, P < 0.0001). T h e effect of test e n v i r o n m e n t (F1,55 = 1.32, P > 0.26) and the treatment × test e n v i r o n m e n t interaction (F1,55 = 1.48, P > 0.23) were not significant. T h e data from both test sessions were analyzed with a three-way A N O V A with repeated m e a s u r e s for one factor that resulted in significant effects of treatment (Fl,s~ = 120.76, P < 0.0001) and test session (F1,55 = 56.59, P < 0.0001), and in significant test e n v i r o n m e n t x test session (F1.55 = 11.31, P < 0.001), treatm e n t X test session (F1,55 = 60.49, P < 0.0001), and test e n v i r o n m e n t X t r e a t m e n t × test session (F1,55 = 10.49, P = 0.002) interactions. The simple effect of test session was significant only in group C O C - H O M E (F1,55 = 22.77, P < 0.0001) and C O C - N O V E L (F1,55 = 134.59, P < 0.0001). Finally, and most importantly, there was a simple test e n v i r o n m e n t × test session interaction in cocaine treated animals (F1,55 = 25.04, P < 0.0001), but not in saline-treated animals (F1,55 < 0.01, P > 0.9), indicating greater cocaine sensitization in the N O V E L group than in the H O M E group.

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Fig. 4. T h e m e a n ( ___S.E.) n u m b e r of rotations following an injection of saline in animals that were pretreated with saline (SAL) or 20 m g / k g cocaine i.p. (COC) either at H O M E ( S A L - H O M E and C O C - H O M E ) or in a N O V E L ( S A L - N O V E L and C O C - N O V E L ) environment. A two-way A N O V A resulted in a significant test envir o n m e n t × t r e a t m e n t interaction (F1,55 = 8.58, P < 0.01) and the asterisk indicates that group C O C - N O V E L differed significantly from all other groups (all P s < 0.0001, Fisher's PLSD tests).

295

lated with the degree of sensitization (delta score) in C O C - H O M E rats, whereas there was no significant correlation in C O C - N O V E L rats. In addition, Fig. 2 (bottom panels) shows the correlation between the initial responses to the drug and the delta scores in H O M E and N O V E L rats, after pooling the data of amphetamine- and cocaine-treated animals. Fig. 4 shows the effects of an injection of saline in rats that have been previously treated with either saline (groups S A L - H O M E and SAL-NOVEL) or cocaine (groups C O C - H O M E and COC-NOVEL). There was a significant conditioned response in the animals that had previously received cocaine in the N O V E L environment, but not in those previously treated in the H O M E environment.

4. Discussion

Four major findings are reported here. (i) Both the acute psychomotor response to amphetamine (rotational behavior in rats with a unilateral 6 - O H D A lesion of the mesostriatal dopamine system) and the rate of sensitization were greater when rats were tested in a N O V E L environment than when they were tested in the H O M E environment. This replicates findings in earlier reports [2,3]. (ii) For cocaine the rate of sensitization was also greater when the treatments were given in a N O V E L (versus H O M E ) environment, but, in contrast to amphetamine, the environment did not have a significant effect on the acute response to cocaine. (iii) For both amphetamine and cocaine there was a significant negative correlation between the initial response to the drug and the magnitude of sensitization (delta scores) in H O M E animals, but no correlation in N O V E L animals. (iv) There was a conditioned rotational response to drug-associated stimuli in animals that had previously received cocaine in the N O V E L environment, but not in those that received the drug in the H O M E environment. It is interesting that the relationship between the acute psychomotor response to amphetamine and cocaine, and the rate of sensitization, differed depending on the environment in which the animals received the drug treatments. The enhancement in sensitization seen in the N O V E L environment, for example, was independent of the acute psychomotor response to the drug, as indicated by three observations. First, in the N O V E L group there was no significant correlation between the response on the first test session and the degree of sensitization, in either Expt. 1 or 2. Robinson [31] reported a similar finding for amphetamine sensitization. Second, group A M P H - N O V E L (LOW) made fewer rotations than group A M P H - H O M E ( H I G H ) on the first test session (although not significantly), but the rate of sensitization was still greater in group

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A M P H - N O V E L (LOW). Third, in Expt. 2 there was no effect of environment on the acute response to cocaine, but N O V E L animals showed greater cocaine sensitization than H O M E animals. Thus, the greater sensitization seen in the N O V E L environment was not simply a function of this environment generally enhancing the psychomotor response to a m p h e t a m i n e and cocaine. In contrast, in the H O M E group there was a significant negative correlation between the rotational scores on the first test session and the amount of sensitization. Similar findings have been reported by Piazza and colleagues [28], who studied the locomotor response to four consecutive daily injections of a m p h e t a m i n e in rats that were preexposed to the test environment the day before the first test session, and were prehabituated to the test environment for 3 h before each test session. These extensive habituation procedures may result in conditions more similar to those for our H O M E group than to our N O V E L group. In Piazza's experiment High Responders (HR), that had a large initial response to amphetamine, did not sensitize, whereas Low Responders (LR), who had only a modest initial response to amphetamine, did sensitize. It seems, therefore, that under some conditions (such as the H O M E environment here or in Piazza's experiment) the initial injection of a given dose of a m p h e t a m i n e or cocaine produces a maximal response in a subgroup of animals, and this response is not subject to sensitization. In other rats the initial injection produces a submaximal response, and then with repeated drug treatments these animals reach the maximal response via sensitization. In contrast, in the N O V E L condition, there was no subgroup of animals that showed a maximal response during the initial test session, and even rats with the highest rotational scores sensitized. It appears, therefore, that exposure to the N O V E L environment facilitates sensitization in some way, above and beyond the sensitization produced by the direct pharmacological action of the drug (which should be the same in the H O M E and N O V E L environment). That is, in the N O V E L environment sensitization seems to involve additional mechanisms not evoked in the H O M E environment. It is not clear, however, what these mechanism(s) might be. We hypothesized [2] that exposure to a N O V E L environment may facilitate sensitization because of some aspect of its action as a 'stressor.' Exposure to a novel environment produces neuroendocrine and neural changes indicative of stress, including an increase in plasma plasma corticosterone levels comparable to those produced by restraint or footshock [5,15,18], and C R H - d e p e n d e n t hypertension, tachicardia and hyperthermia [27]. Consistent with this hypothesis, Shaham and colleagues [36] reported re-

cently that sensitization to the locomotor activating effects of morphine is enhanced when restraint stress is given immediately prior to morphine treatments. Thus, some neuroendocrine or neural events associated with stress may facilitate the process of sensitization. For example, one way a stressor, such as exposure to the N O V E L environment, may enhance amphetamine and cocaine sensitization is by activation the hypothalamic-pituitary-adrenal (HPA) axis and the release of corticosterone, because adrenalectomy is reported to block the development of sensitization produced by restraint stress [12], or social isolation [13]. If exposure to a N O V E L environment enhances amphetamine sensitization because of a stress-induced release of corticosterone, then adrenalectomy should abolish the difference in sensitization between the H O M E and N O V E L groups. We recently tested this hypothesis, however, and found that adrenal hormones are not necessary for the enhancement of amphetamine sensitization seen in animals tested in a N O V E L environment, because adrenalectomy had no significant effect on the development of sensitization to amphetamine in either the H O M E or the N O V E L environment [3]. Alternatively, it is possible that the facilitatory effects of a N O V E L environment on amphetamine and cocaine sensitization could be due to a stress-induced activation of other neuroendocrine systems. For example, there is evidence that corticotropin-releasing hormone ( C R H ) mechanisms are involved in some behavioral responses to stress independently of the H P A axis [7,20,23,24,40]. Furthermore, central CRH, but not peripheral administration of C R H , has been shown to produce sensitization to the locomotor activating effects of amphetamine [8]. Stress-induced activation of dopaminergic systems may be another substrate for the interaction between psychostimulants and exposure to N O V E L environment. It is known, for example, that stress activates the mesostriatal dopaminergic systems [1,29,41] independently of the H P A axis [19], and that these systems are involved in the development of sensitization to a m p h e t a m i n e and cocaine [21,33]. Therefore, the activation of dopamine mechanisms by exposure to the N O V E L environment may have facilitated the development of amphetamine and cocaine sensitization. This hypothesis remain to be tested. An additional possibility is that the differences in sensitization in H O M E versus N O V E L rats were related to differences in the ability of stimuli paired with drug administrations to acquire conditioned stimulus (CS) properties. It has been argued, for example, that sensitization is the result of a progressive increase in the ability of CSs to elicit conditioned psychomotor activation a n d / o r to modify the response to amphetamine or cocaine, thus producing a progressively larger response to the drug. If pairing the N O V E L environment with amphetamine treatment enhanced

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the acquisition of these CSs properties, relative to drug administration at H O M E , and if indeed this contributes significantly to development of sensitization, this could account for greater sensitization in the N O V E L environment. Consistent with this hypothesis, only C O C - N O V E L animals (Expt. 2) showed a conditioned response when given a saline injection in the drug-associated context. There are a number of reasons why this might occur. For example, it is possible that contextual cues associated with the home environment may not become effective CSs because they do not reliably predict the drug, whereas contextual cues associated with the novel environment would reliably predict the drug. Indeed, it is well known that conditioning can be disrupted by pre-exposing the animal to the would-be-CS (latent inhibition), as would occur in the home environment. Interestingly, Kiyatkin [22] found that 120 min of pre-habituation to the test environment reduces the expression of sensitization to cocaine. It is not clear, however, why other cues that reliably predicted drug administration, such as being picked up and jabbed with a needle, did not elicit a conditioned rotational response. Perhaps these cues were not salient enough. In the R e s c o r l a - W a g n e r model of associative learning [30] the changes in the associative strength produced by a CS-US pairing is dependent, among other things, on the salience of the CS. Thus, if the available CSs in the H O M E group were significantly less salient than in the N O V E L group, this may contribute to the difference in sensitization between the two subgroups. Along a similar line, Lubow and colleagues [25,26] reported that rats repeatedly exposed to a distinctive odor in a specific test environment, and then trained to pair the source of that odor to the presence of food either in the same environment or in another environment, learned the task more rapidly in the unfamiliar environment. Lubow and colleagues [25,26] suggested that this enhancement of learning may be due to the arousing properties of the novel environment. Analogously, it is possible that the arousal produced by exposure to the N O V E L environment had similar effect in our A M P H - N O V E L and C O C - N O V E L groups. Although it is possible that differences in conditioning may account for the difference in sensitization in the H O M E vs. N O V E L condition, it is clear that the magnitude of the group differences in the conditioned response to contextual cues (13.7 _+ 1.2 in group H O M E vs. 32.9 + 4.2 in group N O V E L ) cannot account for the magnitude of group differences in cocaine sensitization (expressed as delta scores: 117.4 + 27.7 in group H O M E vs. 294.2 + 38.5 in group NOVEL). In addition, there was no correlation between the magnitude of the conditioned response and the degree of sensitization. It must be noted, however, that no attempt was made here to measure the conditioned response to drug-as-

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sociated interoceptive cues. Furthermore, contextual and interoceptive CSs may have modified the subsequent response to the drug independently of their ability to produce a conditioned response in the absence of the drug [for example, see references [14,37,38]]. In conclusion, the data presented here further emphasize that environmental factors can have a profound influence on the development of sensitization to psychostimulants. We do not yet know what mechanism(s) is responsible for the enhancement of amphetamine and cocaine sensitization in rats given these drugs in a N O V E L environment. The fact that a conditioned psychomotor response to contextual cues developed only when repeated drug treatments were given a N O V E L test environment suggest, however, that differences in associative processes in the H O M E and N O V E L conditions may have contributed to such a phenomenon. Other experiments are necessary to investigate this, as well as other possible explanations for the findings reported here.

Acknowledgements This research was supported by a grant from the National Institute on Drug Abuse (#02494) to T.E.R. We thank Megan Clancy for her assistance in conducting the experiments.

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