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Cocaine locomotor activation, sensitization and place preference in six inbred strains of mice

Cocaine locomotor activation, sensitization and place preference in six inbred strains of mice Background: The expanding set of genomics tools available for inbred mouse strains has renewed interest in phenotyping larger sets of strains. The present study aims to explore phenotypic variability among six commonly- used inbred mouse strains to both the rewarding and locomotor stimulating effects of cocaine in a place conditioning task, including several strains or substrains that have not yet been characterized for some or all of these behaviors. Methods: C57BL/6J (B6), BALB/cJ (BALB), C3H/HeJ (C3H), DBA/2J (D2), FVB/NJ (FVB) and 129S1/SvImJ (129) mice were tested for conditioned place preference to 20 mg/kg cocaine. Results: Place preference was observed in most strains with the exception of D2 and 129. All strains showed a marked increase in locomotor activity in response to cocaine. In BALB mice, however, locomotor activation was context-dependent. Locomotor sensitization to repeated exposure to cocaine was most significant in 129 and D2 mice but was absent in FVB mice. Conclusions: Genetic correlations suggest that no significant correlation between conditioned place preference, acute locomotor activation, and locomotor sensitization exists among these strains indicating that separate mechanisms underlie the psychomotor and rewarding effects of cocaine. Background paradigm, rodents learn to associate a specific environ- The devastating effects of drug addiction on the lives of mental context with the effects of a drug stimulus. Place those who struggle with it and the social and economic conditioning confers many advantages in the study of implications for society as a whole are staggering. Faced drug-induced motivational responses, including the with this challenge, understanding the biological path- short duration and relative simplicity of the procedure ways that predispose individuals to addiction to cocaine in comparison with reinforcement models such as self- (and other drugs) is a top priority in the research com- administration. CPP also provides the opportunity to munity. The perception that genetic background influ- measure the initial acute response and sensitization or ences the predisposition to abuse drugs is supported by tolerance to the locomotor stimulating effects of a drug studies in humans [1] and in animal models [2-4]. following repeated exposure [5,6]. In addition, CPP is While no animal model exists that recapitulates the measured in the absence of drug-related physiological entire spectrum of the drug abuse syndrome in humans, confounds such as locomotor and sensory effects [5]. animal models do exist for the study of specific drug- Encountering environments and stimuli previously asso- ciated with drug use is one of the most common trig- related behaviors, including initial sensitivity (as mea- sured by drug-induced locomotor behavior), sensitiza- gers for relapse in humans [7,8], and the CPP paradigm tion and drug reward and reinforcement paradigms. specifically addresses the effects of context-specific Conditioned place preference (CPP) has been estab- exposures on drug reward and drug-seeking behaviors lished as a standard procedure for assessing the reward- in animal models [9]. ing effects of drugs in rodent models. In the CPP Drug-induced behaviors, including CPP, have a signifi- cant genetic component as demonstrated by the large * Correspondence: lisat@med.unc.edu degree of phenotypic variability among inbred mouse Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA strains [4,10]. The goal of the present study was to Full list of author information is available at the end of the article © 2011 Eisener-Dorman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 2 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 expand upon thecurrent literaturebyinvestigating cocaine-induced response across strains, as previous stu- drug-induced sensitivity, sensitization and place condi- dies suggest this dose is sufficient to induce a drug tioning in six commonly used and genetically diverse response in many strains [4,14,15]. Immediately follow- inbred mouse strains. Several of these strains have ing an intraperitoneal (i.p.) injection with cocaine or sal- already been characterized for CPP, cocaine locomotor ine, each animal was placed in the appropriate chamber activation and sensitization [4], while others, including of the CPP apparatus. FVB/NJ and substrains of 129 (129S1/SvImJ) and BALB (BALB/cJ), have not previously been studied in the place Apparatus preference paradigm. Here, we present strain-specific Conditioned place preference testing was conducted differences that confirm, contradict, and expand upon using a three-chambered conditioned place preference previously reported inbred strain responses to cocaine. apparatus (46.5 × 12.7 × 12.7 cm; MED-CPP-MSAT, Med Associates) in a sound-attenuating enclosure Methods (ENV-016MD, Med Associates). The apparatus con- Animals sisted of a grey center compartment (7.2 × 12.7 cm) Male mice from six inbred strains (129S1/SvImJ (129), with a smooth PVC floor and two choice compartments C57BL/6J (B6), BALB/cJ (BALB), C3H/HeJ (C3H), DBA/ (16.8 × 12.7 cm) on either side. One compartment was 2J (D2) and FVB/NJ (FVB)) were obtained from the in- all black with a stainless steel grid rod floor consisting house breeding colony at the Genomics Institute of the of 3.2 mm rods placed on 7.9 mm centers and the other Novartis Research Foundation (GNF). Inbred strains for was all white with a 6.35 × 6.35 mm stainless steel mesh the GNF breeding colony were initially purchased from floor. Compartments were separated by guillotine doors, the Jackson Laboratory (Bar Harbor, ME, USA), and which were left open to permit free exploration of the breeder stocks were replenished every seventh generation full apparatus during pre-test on Day 1 and the testing to limit genetic drift. Mice were group-housed and main- phase on Day 10 but were closed during training days. tained in an AAALAC-accredited, specific pathogen-free Two identical CPP apparatuses were used and each (SPF) barrier colony in ventilated cages (Thoren Caging apparatus had two training chambers (black and white) Systems, Hazelton, PA, USA) on a 12-hour light-dark for a total of four training chambers. Each mouse was cycle (lights on at 6:00 A.M.). Irradiated food (Pico tested in the same apparatus and the same training rodent chow 20; Purina, St. Louis, MO, USA) and water chamber throughout the experiment. were provided ad libitum. Mice were between 59 and 70 Mouse movement in the apparatus was detected by six days of age at the onset of testing, and all behavioral test- infrared photobeams (spaced 2.8 cm apart and 1.0 cm ing occurred between 8:00 A.M. and 12:00 P.M. from the end wall) in each choice compartment and SixteenB6miceand eightmicefromeachofthe three (spaced 2.8 cm apart) in the center compartment. remaining five strains were tested in the conditioned Photobeams mounted 1.8 cm above the apparatus floor place preference procedure described below. Groups of captured horizontal movement. The absence of z-axis mouse strains were tested in three separate testing ses- photobeams did not permit detection of vertical move- sions over the course of two months, and all mice in a ment, such as rearing. Activity was captured by auto- group were tested on the same day. With the exception mated data collection as movement counts. Movement of B6, all mice of each strain were tested in the same counts are defined as consecutive beam breaks within a session and different strains were tested in each of the chamber to detect horizontal forward locomotion while three sessions. Two sets of B6 mice (8 mice per set) excluding stereotypic behavior. Entrance into a chamber were tested in the first and last sessions as a control for was recorded when the second photobeam into the temporal effects across sessions. chamber was broken. Time spent in each compartment Male mice were chosen for testing to mitigate the was recorded in seconds. variability observed in females due to estrous cycle [11-13]. Conditioned place preference procedure All procedures were approved by the GNF Institu- The place preference procedure consisted of three tional Animal Care and Use Committee and followed phases, as outlined below and in Figure 1. the guidelines set forth by the National Institutes of Pre-test phase Health (NIH) Guide for the Care and Use of Laboratory The purpose of the pre-test was to habituate the animals Animals. to the novelty and stress associated with the apparatus, handling and injection prior to conditioning, as well as Drugs to identify initial chamber preferences. For the pre-test, Cocaine was dissolved in saline (0.9% NaCl). A 20 mg/ all mice received an i.p. saline injection immediately kg dose of cocaine was used to obtain a moderate prior to placement in the apparatus for 20 minutes. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 3 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 1 Timeline of the place preference study. Mice were placed in the grey center compartment at the Multivariate analysis of variance (ANOVA) was used to beginning of the pre-test but were allowed to move analyze the effect of strain for each behavioral measure. freely between compartments. The total time spent in Dependent variables differed based on behavioral mea- each of the three chambers was recorded and then cal- sure and included percent time spent in each chamber culated as a percentage of the total test duration. The for equipment bias assessment and percent time spent percent time spent in the black and white chambers in the cocaine-paired chamber for place preference. only, not including the grey chamber, was also calcu- Locomotor activity (recorded as movement counts) was lated and used as the pre-conditioning value for place assessed for acute locomotor response, sensitization and preference analysis. on the test day (Day 10). Day of testing was included as Conditioning phase an independent variable to assess the effects of cocaine For the conditioning procedure, animals from each on time spent in the cocaine-paired chamber and also strain were randomly assigned to one of two condition- for locomotor activity over multiple days of testing ing subgroups. Mice in one subgroup (N = 4 per strain; (acute and sensitized locomotor activity). Based on B6 N = 8) received cocaine paired with the black cham- results from the pre-test session indicating that the ber and saline paired with the white chamber. Mice in equipment was unbiased, data were collapsed across thesecondsubgroup(N=4per strain;B6N=8) training chambers for analysis of place preference. How- received cocaine paired with the white chamber and sal- ever, locomotor activity during the conditioning phase ine paired with the black chamber. On days 2, 4, 6 and differed between black and white chambers for some 8, mice were injected with saline and placed in the strains; therefore, chamber was included as an indepen- unpaired chamber. On days 3, 5, 7 and 9, mice were dent variable for activity analyses. Locomotor activity injected with cocaine and placed in the drug-paired was also used as a covariate in the CPP analysis. Post- chamber. Conditioning took place across eight subse- hoc Tukey HSD and t-tests were employed for indivi- quent days, and trials were 30 minutes in duration (one dual post-hoc comparisons. trial per day). Movement counts in the black and white The two groups of B6 mice were analyzed by one-way chambers were recorded. ANOVA with group as the independent variable. Dependent variables included acute locomotor response, Test day sensitization and place preference. For the testing phase on Day 10, mice received an i.p. injection of saline immediately prior to placement in the Genetic correlations were assessed using partial corre- grey center compartment of the apparatus and were lation of percent CPP (Day 10 - Day 1), total locomotor allowed to move freely between the compartments for activity in the black and white chambers on the test day the duration of the 30-minute testing trial. The primary (Day 10 movements), cocaine locomotor sensitization dependent variable was percent time spent in the (Day 9 - Day 3 movements), acute locomotor response cocaine-paired chamber during the testing trial, which to cocaine (Day 3 - Day 2 movements) and saline- was calculated by dividing time spent in the drug-paired induced basal locomotor activity (Day 2 movements), chamber by total time spent in the black and white therefore controlling for the effects of strain. Percent chambers and multiplying by 100. Conditioned place time spent in the drug-paired chamber on Day 1 was preference was measured as percent time spent in the subtracted from percent time spent in the drug paired cocaine-paired chamber before (Day 1) and after (Day chamber on Day 10 to yield the CPP value used for cor- 10) conditioning, and the development of place prefer- relation analyses. ence was defined as a significant difference between pre- and post-conditioning values. Movement counts in the Results black and white compartments were also recorded. Pre-test chamber bias Training chamber bias was examined by two-way Statistical analysis ANOVA (strain and chamber) of time spent in each of All data were analyzed using the SPSS statistical package the three chambers. A significant main effect of cham- (version 16.0 for Macintosh, SPSS, Chicago IL, USA). ber was observed (F =16.6;p <0.001)aswellasa (2,167) Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 4 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 strain by chamber interaction (F =4.5;p < 0.001). Cocaine place preference (10,167) Tukey post-hoc comparisons of the three chambers indi- A two-way ANCOVA (strain by day with locomotor cated that there was no difference in the time mice activity as the covariate) yielded a significant effect of spent in the black and white chambers (p =0.374)(Fig- day (F =7.3;p < 0.01) indicating that mice spent (1,95) ure 2). Therefore, mice were assigned to the training more time in the cocaine-paired chamber on Day 10 fol- lowing conditioning than on Day 1 during the pre-test. chamber in an unbiased manner and place preference The effect of locomotor activity was not significant (F data analysis was conducted on the group as a whole =0.78;p > 0.05). Strain (F =1.5;p >0.05) and regardless of training chamber. (1,95) (4,95) strain by day interaction effects (F =1.2;p > 0.05) Visual inspection of Day 1 data indicated that three (4,95) out of eight 129 mice spent almost 100% of the time in were also not observed indicating that no strain differ- a single chamber during the pre-test, and one mouse ences in place preference were detected. Post-hoc t-tests, spent over 83% (data not shown). Therefore, 129 mice however, showed that D2 mice did not spend signifi- were excluded from overall analysis of place preference cantly more time in the cocaine-paired chamber on Day to avoid skewing interstrain comparisons due to 129 10 than on Day 1 (t(14) = -0.09;p > 0.05; Figure 3). strain-specific equipment bias effects. Place preference 129 mice spent more time in the drug-paired chamber in the 129 mice was analyzed separately from the other after conditioning, but the difference was not significant strains with the four outliers excluded. (t(14) = -1.5;p > 0.05) indicating that this substrain of 129 does not exhibit place preference to 20 mg/kg B6 Control Groups under these experimental conditions (Figure 3). How- One-way ANOVA identified no significant effect of B6 ever, variability in 129 mice was much higher than in group on either CPP (F =0.21;p > 0.05) or sensiti- other strains, possibly due to locomotor hypoactivity (1,15) zation (F(1,15) = 0.13;p > 0.05). A significant effect of often observed in this inbred strain. acute locomotor response to cocaine was observed (F (1,15) = 4.9;p < 0.05). Animals in Group 1 show greater Chamber effects on locomotor activity acute sensitivity to cocaine than animals in Group 2. A Differences in locomotor activity in the black and white closer examination of the data indicates that the groups chambers are an important consideration when analyz- do not differ on Day 2 baseline locomotor activity (t(14) ing locomotor response to cocaine in the CPP proce- dure. Although strains spentequal amountsoftimein =0.26;p > 0.05), but B6 animals from Group 1 are sig- the black and white chambers on Day 1, two-way nificantly more activated by cocaine on Day 3 (t(14) = ANOVA (strain × chamber) of locomotor movements in 2.4;p < 0.05). Extending the analysis to the entire experi- the CPP apparatus during the pre-test indicated that ment, we observed that the two groups do not differ for saline-induced locomotor behavior (Days 2, 4, 6 and 8) there were significant main effects of strain (F = (5,111) but consistently differ for cocaine-induced locomotor 28.2;p < 0.001) and chamber (F = 39.1;p < 0.001), (1,111) behavior (Days 3, 5, 7 and 9) (data not shown). as well as a significant interaction effect (F =2.5;p (5,111) < 0.05). Strain differences were reflective of normal var- iation in locomotor activity among inbred strains and had the following pattern: 129 = C3H < B6 = D2 = FVB < BALB. Overall, mice were more active in the black chamber. Post-hoc t-tests indicated that increased activ- ity in the black chamber was only significant for B6 (t (30) = 6.8;p < 0.001), D2 (t(14) = 3.9;p <0.01) and FVB (t(14) = 5.5;p < 0.001) strains. However, locomotor activity differences in black vs. white chambers were no longer significant on the sec- ond day of testing when mice were restricted to the unpaired chamber in which they received saline and before their first exposure to cocaine. On Day 2, only strain effects were significant (F =6.6;p < 0.001) (5,55) Figure 2 Initial bias for each chamber of the three-chamber and no chamber (F = 0.75;p = 0.39) or interaction (1,55) place preference apparatus during the pre-test session. All effects (F =1.3;p = 0.27) were observed. Neverthe- (5,55) strains were included in the analysis. Separate analysis excluding less, cocaine-paired chamber was included as an inde- 129 mice yielded similar results (data not shown). Error bars are pendent variable in all locomotor activity analyses to SEM. ***p < 0.001. assess the effect of chamber on the dependent variable. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 5 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 3 Cocaine-induced place preference in six inbred strains. Percent time spent in the cocaine-paired chamber both pre- (white bars) and post-conditioning (grey bars) is shown. Error bars are SEM. *p < 0.05, **p < 0.01. Acute locomotor response to cocaine However, although most strains showed a pattern of Acute locomotor response was measured by comparison increasing locomotor response with repeated exposures, of locomotor activity on Day 2 (saline) and Day 3 after post-hoc Tukey’s analysis by strain indicates that only the first exposure to cocaine. Significant strain (F = 129 and D2 mice showed significant increases in loco- (5,111) 6.46;p < 0.001) and day of testing (F = 62.1;p < motor activity after the initial dose of cocaine (Figure 5). (1,111) 0.001) effects and a significant strain by day of testing Locomotor activity in response to saline was also interaction effect (F =3.23;p < 0.05) were observed assessed by two-way ANOVA, and a main effect of (5,111) by two-way ANOVA. Post-hoc t-tests of individual strain was observed (F = 18.7;p < 0.001) but no day (5,223) strains indicate that all strains showed a significant of treatment (F =1.5;p =0.206) orstrainbyday (3,223) increase in locomotor activity in response to acute interaction effects (F =1.1;p = 0.380). However, (15,223) cocaine with the exception of BALB (Figure 4). No no generalized locomotor changes across days of saline effect of cocaine-paired chamber was observed (F = treatment were observed (Figure 5). (1,111) 0.19;p = 0.66) indicating that acute locomotor activation An effect of cocaine-paired chamber was also observed was not affected by the chamber in which the mice during both cocaine treatment days (F =10.9;p < (1,223) received cocaine. 0.01) and saline treatment days (F =8.8;p <0.01), (1,223) as well as strain by cocaine-paired chamber interaction Cocaine locomotor sensitization effects (F = 10.2;p < 0.001 and F =4.3;p < (5,223) (5,223) Locomotor sensitization for all strains was assessed by 0.01, respectively). These data indicate that inbred examining locomotor behavior across all four days of strains differed in their locomotor behavior depending cocaine treatment. Significant main effects of strain (F upon the chamber to which they were restricted during = 18.2;p < 0.001) and day of treatment (F = the conditioning trials. Several strains, including B6, (5,223) (3,223) 5.9;p < 0.01) but no strain by day interaction effect (F C3H and FVB, appear to have a generalized increase in = 0.42;p = 0.97) were observed by ANOVA. locomotor activity in the black chamber regardless of (15,223) Cocaine-induced locomotor activation increased with treatment with either saline or cocaine (Figure 6). D2 repeated treatments across all strains indicating that mice showed no difference in activity in either black or sensitization was occurring. Post-hoc Tukey comparisons white chambers. Two strains in particular, BALB and collapsed across strains indicate that locomotor behavior 129, exhibited a chamber and/or drug-dependent loco- increased significantly by the third cocaine challenge. motor response. 129 mice showed reciprocal differences Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 6 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 4 Acute locomotor response across strains to a single 20 mg/kg cocaine challenge. Saline locomotor activity (white bars) was recorded on day 2 of testing and cocaine locomotor activity (grey bars) was recorded on day 3. Error bars are SEM. **p < 0.01, ***p < 0.001. Figure 5 Cocaine locomotor sensitization across strains. Locomotor activity for 30-minute sessions across eight days of conditioning. Saline treatment days (white bars) and cocaine treatment days (grey bars) are shown. Error bars are SEM. *p < 0.05. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 7 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 6 Effect of training chamber on locomotor activity during repeated exposures to either cocaine or saline.Barsrepresent locomotor activity of groups of mice (N = 4 per strain; B6 N = 8) exposed to cocaine and saline in either the black or white chamber. The first white bar is cocaine-induced activity in white chambers. The second white bar is saline-induced activity in white chambers. Error bars are SEM. B6, C3H and FVB exhibited more locomotor activity in the black chamber regardless of treatment with either saline or cocaine. D2 mice showed no difference in activity in either black or white chambers. 129 mice showed reciprocal differences in activity and were more active in the black chamber after exposure to cocaine and more active in the white chamber after exposure to saline. BALB mice showed similar amounts of locomotor activity in response to saline in both the black and white chambers and showed a significantly higher response to cocaine only when it was administered in the white chamber. correlation and the results presented in Table 1. No sig- in activity and were more active in the black chamber after exposure to cocaine and more active in the white nificant correlations were observed. chamber after exposure to saline. BALB mice showed A relationship between baseline and acute locomotor similar amounts of locomotor activity in response to sal- activity in response to cocaine has been previously ine in both the black and white chambers and, surpris- reported [16,17]. Partial correlation analysis of saline- ingly, showed a significantly higher response to cocaine induced baseline activity and cocaine-induced locomotor only when it was administered in the white chamber activation did show a significant negative correlation (r (Figure 6). (45) = -0.40; p < 0.01) indicating that strains with higher baseline locomotor activity exhibited lesser increases in Correlation analyses locomotor response to cocaine. Partial correlations were performed to assess relation- ships between the stimulatory and rewarding effects of Discussion cocaine while controlling for strain effects. The effect of In this study of six commonly-used inbred strains, our locomotor activity on the test day was assessed with results show significant strain differences in locomotor regard to its effect on place preference for all strains response to an acute cocaine challenge, in addition to except 129. A partial correlation of total locomotor locomotor sensitization and conditioned place prefer- movements on Day 10 and percent place preference ence to cocaine for most strains. Despite the absence of indicated that activity did not have a significant effect CPP in 129S1/SvImJ and DBA/2J mice, these strains on place preference behavior (Table 1; r(45) = 0.21;p > exhibited robust acute locomotor and sensitization 0.05). responses to 20 mg/kg of cocaine. Both FVB/NJ and The relationships between acute locomotor stimula- BALB/cJ developed CPP, but FVB showed low acute tion, sensitization and CPP were also assessed by partial locomotor activation and no significant sensitization, Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 8 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Table 1 Partial correlations of behavioral variables controlling for strain Acute Locomotor Locomotor Day 10 Baseline Locomotor Stimulation Sensitization Movements Activity Locomotor Sensitization r -0.077 p 0.607 df 45 Day 10 Movements r 0.004 0.153 p 0.976 0.303 df 45 45 Baseline Locomotor r -0.402 -0.035 0.487 Activity p 0.005 0.815 0.001 df 45 45 45 Place Preference r -0.057 0.055 0.214 -0.091 p 0.704 0.711 0.149 0.543 df 45 45 45 45 whereas BALB showed no acute locomotor activation Our study includes three strains or substrains that, to but strong context-specific cocaine sensitization. C57BL/ the best of our knowledge, have not yet been character- 6J and C3H/HeJ mice developed CPP as well as strong ized for cocaine-induced CPP - FVB/NJ, 129S1/SvImJ acute locomotor stimulatory and sensitization responses. and BALB/cJ. FVB mice and 129 ES cells are frequently The results of this study highlight the significant role of used in the generation of transgenic and knockout lines, genetic background in determining behavioral responses therefore, characterization of these strains’ responses to to drugs of abuse, such as cocaine. the rewarding and stimulating properties of cocaine has It should be noted that these results are limited to a significant implications for behavioral effects related to single dose of 20 mg/kg and dose-dependent differences genetic background. Similar to the results of a study by in place preference have been noted by others [18-20]. Zombeck et al. [26], we found that acute locomotor In addition, other behaviors such as rearing or stereoty- response to 20 mg/kg cocaine in FVB mice is lower rela- pies may interfere with the measurement of locomotor tive to the other strains, except BALB (Figure 4). FVB mice also do not show significant sensitization to behavior. In general, peripherally-administered cocaine repeated doses of cocaine under our experimental con- results in decreased rearing behavior, although this effect is strain- and dose-dependent [21,22]. Measure- ditions (Figure 5). Although acute locomotor response ment of rearing behavior is not possible with our CPP to cocaine is relatively low, FVB mice do show robust apparatus and strain differences in rearing behavior place preference (Figure 3) indicating that this strain is could have affected locomotor response; however, at sensitive to the rewarding effects of cocaine. least one study has shown dissociation between Cocaine-mediated behaviors in the 129S1 strain have cocaine’s effects on rearing and locomotor behaviors not yet been reported; however, several other 129 sub- [23]. Stereotypy in response to cocaine is also dose- and strains have been characterized for cocaine locomotor strain-dependent. Stereotypic responses to repeated, but activity with mixed results [21,25,27-29]. Taken not acute, injections of cocaine have been reported for together, these results suggest that locomotor activation B6 and D2 strains [24,25]. Strain differences in stereo- in 129 micemaybesubstrain or dose-dependent and typy can also interfere with locomotor responses and may be sensitive to experimental parameters. may play a factor in our results. Regardless, strain differ- Studies assessing the rewarding effects of cocaine in ences in locomotor activity due to stereotypy still reflect 129 substrains are more variable with some studies real differences in behavioral sensitivity to cocaine. observing no place preference [28] and others observing Finally, differences in cocaine-induced locomotor acti- significant place preference [27]. We found that 129S1 vation in the B6 groups suggest that the strain differ- mice do not show significant place preference to 20 mg/ ences in locomotor response to cocaine could be kg cocaine, similar to the observation of Miner [28] confounded by temporal differences. However, we do although at lower doses. Our results may have been not believe this to be the case based on the congruence influenced by the baseline hypoactivity observed in 129S1 mice, which are extremely inactive in many beha- of our strain data with published studies on cocaine vioral assays [30-32]. These data underscore the locomotor activation. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 9 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 importance of considering the unique behavioral charac- teristics of different inbred mouse strains that may influ- ence experimental outcomes. As we observed in the 129 mice, the role of locomotor activity in behavioral assays cannot be overlooked. The extent to which basal locomotor activity correlates with initial drug sensitivity has been examined with varied results. Several studies report no correlation between acute locomotor stimulation and baseline locomotion [33,34], while others observe a significant correlation [16,17]. In our sample, baseline locomotor activity does predict acute response to cocaine, as demonstrated by Figure 7 White vs. black chamber effect on cocaine-induced the correlation between saline-induced and acute locomotor activity and sensitization observed for BALB/cJ mice cocaine-induced activity. in the CPP apparatus. Results are separated by chamber in which Correlations between activity and CPP may reflect mice received cocaine during conditioning trials. Conditioning days interference between conditioned activity and the devel- and treatment are shown sequentially along the x-axis. Error bars are SEM. opment of place preference or strain differences in either basal or psychostimulant-induced locomotor response during training [35-37]. Conditioned activity does not appear to influence CPP in our group, as we occurring, resulting in context-dependent sensitization did not observe a correlation between CPP and locomo- in BALB mice. tor activity on the test day. The context in which a drug is experienced can signifi- The measurement of acute response, sensitization and cantly influence both acute and sensitized responses to the the rewarding effects of cocaine allow us to examine drug [47,48]. Context-dependent sensitization has also one prominent hypothesis of addiction. The incentive- been attributed to associative learning or increased stress sensitization model of drug craving suggests that [47,49-51]. It is possible that the white chamber may be chronic drug abuse causes hypersensitivity of the under- anxiogenic for BALB mice, resulting in greater sensitiza- lying brain circuitry as measured by sensitization, which tion. However, this is unlikely since BALB mice spend exacerbates incentive salience and may explain the com- equivalent amounts of time in both chambers during the pulsive drug-seeking that drives addiction [38]. Similar pre-test session on Day 1. Alternatively, features of the to observations by Cunningham et al. [14], our data do white chamber may cause BALB mice to more readily not appear to support theories of a positive link between associate the context with the drug effects. Willner et al. drug craving and sensitization [38] or the rewarding and have shown that the extent of sensitization is determined stimulating effects of drugs [39], as we observed no cor- by the behavior elicited by the drug [52], thus BALB mice relation between place preference and either acute loco- may develop greater sensitization as a result of a greater motor stimulation or sensitization. stimulatory response to cocaine in the white chamber. Similar to our results, most studies in BALB mice Acute locomotor response to cocaine is certainly higher report low levels of locomotor activation or no effect at for BALB mice in the white chamber (Figure 7) but this all in response to cocaine [22,26,40-46]. Further, BALB does not explain why this strain, in particular, shows mice reportedly do not develop place preference to greater sensitivity to the psychomotor effects of cocaine in moderate cocaine doses [18]. However, the level of loco- this context. The mechanisms by which drug effects inter- motor activation in our study was dependent on the act with context to result in behavioral differences remain chamber in which the cocaine was administered. BALB to be determined. Further experiments are necessary to mice receiving cocaine in the white chamber showed replicate these results and to gain a better understanding significant locomotor activation that exceeded the of this phenomenon in BALB mice. responses of other strains whereas BALB mice receiving Our observation that D2 mice did not exhibit signifi- cocaine in the black chamber did not display locomotor cant place preference under our assay conditions aligns activation (Figure 6). This level of activation was not with previous reports using higher doses of cocaine (32 observed after acute administration of cocaine but was mg/kg [4]; 30 mg/kg [14]) and deviates from others observed on all subsequent days of cocaine administra- reporting place conditioning in response to moderate tion in the white chamber (Figure 7) indicating that the doses (10 mg/kg [14]). Taken together, these studies locomotor activation developed upon repeated drug dos- support dose-dependent place preference in D2 mice. ing. Taken together, these data indicate that a specific However, modification of experimental parameters can interaction between the drug and the environment is also influence place conditioning and should be carefully Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 10 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 2. Crabbe JC, Belknap JK, Buck KJ: Genetic animal models of alcohol and considered when planning experiments and reporting drug abuse. Science 1994, 264:1715-1723. results [14]. 3. George FR, Goldberg SR: Genetic approaches to the analysis of addiction processes. Trends Pharmacol Sci 1989, 10:78-83. 4. Seale TW, Carney JM: Genetic determinants of susceptibility to the Conclusions rewarding and other behavioral actions of cocaine. J Addict Dis 1991, This study expands upon current literature in the field, 10:141-162. describing cocaine-induced conditioned place preference 5. Cunningham CL, Gremel CM, Groblewski PA: Drug-induced conditioned place preference and aversion in mice. Nat Protoc 2006, 1:1662-1670. in three strains/substrains for which it had not pre- 6. Sanchis-Segura C, Spanagel R: Behavioural assessment of drug viously been reported. Further, we have also shown con- reinforcement and addictive features in rodents: an overview. Addict Biol text-dependent locomotor sensitization in response to 2006, 11:2-38. 7. Gerasimov MR, Schiffer WK, Gardner EL, Marsteller DA, Lennon IC, Taylor SJ, cocaine in BALB/cJ mice. Of the strains included in our Brodie JD, Ashby CR, Dewey SL: GABAergic blockade of cocaine- study, B6 and C3H emerge as the most appropriate for associated cue-induced increases in nucleus accumbens dopamine. Eur J the study of responses to cocaine, as these mice develop Pharmacol 2001, 414:205-209. 8. Self DW, Nestler EJ: Relapse to drug-seeking: neural and molecular place preference and show acute locomotor activation mechanisms. Drug Alcohol Depend 1998, 51:49-60. and sensitization. The use of strains such as FVB and 9. Bardo MT, Bevins RA: Conditioned place preference: what does it add to BALB may benefit studies aiming to dissociate the our preclinical understanding of drug reward? Psychopharmacology (Berl) 2000, 153:31-43. mechanisms underlying these cocaine-induced beha- 10. Ruiz-Durantez E, Hall SK, Steffen C, Self DW: Enhanced acquisition of viors. These results highlight the importance of consid- cocaine self-administration by increasing percentages of C57BL/6J genes ering both context and genetic background in the in mice with a nonpreferring outbred background. Psychopharmacology (Berl) 2006, 186:553-560. analysis of cocaine-induced behaviors. 11. Griffin WC, Randall PK, Middaugh LD: Intravenous cocaine self- Much remains unknown regarding the neural circuitry administration: individual differences in male and female C57BL/6J mice. and genetic mechanisms underlying drug addiction. The Pharmacol Biochem Behav 2007, 87:267-279. 12. Festa ED, Quinones-Jenab V: Gonadal hormones provide the biological tremendous genetic variability among inbred mouse basis for sex differences in behavioral responses to cocaine. Horm Behav strains and our ability to model aspects of addiction 2004, 46:509-519. with various behavioral paradigms, such as CPP, will 13. Ambrose-Lanci LM, Sterling RC, Van Bockstaele EJ: Cocaine withdrawal- induced anxiety in females: impact of circulating estrogen and potential eventually lead to the identification of genes and gene use of delta-opioid receptor agonists for treatment. J Neurosci Res networks that influence addiction pathways in the brain 88:816-824. and promise to have a profound effect on the treatment 14. Cunningham CL, Dickinson SD, Grahame NJ, Okorn DM, McMullin CS: Genetic differences in cocaine-induced conditioned place preference in of addiction in the clinic. mice depend on conditioning trial duration. Psychopharmacology (Berl) 1999, 146:73-80. 15. Jones BC, Tarantino LM, Rodriguez LA, Reed CL, McClearn GE, Plomin R, Acknowledgements Erwin VG: Quantitative-trait loci analysis of cocaine-related behaviours The authors wish to thank Dr. Christopher Cunningham for helpful and neurochemistry. Pharmacogenetics 1999, 9:607-617. discussions on both the data and manuscript. This research was supported 16. Miner LL, Marley RJ: Chromosomal mapping of the psychomotor by funding from NIH NIDA Grants DA022392 and DA023690 to LMT and a stimulant effects of cocaine in BXD recombinant inbred mice. Novartis Grant SFP-1406 from the Genomics Institute of the Novartis Psychopharmacology (Berl) 1995, 122:209-214. Research Foundation. 17. Phillips TJ, Huson MG, McKinnon CS: Localization of genes mediating Acknowledgement of grant funding acute and sensitized locomotor responses to cocaine in BXD/Ty This work was sponsored by grants DA022392 and DA023690 from the/ recombinant inbred mice. J Neurosci 1998, 18:3023-3034. National Institute on Drug Abuse/National Institutes of Health. 18. Belzung C, Barreau S: Differences in drug-induced place conditioning between BALB/c and C57Bl/6 mice. Pharmacol Biochem Behav 2000, Author details 65:419-423. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA. 19. Bardo MT, Rowlett JK, Harris MJ: Conditioned place preference using Genomics Institute of the Novartis Research Foundation, San Diego, CA, opiate and stimulant drugs: a meta-analysis. Neurosci Biobehav Rev 1995, USA. 19:39-51. 20. Orsini C, Bonito-Oliva A, Conversi D, Cabib S: Susceptibility to conditioned Authors’ contributions place preference induced by addictive drugs in mice of the C57BL/6 AFED contributed to the statistical analysis and the drafting of the and DBA/2 inbred strains. Psychopharmacology (Berl) 2005, 181:327-336. manuscript. LGB carried out the behavioral testing and contributed to the 21. Kuzmin A, Johansson B: Reinforcing and neurochemical effects of study design. LMT conceived of the study, participated in its design and cocaine: differences among C57, DBA, and 129 mice. Pharmacol Biochem coordination, contributed to the statistical analysis and helped to draft the Behav 2000, 65:399-406. manuscript. All authors read and approved the final manuscript. 22. 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Behavioral and Brain Functions 2011, 7:29 Page 11 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 25. Schlussman SD, Ho A, Zhou Y, Curtis AE, Kreek MJ: Effects of “binge” 49. Badiani A, Cabib S, Puglisi-Allegra S: Chronic stress induces strain- pattern cocaine on stereotypy and locomotor activity in C57BL/6J and dependent sensitization to the behavioral effects of amphetamine in 129/J mice. Pharmacol Biochem Behav 1998, 60:593-599. the mouse. Pharmacol Biochem Behav 1992, 43:53-60. 26. Zombeck JA, Swearingen SP, Rhodes JS: Acute locomotor responses to 50. Caprioli D, Celentano M, Paolone G, Badiani A: Modeling the role of cocaine in adolescents vs. adults from four divergent inbred mouse environment in addiction. Prog Neuropsychopharmacol Biol Psychiatry 2007, strains. Genes Brain Behav 2010, 9:892-898. 31:1639-1653. 27. Zhang Y, Mantsch JR, Schlussman SD, Ho A, Kreek MJ: Conditioned place 51. 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Ito S, Mori T, Namiki M, Suzuki T, Sawaguchi T: Complicated interaction and take full advantage of: between psychostimulants and morphine in expression of phenotype of behavior in the dopaminergic system of BALB/c mice. Journal of • Convenient online submission pharmacological sciences 2007, 105:326-333. 46. Shuster L, Yu G, Bates A: Sensitization to cocaine stimulation in mice. • Thorough peer review Psychopharmacology (Berl) 1977, 52:185-190. • No space constraints or color figure charges 47. Badiani A, Robinson TE: Drug-induced neurobehavioral plasticity: the role • Immediate publication on acceptance of environmental context. Behav Pharmacol 2004, 15:327-339. 48. Badiani A, Browman KE, Robinson TE: Influence of novel versus home • Inclusion in PubMed, CAS, Scopus and Google Scholar environments on sensitization to the psychomotor stimulant effects of • Research which is freely available for redistribution cocaine and amphetamine. Brain Res 1995, 674:291-298. 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Cocaine locomotor activation, sensitization and place preference in six inbred strains of mice

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Springer Journals
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Copyright © 2011 by Eisener-Dorman et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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21806802
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Abstract

Background: The expanding set of genomics tools available for inbred mouse strains has renewed interest in phenotyping larger sets of strains. The present study aims to explore phenotypic variability among six commonly- used inbred mouse strains to both the rewarding and locomotor stimulating effects of cocaine in a place conditioning task, including several strains or substrains that have not yet been characterized for some or all of these behaviors. Methods: C57BL/6J (B6), BALB/cJ (BALB), C3H/HeJ (C3H), DBA/2J (D2), FVB/NJ (FVB) and 129S1/SvImJ (129) mice were tested for conditioned place preference to 20 mg/kg cocaine. Results: Place preference was observed in most strains with the exception of D2 and 129. All strains showed a marked increase in locomotor activity in response to cocaine. In BALB mice, however, locomotor activation was context-dependent. Locomotor sensitization to repeated exposure to cocaine was most significant in 129 and D2 mice but was absent in FVB mice. Conclusions: Genetic correlations suggest that no significant correlation between conditioned place preference, acute locomotor activation, and locomotor sensitization exists among these strains indicating that separate mechanisms underlie the psychomotor and rewarding effects of cocaine. Background paradigm, rodents learn to associate a specific environ- The devastating effects of drug addiction on the lives of mental context with the effects of a drug stimulus. Place those who struggle with it and the social and economic conditioning confers many advantages in the study of implications for society as a whole are staggering. Faced drug-induced motivational responses, including the with this challenge, understanding the biological path- short duration and relative simplicity of the procedure ways that predispose individuals to addiction to cocaine in comparison with reinforcement models such as self- (and other drugs) is a top priority in the research com- administration. CPP also provides the opportunity to munity. The perception that genetic background influ- measure the initial acute response and sensitization or ences the predisposition to abuse drugs is supported by tolerance to the locomotor stimulating effects of a drug studies in humans [1] and in animal models [2-4]. following repeated exposure [5,6]. In addition, CPP is While no animal model exists that recapitulates the measured in the absence of drug-related physiological entire spectrum of the drug abuse syndrome in humans, confounds such as locomotor and sensory effects [5]. animal models do exist for the study of specific drug- Encountering environments and stimuli previously asso- ciated with drug use is one of the most common trig- related behaviors, including initial sensitivity (as mea- sured by drug-induced locomotor behavior), sensitiza- gers for relapse in humans [7,8], and the CPP paradigm tion and drug reward and reinforcement paradigms. specifically addresses the effects of context-specific Conditioned place preference (CPP) has been estab- exposures on drug reward and drug-seeking behaviors lished as a standard procedure for assessing the reward- in animal models [9]. ing effects of drugs in rodent models. In the CPP Drug-induced behaviors, including CPP, have a signifi- cant genetic component as demonstrated by the large * Correspondence: lisat@med.unc.edu degree of phenotypic variability among inbred mouse Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA strains [4,10]. The goal of the present study was to Full list of author information is available at the end of the article © 2011 Eisener-Dorman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 2 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 expand upon thecurrent literaturebyinvestigating cocaine-induced response across strains, as previous stu- drug-induced sensitivity, sensitization and place condi- dies suggest this dose is sufficient to induce a drug tioning in six commonly used and genetically diverse response in many strains [4,14,15]. Immediately follow- inbred mouse strains. Several of these strains have ing an intraperitoneal (i.p.) injection with cocaine or sal- already been characterized for CPP, cocaine locomotor ine, each animal was placed in the appropriate chamber activation and sensitization [4], while others, including of the CPP apparatus. FVB/NJ and substrains of 129 (129S1/SvImJ) and BALB (BALB/cJ), have not previously been studied in the place Apparatus preference paradigm. Here, we present strain-specific Conditioned place preference testing was conducted differences that confirm, contradict, and expand upon using a three-chambered conditioned place preference previously reported inbred strain responses to cocaine. apparatus (46.5 × 12.7 × 12.7 cm; MED-CPP-MSAT, Med Associates) in a sound-attenuating enclosure Methods (ENV-016MD, Med Associates). The apparatus con- Animals sisted of a grey center compartment (7.2 × 12.7 cm) Male mice from six inbred strains (129S1/SvImJ (129), with a smooth PVC floor and two choice compartments C57BL/6J (B6), BALB/cJ (BALB), C3H/HeJ (C3H), DBA/ (16.8 × 12.7 cm) on either side. One compartment was 2J (D2) and FVB/NJ (FVB)) were obtained from the in- all black with a stainless steel grid rod floor consisting house breeding colony at the Genomics Institute of the of 3.2 mm rods placed on 7.9 mm centers and the other Novartis Research Foundation (GNF). Inbred strains for was all white with a 6.35 × 6.35 mm stainless steel mesh the GNF breeding colony were initially purchased from floor. Compartments were separated by guillotine doors, the Jackson Laboratory (Bar Harbor, ME, USA), and which were left open to permit free exploration of the breeder stocks were replenished every seventh generation full apparatus during pre-test on Day 1 and the testing to limit genetic drift. Mice were group-housed and main- phase on Day 10 but were closed during training days. tained in an AAALAC-accredited, specific pathogen-free Two identical CPP apparatuses were used and each (SPF) barrier colony in ventilated cages (Thoren Caging apparatus had two training chambers (black and white) Systems, Hazelton, PA, USA) on a 12-hour light-dark for a total of four training chambers. Each mouse was cycle (lights on at 6:00 A.M.). Irradiated food (Pico tested in the same apparatus and the same training rodent chow 20; Purina, St. Louis, MO, USA) and water chamber throughout the experiment. were provided ad libitum. Mice were between 59 and 70 Mouse movement in the apparatus was detected by six days of age at the onset of testing, and all behavioral test- infrared photobeams (spaced 2.8 cm apart and 1.0 cm ing occurred between 8:00 A.M. and 12:00 P.M. from the end wall) in each choice compartment and SixteenB6miceand eightmicefromeachofthe three (spaced 2.8 cm apart) in the center compartment. remaining five strains were tested in the conditioned Photobeams mounted 1.8 cm above the apparatus floor place preference procedure described below. Groups of captured horizontal movement. The absence of z-axis mouse strains were tested in three separate testing ses- photobeams did not permit detection of vertical move- sions over the course of two months, and all mice in a ment, such as rearing. Activity was captured by auto- group were tested on the same day. With the exception mated data collection as movement counts. Movement of B6, all mice of each strain were tested in the same counts are defined as consecutive beam breaks within a session and different strains were tested in each of the chamber to detect horizontal forward locomotion while three sessions. Two sets of B6 mice (8 mice per set) excluding stereotypic behavior. Entrance into a chamber were tested in the first and last sessions as a control for was recorded when the second photobeam into the temporal effects across sessions. chamber was broken. Time spent in each compartment Male mice were chosen for testing to mitigate the was recorded in seconds. variability observed in females due to estrous cycle [11-13]. Conditioned place preference procedure All procedures were approved by the GNF Institu- The place preference procedure consisted of three tional Animal Care and Use Committee and followed phases, as outlined below and in Figure 1. the guidelines set forth by the National Institutes of Pre-test phase Health (NIH) Guide for the Care and Use of Laboratory The purpose of the pre-test was to habituate the animals Animals. to the novelty and stress associated with the apparatus, handling and injection prior to conditioning, as well as Drugs to identify initial chamber preferences. For the pre-test, Cocaine was dissolved in saline (0.9% NaCl). A 20 mg/ all mice received an i.p. saline injection immediately kg dose of cocaine was used to obtain a moderate prior to placement in the apparatus for 20 minutes. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 3 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 1 Timeline of the place preference study. Mice were placed in the grey center compartment at the Multivariate analysis of variance (ANOVA) was used to beginning of the pre-test but were allowed to move analyze the effect of strain for each behavioral measure. freely between compartments. The total time spent in Dependent variables differed based on behavioral mea- each of the three chambers was recorded and then cal- sure and included percent time spent in each chamber culated as a percentage of the total test duration. The for equipment bias assessment and percent time spent percent time spent in the black and white chambers in the cocaine-paired chamber for place preference. only, not including the grey chamber, was also calcu- Locomotor activity (recorded as movement counts) was lated and used as the pre-conditioning value for place assessed for acute locomotor response, sensitization and preference analysis. on the test day (Day 10). Day of testing was included as Conditioning phase an independent variable to assess the effects of cocaine For the conditioning procedure, animals from each on time spent in the cocaine-paired chamber and also strain were randomly assigned to one of two condition- for locomotor activity over multiple days of testing ing subgroups. Mice in one subgroup (N = 4 per strain; (acute and sensitized locomotor activity). Based on B6 N = 8) received cocaine paired with the black cham- results from the pre-test session indicating that the ber and saline paired with the white chamber. Mice in equipment was unbiased, data were collapsed across thesecondsubgroup(N=4per strain;B6N=8) training chambers for analysis of place preference. How- received cocaine paired with the white chamber and sal- ever, locomotor activity during the conditioning phase ine paired with the black chamber. On days 2, 4, 6 and differed between black and white chambers for some 8, mice were injected with saline and placed in the strains; therefore, chamber was included as an indepen- unpaired chamber. On days 3, 5, 7 and 9, mice were dent variable for activity analyses. Locomotor activity injected with cocaine and placed in the drug-paired was also used as a covariate in the CPP analysis. Post- chamber. Conditioning took place across eight subse- hoc Tukey HSD and t-tests were employed for indivi- quent days, and trials were 30 minutes in duration (one dual post-hoc comparisons. trial per day). Movement counts in the black and white The two groups of B6 mice were analyzed by one-way chambers were recorded. ANOVA with group as the independent variable. Dependent variables included acute locomotor response, Test day sensitization and place preference. For the testing phase on Day 10, mice received an i.p. injection of saline immediately prior to placement in the Genetic correlations were assessed using partial corre- grey center compartment of the apparatus and were lation of percent CPP (Day 10 - Day 1), total locomotor allowed to move freely between the compartments for activity in the black and white chambers on the test day the duration of the 30-minute testing trial. The primary (Day 10 movements), cocaine locomotor sensitization dependent variable was percent time spent in the (Day 9 - Day 3 movements), acute locomotor response cocaine-paired chamber during the testing trial, which to cocaine (Day 3 - Day 2 movements) and saline- was calculated by dividing time spent in the drug-paired induced basal locomotor activity (Day 2 movements), chamber by total time spent in the black and white therefore controlling for the effects of strain. Percent chambers and multiplying by 100. Conditioned place time spent in the drug-paired chamber on Day 1 was preference was measured as percent time spent in the subtracted from percent time spent in the drug paired cocaine-paired chamber before (Day 1) and after (Day chamber on Day 10 to yield the CPP value used for cor- 10) conditioning, and the development of place prefer- relation analyses. ence was defined as a significant difference between pre- and post-conditioning values. Movement counts in the Results black and white compartments were also recorded. Pre-test chamber bias Training chamber bias was examined by two-way Statistical analysis ANOVA (strain and chamber) of time spent in each of All data were analyzed using the SPSS statistical package the three chambers. A significant main effect of cham- (version 16.0 for Macintosh, SPSS, Chicago IL, USA). ber was observed (F =16.6;p <0.001)aswellasa (2,167) Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 4 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 strain by chamber interaction (F =4.5;p < 0.001). Cocaine place preference (10,167) Tukey post-hoc comparisons of the three chambers indi- A two-way ANCOVA (strain by day with locomotor cated that there was no difference in the time mice activity as the covariate) yielded a significant effect of spent in the black and white chambers (p =0.374)(Fig- day (F =7.3;p < 0.01) indicating that mice spent (1,95) ure 2). Therefore, mice were assigned to the training more time in the cocaine-paired chamber on Day 10 fol- lowing conditioning than on Day 1 during the pre-test. chamber in an unbiased manner and place preference The effect of locomotor activity was not significant (F data analysis was conducted on the group as a whole =0.78;p > 0.05). Strain (F =1.5;p >0.05) and regardless of training chamber. (1,95) (4,95) strain by day interaction effects (F =1.2;p > 0.05) Visual inspection of Day 1 data indicated that three (4,95) out of eight 129 mice spent almost 100% of the time in were also not observed indicating that no strain differ- a single chamber during the pre-test, and one mouse ences in place preference were detected. Post-hoc t-tests, spent over 83% (data not shown). Therefore, 129 mice however, showed that D2 mice did not spend signifi- were excluded from overall analysis of place preference cantly more time in the cocaine-paired chamber on Day to avoid skewing interstrain comparisons due to 129 10 than on Day 1 (t(14) = -0.09;p > 0.05; Figure 3). strain-specific equipment bias effects. Place preference 129 mice spent more time in the drug-paired chamber in the 129 mice was analyzed separately from the other after conditioning, but the difference was not significant strains with the four outliers excluded. (t(14) = -1.5;p > 0.05) indicating that this substrain of 129 does not exhibit place preference to 20 mg/kg B6 Control Groups under these experimental conditions (Figure 3). How- One-way ANOVA identified no significant effect of B6 ever, variability in 129 mice was much higher than in group on either CPP (F =0.21;p > 0.05) or sensiti- other strains, possibly due to locomotor hypoactivity (1,15) zation (F(1,15) = 0.13;p > 0.05). A significant effect of often observed in this inbred strain. acute locomotor response to cocaine was observed (F (1,15) = 4.9;p < 0.05). Animals in Group 1 show greater Chamber effects on locomotor activity acute sensitivity to cocaine than animals in Group 2. A Differences in locomotor activity in the black and white closer examination of the data indicates that the groups chambers are an important consideration when analyz- do not differ on Day 2 baseline locomotor activity (t(14) ing locomotor response to cocaine in the CPP proce- dure. Although strains spentequal amountsoftimein =0.26;p > 0.05), but B6 animals from Group 1 are sig- the black and white chambers on Day 1, two-way nificantly more activated by cocaine on Day 3 (t(14) = ANOVA (strain × chamber) of locomotor movements in 2.4;p < 0.05). Extending the analysis to the entire experi- the CPP apparatus during the pre-test indicated that ment, we observed that the two groups do not differ for saline-induced locomotor behavior (Days 2, 4, 6 and 8) there were significant main effects of strain (F = (5,111) but consistently differ for cocaine-induced locomotor 28.2;p < 0.001) and chamber (F = 39.1;p < 0.001), (1,111) behavior (Days 3, 5, 7 and 9) (data not shown). as well as a significant interaction effect (F =2.5;p (5,111) < 0.05). Strain differences were reflective of normal var- iation in locomotor activity among inbred strains and had the following pattern: 129 = C3H < B6 = D2 = FVB < BALB. Overall, mice were more active in the black chamber. Post-hoc t-tests indicated that increased activ- ity in the black chamber was only significant for B6 (t (30) = 6.8;p < 0.001), D2 (t(14) = 3.9;p <0.01) and FVB (t(14) = 5.5;p < 0.001) strains. However, locomotor activity differences in black vs. white chambers were no longer significant on the sec- ond day of testing when mice were restricted to the unpaired chamber in which they received saline and before their first exposure to cocaine. On Day 2, only strain effects were significant (F =6.6;p < 0.001) (5,55) Figure 2 Initial bias for each chamber of the three-chamber and no chamber (F = 0.75;p = 0.39) or interaction (1,55) place preference apparatus during the pre-test session. All effects (F =1.3;p = 0.27) were observed. Neverthe- (5,55) strains were included in the analysis. Separate analysis excluding less, cocaine-paired chamber was included as an inde- 129 mice yielded similar results (data not shown). Error bars are pendent variable in all locomotor activity analyses to SEM. ***p < 0.001. assess the effect of chamber on the dependent variable. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 5 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 3 Cocaine-induced place preference in six inbred strains. Percent time spent in the cocaine-paired chamber both pre- (white bars) and post-conditioning (grey bars) is shown. Error bars are SEM. *p < 0.05, **p < 0.01. Acute locomotor response to cocaine However, although most strains showed a pattern of Acute locomotor response was measured by comparison increasing locomotor response with repeated exposures, of locomotor activity on Day 2 (saline) and Day 3 after post-hoc Tukey’s analysis by strain indicates that only the first exposure to cocaine. Significant strain (F = 129 and D2 mice showed significant increases in loco- (5,111) 6.46;p < 0.001) and day of testing (F = 62.1;p < motor activity after the initial dose of cocaine (Figure 5). (1,111) 0.001) effects and a significant strain by day of testing Locomotor activity in response to saline was also interaction effect (F =3.23;p < 0.05) were observed assessed by two-way ANOVA, and a main effect of (5,111) by two-way ANOVA. Post-hoc t-tests of individual strain was observed (F = 18.7;p < 0.001) but no day (5,223) strains indicate that all strains showed a significant of treatment (F =1.5;p =0.206) orstrainbyday (3,223) increase in locomotor activity in response to acute interaction effects (F =1.1;p = 0.380). However, (15,223) cocaine with the exception of BALB (Figure 4). No no generalized locomotor changes across days of saline effect of cocaine-paired chamber was observed (F = treatment were observed (Figure 5). (1,111) 0.19;p = 0.66) indicating that acute locomotor activation An effect of cocaine-paired chamber was also observed was not affected by the chamber in which the mice during both cocaine treatment days (F =10.9;p < (1,223) received cocaine. 0.01) and saline treatment days (F =8.8;p <0.01), (1,223) as well as strain by cocaine-paired chamber interaction Cocaine locomotor sensitization effects (F = 10.2;p < 0.001 and F =4.3;p < (5,223) (5,223) Locomotor sensitization for all strains was assessed by 0.01, respectively). These data indicate that inbred examining locomotor behavior across all four days of strains differed in their locomotor behavior depending cocaine treatment. Significant main effects of strain (F upon the chamber to which they were restricted during = 18.2;p < 0.001) and day of treatment (F = the conditioning trials. Several strains, including B6, (5,223) (3,223) 5.9;p < 0.01) but no strain by day interaction effect (F C3H and FVB, appear to have a generalized increase in = 0.42;p = 0.97) were observed by ANOVA. locomotor activity in the black chamber regardless of (15,223) Cocaine-induced locomotor activation increased with treatment with either saline or cocaine (Figure 6). D2 repeated treatments across all strains indicating that mice showed no difference in activity in either black or sensitization was occurring. Post-hoc Tukey comparisons white chambers. Two strains in particular, BALB and collapsed across strains indicate that locomotor behavior 129, exhibited a chamber and/or drug-dependent loco- increased significantly by the third cocaine challenge. motor response. 129 mice showed reciprocal differences Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 6 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 4 Acute locomotor response across strains to a single 20 mg/kg cocaine challenge. Saline locomotor activity (white bars) was recorded on day 2 of testing and cocaine locomotor activity (grey bars) was recorded on day 3. Error bars are SEM. **p < 0.01, ***p < 0.001. Figure 5 Cocaine locomotor sensitization across strains. Locomotor activity for 30-minute sessions across eight days of conditioning. Saline treatment days (white bars) and cocaine treatment days (grey bars) are shown. Error bars are SEM. *p < 0.05. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 7 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Figure 6 Effect of training chamber on locomotor activity during repeated exposures to either cocaine or saline.Barsrepresent locomotor activity of groups of mice (N = 4 per strain; B6 N = 8) exposed to cocaine and saline in either the black or white chamber. The first white bar is cocaine-induced activity in white chambers. The second white bar is saline-induced activity in white chambers. Error bars are SEM. B6, C3H and FVB exhibited more locomotor activity in the black chamber regardless of treatment with either saline or cocaine. D2 mice showed no difference in activity in either black or white chambers. 129 mice showed reciprocal differences in activity and were more active in the black chamber after exposure to cocaine and more active in the white chamber after exposure to saline. BALB mice showed similar amounts of locomotor activity in response to saline in both the black and white chambers and showed a significantly higher response to cocaine only when it was administered in the white chamber. correlation and the results presented in Table 1. No sig- in activity and were more active in the black chamber after exposure to cocaine and more active in the white nificant correlations were observed. chamber after exposure to saline. BALB mice showed A relationship between baseline and acute locomotor similar amounts of locomotor activity in response to sal- activity in response to cocaine has been previously ine in both the black and white chambers and, surpris- reported [16,17]. Partial correlation analysis of saline- ingly, showed a significantly higher response to cocaine induced baseline activity and cocaine-induced locomotor only when it was administered in the white chamber activation did show a significant negative correlation (r (Figure 6). (45) = -0.40; p < 0.01) indicating that strains with higher baseline locomotor activity exhibited lesser increases in Correlation analyses locomotor response to cocaine. Partial correlations were performed to assess relation- ships between the stimulatory and rewarding effects of Discussion cocaine while controlling for strain effects. The effect of In this study of six commonly-used inbred strains, our locomotor activity on the test day was assessed with results show significant strain differences in locomotor regard to its effect on place preference for all strains response to an acute cocaine challenge, in addition to except 129. A partial correlation of total locomotor locomotor sensitization and conditioned place prefer- movements on Day 10 and percent place preference ence to cocaine for most strains. Despite the absence of indicated that activity did not have a significant effect CPP in 129S1/SvImJ and DBA/2J mice, these strains on place preference behavior (Table 1; r(45) = 0.21;p > exhibited robust acute locomotor and sensitization 0.05). responses to 20 mg/kg of cocaine. Both FVB/NJ and The relationships between acute locomotor stimula- BALB/cJ developed CPP, but FVB showed low acute tion, sensitization and CPP were also assessed by partial locomotor activation and no significant sensitization, Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 8 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 Table 1 Partial correlations of behavioral variables controlling for strain Acute Locomotor Locomotor Day 10 Baseline Locomotor Stimulation Sensitization Movements Activity Locomotor Sensitization r -0.077 p 0.607 df 45 Day 10 Movements r 0.004 0.153 p 0.976 0.303 df 45 45 Baseline Locomotor r -0.402 -0.035 0.487 Activity p 0.005 0.815 0.001 df 45 45 45 Place Preference r -0.057 0.055 0.214 -0.091 p 0.704 0.711 0.149 0.543 df 45 45 45 45 whereas BALB showed no acute locomotor activation Our study includes three strains or substrains that, to but strong context-specific cocaine sensitization. C57BL/ the best of our knowledge, have not yet been character- 6J and C3H/HeJ mice developed CPP as well as strong ized for cocaine-induced CPP - FVB/NJ, 129S1/SvImJ acute locomotor stimulatory and sensitization responses. and BALB/cJ. FVB mice and 129 ES cells are frequently The results of this study highlight the significant role of used in the generation of transgenic and knockout lines, genetic background in determining behavioral responses therefore, characterization of these strains’ responses to to drugs of abuse, such as cocaine. the rewarding and stimulating properties of cocaine has It should be noted that these results are limited to a significant implications for behavioral effects related to single dose of 20 mg/kg and dose-dependent differences genetic background. Similar to the results of a study by in place preference have been noted by others [18-20]. Zombeck et al. [26], we found that acute locomotor In addition, other behaviors such as rearing or stereoty- response to 20 mg/kg cocaine in FVB mice is lower rela- pies may interfere with the measurement of locomotor tive to the other strains, except BALB (Figure 4). FVB mice also do not show significant sensitization to behavior. In general, peripherally-administered cocaine repeated doses of cocaine under our experimental con- results in decreased rearing behavior, although this effect is strain- and dose-dependent [21,22]. Measure- ditions (Figure 5). Although acute locomotor response ment of rearing behavior is not possible with our CPP to cocaine is relatively low, FVB mice do show robust apparatus and strain differences in rearing behavior place preference (Figure 3) indicating that this strain is could have affected locomotor response; however, at sensitive to the rewarding effects of cocaine. least one study has shown dissociation between Cocaine-mediated behaviors in the 129S1 strain have cocaine’s effects on rearing and locomotor behaviors not yet been reported; however, several other 129 sub- [23]. Stereotypy in response to cocaine is also dose- and strains have been characterized for cocaine locomotor strain-dependent. Stereotypic responses to repeated, but activity with mixed results [21,25,27-29]. Taken not acute, injections of cocaine have been reported for together, these results suggest that locomotor activation B6 and D2 strains [24,25]. Strain differences in stereo- in 129 micemaybesubstrain or dose-dependent and typy can also interfere with locomotor responses and may be sensitive to experimental parameters. may play a factor in our results. Regardless, strain differ- Studies assessing the rewarding effects of cocaine in ences in locomotor activity due to stereotypy still reflect 129 substrains are more variable with some studies real differences in behavioral sensitivity to cocaine. observing no place preference [28] and others observing Finally, differences in cocaine-induced locomotor acti- significant place preference [27]. We found that 129S1 vation in the B6 groups suggest that the strain differ- mice do not show significant place preference to 20 mg/ ences in locomotor response to cocaine could be kg cocaine, similar to the observation of Miner [28] confounded by temporal differences. However, we do although at lower doses. Our results may have been not believe this to be the case based on the congruence influenced by the baseline hypoactivity observed in 129S1 mice, which are extremely inactive in many beha- of our strain data with published studies on cocaine vioral assays [30-32]. These data underscore the locomotor activation. Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 9 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 importance of considering the unique behavioral charac- teristics of different inbred mouse strains that may influ- ence experimental outcomes. As we observed in the 129 mice, the role of locomotor activity in behavioral assays cannot be overlooked. The extent to which basal locomotor activity correlates with initial drug sensitivity has been examined with varied results. Several studies report no correlation between acute locomotor stimulation and baseline locomotion [33,34], while others observe a significant correlation [16,17]. In our sample, baseline locomotor activity does predict acute response to cocaine, as demonstrated by Figure 7 White vs. black chamber effect on cocaine-induced the correlation between saline-induced and acute locomotor activity and sensitization observed for BALB/cJ mice cocaine-induced activity. in the CPP apparatus. Results are separated by chamber in which Correlations between activity and CPP may reflect mice received cocaine during conditioning trials. Conditioning days interference between conditioned activity and the devel- and treatment are shown sequentially along the x-axis. Error bars are SEM. opment of place preference or strain differences in either basal or psychostimulant-induced locomotor response during training [35-37]. Conditioned activity does not appear to influence CPP in our group, as we occurring, resulting in context-dependent sensitization did not observe a correlation between CPP and locomo- in BALB mice. tor activity on the test day. The context in which a drug is experienced can signifi- The measurement of acute response, sensitization and cantly influence both acute and sensitized responses to the the rewarding effects of cocaine allow us to examine drug [47,48]. Context-dependent sensitization has also one prominent hypothesis of addiction. The incentive- been attributed to associative learning or increased stress sensitization model of drug craving suggests that [47,49-51]. It is possible that the white chamber may be chronic drug abuse causes hypersensitivity of the under- anxiogenic for BALB mice, resulting in greater sensitiza- lying brain circuitry as measured by sensitization, which tion. However, this is unlikely since BALB mice spend exacerbates incentive salience and may explain the com- equivalent amounts of time in both chambers during the pulsive drug-seeking that drives addiction [38]. Similar pre-test session on Day 1. Alternatively, features of the to observations by Cunningham et al. [14], our data do white chamber may cause BALB mice to more readily not appear to support theories of a positive link between associate the context with the drug effects. Willner et al. drug craving and sensitization [38] or the rewarding and have shown that the extent of sensitization is determined stimulating effects of drugs [39], as we observed no cor- by the behavior elicited by the drug [52], thus BALB mice relation between place preference and either acute loco- may develop greater sensitization as a result of a greater motor stimulation or sensitization. stimulatory response to cocaine in the white chamber. Similar to our results, most studies in BALB mice Acute locomotor response to cocaine is certainly higher report low levels of locomotor activation or no effect at for BALB mice in the white chamber (Figure 7) but this all in response to cocaine [22,26,40-46]. Further, BALB does not explain why this strain, in particular, shows mice reportedly do not develop place preference to greater sensitivity to the psychomotor effects of cocaine in moderate cocaine doses [18]. However, the level of loco- this context. The mechanisms by which drug effects inter- motor activation in our study was dependent on the act with context to result in behavioral differences remain chamber in which the cocaine was administered. BALB to be determined. Further experiments are necessary to mice receiving cocaine in the white chamber showed replicate these results and to gain a better understanding significant locomotor activation that exceeded the of this phenomenon in BALB mice. responses of other strains whereas BALB mice receiving Our observation that D2 mice did not exhibit signifi- cocaine in the black chamber did not display locomotor cant place preference under our assay conditions aligns activation (Figure 6). This level of activation was not with previous reports using higher doses of cocaine (32 observed after acute administration of cocaine but was mg/kg [4]; 30 mg/kg [14]) and deviates from others observed on all subsequent days of cocaine administra- reporting place conditioning in response to moderate tion in the white chamber (Figure 7) indicating that the doses (10 mg/kg [14]). Taken together, these studies locomotor activation developed upon repeated drug dos- support dose-dependent place preference in D2 mice. ing. Taken together, these data indicate that a specific However, modification of experimental parameters can interaction between the drug and the environment is also influence place conditioning and should be carefully Eisener-Dorman et al. Behavioral and Brain Functions 2011, 7:29 Page 10 of 11 http://www.behavioralandbrainfunctions.com/content/7/1/29 2. 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