Neurobiology of Learning and Memory 98 (2012) 329–340
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Indices of extinction-induced ‘‘depression’’ after operant learning using a runway vs. a cued free-reward delivery schedule Bianca Topic, Inga Kröger, Petya G. Vildirasova, Joseph P. Huston ⇑ Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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Article history: Received 29 August 2012 Revised 24 September 2012 Accepted 24 September 2012 Available online 5 October 2012 Keywords: Animal model of depression Avoidance Emotionality Extinction Instrumental learning Operant conditioning
a b s t r a c t Loss of reward is one of the etiological factors leading to affective disorders, such as major depression. We have proposed several variants of an animal model of depression based on extinction of reinforced behavior of rats. A number of behaviors emitted during extinction trials were found to be attenuated by antidepressant treatment and, thus, qualified as indices of extinction-induced ‘‘despair’’. These include increases in immobility in the Morris water maze and withdrawal from the former source of reward as well as biting behavior in operant chambers. Here, we assess the effects of reward omission on behaviors after learning of (a) a cued free-reward delivery in an operant chamber and (b) food-reinforced runway behavior. Sixty adult male Wistar rats were either trained to receive food reinforcement every 90 s (s) after a 5 s lasting cue light (FI 90), or to traverse an alley to gain food reward. Daily drug treatment with either the selective serotonin reuptake inhibitor citalopram or the tricyclic antidepressant imipramine (each 10 mg/kg) or vehicle was begun either 25 days (operant chamber) or 3 days (runway) prior to extinction. The antidepressants suppressed rearing behavior in both paradigms specifically during the extinction trials, which indicates this measure as a useful marker of depression-related behavior, possibly indicating vertical withdrawal. In the operant chamber, only marginal effects on operant learning responses during extinction were found. In the runway, the operant learned responses run time and distance to the goal, as well as total distance moved, grooming and quiescence were also influenced by the antidepressants, providing a potential set of markers for extinction-induced ‘‘depression’’ in the runway. Both paradigms differ substantially with respect to the anticipation of reward, behaviors that are learned and that accompany extinction. Accordingly, antidepressant treatment influenced different sets of behaviors in these two learning tasks. Ó 2012 Elsevier Inc. All rights reserved.
1. Introduction Loss of reward and reinforcement in the onset and maintenance of affective disorders, especially major depression (MD), have been implicated in psychopathological theories of depression (Ferster, 1973). The episodes of depression are often triggered by the loss of positive reinforcer, such as loss of employment, partnership, health, and physical abilities (Hammen, 2005), resulting in avoidance behavior, such as escape and withdrawal, which represent a critical precursor predisposing to as well as contributing to the maintenance of depression (Ferster, 1973; Trew, 2011). Besides feelings of despair, helplessness as well as psychomotor agitation or slowness of movement (American Psychiatric Association, 1994), avoidance and withdrawal behaviors as a result of loss of reinforcement, represent core symptoms of depression (Ferster, 1973; Trew, 2011).
⇑ Corresponding author. Fax: +49 (0)211 81 12024. E-mail addresses:
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[email protected] (J.P. Huston). 1074-7427/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nlm.2012.09.007
Given the close relationship between absence of reward and the occurrence of affective disorders, particularly MD, we set out to examine the effects of operant extinction on rodent behavior. In our earlier studies, we focused on the extinction of negatively reinforced behavior and provided evidence that the behavioral effects of the extinction procedure resemble those found in other animal models of depression. In the Morris water maze, where rodents learn to escape from the aversive water onto an invisible platform (negative reinforcement), the amount of immobility displayed increased over trials, when the platform was no longer present (loss of negative reinforcement – extinction) (Schulz, Buddenberg, & Huston, 2007a; Schulz, Huston, Buddenberg, & Topic, 2007b; Schulz, Topic, de Souza Silva, & Huston, 2004). This extinctioninduced immobility was attenuated by the antidepressant desipramine (Schulz et al., 2007a) and correlated with a number of anxiety-related behaviors (Schulz et al., 2007a, 2007b), mimicking the co-morbidity with anxiety disorders found in human patients (Mineka, Watson, & Clark, 1998). Furthermore, a number of neurobiological alterations also seen in major depression, including stress markers of the hypothalamus-pituitary adrenal (HPA) axis,
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changes in monoamine neurotransmitters as well as neurotrophins in specific regions of the brain involved in MD, were accompanied by the behavioral alterations found after extinction (Schulz et al., 2004; Topic, Oitzl, Meijer, Huston, & de Souza Silva, 2008b; Topic et al., 2008a; for review see Huston, Schulz, & Topic, 2009), supporting the hypothesis that the procedure of operant extinction in rodents leads to depressive-like behaviors. Given the important role of the loss of positive reinforcer in human depression (Carvalho, Trent, & Hopko, 2011; Ferster, 1973), we also started to employ the extinction-induced depression model on the basis of positive reinforcement derived from food reward (Huston, van den Brink, Komorowski, Huq, & Topic, 2012; Komorowski et al., 2012). Operant extinction results in elevated levels of corticosterone in rodents (Coover, Goldman, & Levine, 1971; Kawasaki & Iwasaki, 1997), indicating that the loss of reinforcement represents stress for the animal. Furthermore, during operant extinction rats exhibit a greater spatial variability (Devenport, 1984) and respond to it with an increase in aggressiveness (Azrin, Hutchinson, & Hake, 1966; Dantzer, Arnone, & Mormede, 1980), motor activation (Flaherty, 1982; Flaherty, Troncoso, & Deschu, 1979), anxiety-like behavior (Komorowski et al., 2012; Schulz et al., 2007a) or escape responses (Bentosela, Barrera, Jakovcevic, Elgier, & Mustaca, 2008; Daly, 1974; Huston et al., 2012; Komorowski et al., 2012; Norris, Pérez-Acosta, Ortega, & Papini, 2009). We hypothesized, that withdrawal from positive reward during extinction could serve as a behavioral marker of a depressive-like state and examined this question by using a cued fixed-time reward delivery paradigm in an elongated operant chamber as well as food-reinforced lever-pressing response in a Skinner-box, which was connected to a withdrawal chamber (Huston et al., 2012; Komorowski et al., 2012). We found an attenuating effect of antidepressants on rearing and aggressive biting behavior during extinction in the two-compartment chamber (Huston et al., 2012). Also the withdrawal behavior shown by vehicle-treated rats, assessed by the number of entries and sojourn time in the lever-pressing paradigm and the distance gradient in the elongated operant chamber, was reduced by antidepressant treatment (Huston et al., 2012; Komorowski et al., 2012). Furthermore, the extinction procedure induced anxiogenic-like effects in the open field, which were alleviated by antidepressant treatment (Komorowski et al., 2012). These results indicated that withdrawal and avoidance behavior, common symptoms of MD, may serve as behavioral markers for extinction-induced depression. Besides the spatial horizontal withdrawal and avoidance behavior, animals also exhibit so called exploratory-related behavior during extinction, usually interpreted as being emitted in the service of information gathering (e.g. Fowler, 1965). In our previous study with the two-compartment chamber, we found indication that also rearing behavior may be sensitive to antidepressant treatment and, thus, qualify as a behavioral marker for depression (Huston et al., 2012). However, also a reducing effect on general activity levels upon imipramine treatment was found, which may have confounded the results. Here, the selective serotonin reuptake inhibitor (SSRI) citalopram and the tricyclic antidepressant (TCA) imipramine were applied chronically in a lower dose of 10 mg/kg, which was derived on the basis of our previous study (Komorowski et al., 2012). Treatment was administered during the final acquisition trials and subsequent extinction trials. Furthermore, in order to assess, whether the behavioral markers for extinction-induced depression found upon extinction in variants of the operant chamber also hold in other operant paradigms, we also investigated the effects of antidepressants on extinction behavior in a straight runway. We expected to find a set of operant as well as other behaviors, such as rearing, to be sensitive to antidepressant treatment in both task situations.
2. Materials and methods 2.1. Subjects In total 60 male outbred Wistar rats (weight: 303.60 g ± 2.07 SEM) with an age of 3 months and derived from the animal breeding facility of the University of Düsseldorf, were used. They were housed in standard Macrolon cages of type IV in groups of five animals per cage and maintained under standard laboratory conditions with a reversed light/dark cycle (lights off from 7:00 AM to 7:00 PM). Animals had free access to water, but were food deprived for 5 days before beginning of the experiment during which they received 10 g of standard laboratory food chow (Ssniff Spezialdiät) per rat and day between 4:00 and 6:00 PM. Upon feeding, care was taken that each animal ate something of the chow and they were weighed daily. The experiments were carried out during the active period of the rats between 8:30 AM and 2:00 PM. Experiments were performed in accordance with the German law on protection of the animals and approved by the state authority (Bezirksregierung Düsseldorf). 2.2. Drug administration The SSRI citalopram (Cipramil, Lundbeck, Germany) or the TCA imipramine (10,11-Dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine5-propanamine hydrochloride, 5-[3-(Dimethylamino)propyl]-10, 11-dihydro-5H-dibenz[b,f]azepine hydrochloride; Sigma–Aldrich, Germany) was diluted in distilled water, which was used as the vehicle. According to the random group assignment, animals received an intraperitoneal (i.p.) injection of either vehicle or citalopram or imipramine in a dosage of 10 mg/kg with an injection volume of 1 ml/kg body weight. 2.3. Operant chamber and procedures 2.3.1. Apparatus Two standard modular operant chambers (1200 W 1000 D 00 12 H; Habitest; Coulbourn Instruments, USA), made of two clear transparent and two stainless steel walls placed opposite to each other and having a grid floor, were used. In the middle of one side of the steel walls a triple cue light (yellow, green, red) was positioned in a height of 8 cm. The opposite wall was equipped with a house light mounted in the middle near the top, providing illumination of about 1 lux during the whole testing session. A food cup with an integrated photo detector was located in a height of 5 cm from the bottom of the chamber below the house light. This food cup was connected to a food magazine outside of the operant chamber containing BioServÒ Dustless precision pellets. The operant chambers were situated separately in dark, sound attenuating boxes, equipped with a masking white noise generator and two video cameras (Sony, CCD), one at the top and one at one side of the chambers, to allow observation of behavior. The cameras were connected to a TV screen and a DVD recorder for video recording and post hoc analysis of the behavior, which was carried out via the manually recorded behavior module of the Any-Maze Software (Version 4.5, Stoelting, USA). All modules from the operant chambers were connected to a computer and controlled by the related GraphicState program (Version 3, Coulbourn Instruments, USA). The operant chambers were cleaned with an ethanol solution (70%) after each trial. 2.3.2. Procedure For the operant chambers 40 animals were used. They were brought to a holding room located next to the experimental room at least 30 min before beginning of testing to allow acclimatization.
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Magazine training started five days after beginning of food deprivation. For magazine training, a hand-switch was connected to the apparatus for manually shaping of the behavior. At the beginning of the 15-min long shaping session 3 food pellets were placed into the food cup. During this trial, all behavior shown not related to food cup exploration was reinforced manually via the handswitch and a single food pellet was delivered to the food cup. This shaping procedure was chosen in order to avoid a nearly exclusive sojourn time of the animals near the food cup while awaiting the cued delivery of food at a fixed interval of 90 s. On the next day, acquisition training without substance application was begun and continued once per day for eleven days. Each training session lasted 15 min during which the triple cue light was illuminated for 5 s with a fixed interval of 90 s (FI 90). Illumination of the cue light indicated delivery of two food pellets into the food cup when the lights turned off. After 11 days of acquisition training without substance application the animals were randomly assigned to either vehicle (n = 13), imipramine (n = 13) or citalopram (n = 14) group and received daily treatment until the end of the experiment, whereby substance application took place at least 1 h after the end of each experimental day and before feeding. For the following 14 days, acquisition training was continued only every third day to prevent overtraining. Thus, animals underwent acquisition training under drug treatment on experimental days 15, 18, 21, 24 and 25. On testing days 26–30, illumination of the triple cue light no longer led to reinforcement (extinction), whereas all other conditions remained the same as during acquisition. On day 31, one single re-acquisition session, with cued food delivery (FI 90) was carried out. The experimental time schedule is shown in Fig. 1A. 2.3.3. Behavioral analysis The time from illumination of the cue-light to the first subsequent breaking of the photo detector in the food cup in seconds (inter-response time) as well as the total number of beam-breaks per session were derived automatically via the GraphicState Software during all experimental phases. Additionally, for the phases ‘acquisition – treatment’ and ‘extinction’, the number and duration (s) of rearings, groomings, quiescence, ‘‘exploration’’ of the food cup, as well as sign-tracking (each behavioral approach to the triple cuelight) were recorded post hoc by a blind observer with the help of the manually recorded behavior module of the AnyMaze Software.
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2.4. Runway apparatus and procedures 2.4.1. Apparatus The runway consisted of a grey rectangular box; 192 cm length 14 cm width 22.5 cm height. The top of the runway apparatus was covered with clear Plexiglas to prevent escape. At each end of the box a round pellet-cup (around 1.5 cm in diameter), made of stainless steel was embedded within the floor of the runway 3 cm away from the wall. The runway was illuminated indirectly by four white bulbs providing a light density of around 3 lux within the runway. Masking noise of about 55 dB was provided by a sound generator. A video camera was positioned 150 cm above the middle of the runway and connected to a TV screen, a DVD-recorder and a computer system, which were all located in an adjoining room. 2.4.2. Procedure For the runway experiment 20 animals were used. Similarly to the procedure of the operant chamber, the animals were brought to a holding room located next to the experimental room on each testing day. Acclimatization to room conditions was allowed for at least 30 min. On day one, two habituation trials were carried out. In the first habituation trial, animals were exposed to the runway apparatus for 5 min for free exploration. During the second habituation trial 120 min later, 10 food pellets (BioServÒ Dustless precision pellets) were placed on the floor equidistant to the beginning and goal (food cup) of the runway. The second habituation trial ended either, when the animal had eaten all pellets, including additional five pellets that were placed into the food cup, or when 5 min had elapsed. If a rat failed to eat the pellets within the 5 min, it was gently pushed to the goal food cup by the experimenter. Rats were tested in the acquisition phase for 10 consecutive days, with four trials per day and an inter-trial interval (ITI) of 60 s, during which they were place into a holding cage located next to the runway. If an animal failed to reach the food cup within 120 s, it was gently guided to it by the experimenter. The time to reach the food cup (s) was recorded manually by a stop-watch. This acquisition phase was followed by an extinction phase without food reward for five consecutive days to examine extinction of the learned behavior. Here, animals again received four trials per day and were exposed to the runway for 120 s per trial for free exploration with an ITI of 60 s. The time to reach the food cup (s) was recorded manually by a stop-watch, whereas the distance moved (cm) and average
Fig. 1. Timeline of testing in (A) the operant chamber and (B) the runway.
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distance to the food cup were automatically recorded via the EthoVision tracking software (Version 3, Noldus, Wageningen, The Netherlands). Additionally, the total number and duration (s) of rearings, groomings, and quiescence were recorded with the ‘manually recorded behavior’ module of the EthoVision software, by an observer blind to the treatment conditions. The extinction phase was followed by another two days of re-acquisition training with the same procedure as during the first acquisition phase. For statistical analysis the mean of the four trials per rat and day for each variable was calculated. Drug administration started after 7 days of acquisition training and continued for the rest of the experiment. Animals were randomly assigned to one of the following treatment groups: vehicle (n = 6), citalopram (n = 7), imipramine (n = 7) and received an i.p. injection of the respective solution 30 min before the first exposure to the runway apparatus on each day. For the experimental timeline see Fig. 1B. 2.5. Statistical analysis Data are presented as mean + standard error of the mean (SEM). For the acquisition phase without drug treatment one-way repeated measures ANOVA was performed on each variable measured to assess behavioral changes during acquisition for the whole drug-free group. Two-way repeated measures analyses of variance (ANOVAs) with pair-wise multiple comparisons using Bonferroni adjustment were conducted, with treatment as between-groups factor and days as the repeated-measures factor for each experimental drugtreatment phase of testing in the operant chamber and runway apparatus (computed on mean of trials per day). In order to break significant interaction effects with the repeated – measures factor, the ANOVA was followed by one-way ANOVA with single days or trials as dependent measures. When appropriate, Dunnett’s t-test was used as the post hoc test to determine specific treatment differences. Since we were especially interested in behavior during the extinction phase, only data of extinction and the following reacquisition in the operant chamber and runway are presented in the figures. The significance level (two-tailed) was set at p 6 .05. 3. Results 3.1. Cued food delivery in operant chamber 3.1.1. Acquisition without treatment On the average, all animals exhibited 123.525 (±3.832 SEM) beam-breaks along with an inter-response time of 6.506 s (±0.292 SEM) on the first day of acquisition. On the last day of this experimental phase, the number of beam-breaks significantly decreased to a level of 99.175 (±4.366 SEM; F(10,390) = 13.959; p < 0.001). Also, a reduction in the inter-response time over the course of acquisition training without substance application was revealed (F(10,390) = 38.028; p < 0.001), whereby the animals responded on the average 3.356 s (±0.188 SEM) after onset of the cue lights. 3.1.2. Acquisition with treatment Over the course of acquisition-treatment trials, no further significant changes in the number of beam-breaks was revealed by the ANOVA (F(4,148) = 1.030; p = 0.394). However, the interresponse time (F(4,148) = 5.387; p < 0.001) as well as the number of explorations of the food cup (F(4,140) = 29.063, p < 0.001) decreased, whereas the duration of explorations of the food cup increased (F(4,140) = 7.212, p < 0.001). Significant increases in the number and duration of sign trackings (number: F(4,140) = 31.383, p < 0.001; duration: F(4,140) = 6.541, p < 0.001) as well as groomings (number: F(4,140) = 3.457; p = 0.010, duration: F(4,140) = 7.123,
p < 0.001) and number of times the animal spent quiet (F(4,140) = 3.272, p = 0.013; duration: F(4,140) = 1.385, p = 0.242) were also found. On the other hand, animals exhibited a decrease in the number and duration of rearings (number: F(4,140) = 13.674, p < 0.001; duration: F(4,140) = 5.522, p < 0.001) over trials. No interactions (all F 6 1.823, all p P 0.078) or main between-groups treatment effects were found by the repeated-measures ANOVAs (all F 6 2.741, all p P 0.191), except for the number of groomings (F(4,140) = 4.530, p = 0.018). Here, post hoc Dunnett’s t-test revealed, that animals treated with imipramine exhibited less groomings compared to vehicle treated controls (p = 0.010; citalopram vs. vehicle: p = 0.146). 3.1.3. Extinction trials Data for the extinction trials are shown in Figs. 2 and 3. Over the course of extinction trials, the animals exhibited a significant decrease in the number of beam-breaks (F(4,148) = 71.198, p < 0.001), reaching a level of below 30 beam-breaks during the last trial. Although the repeated measures ANOVA failed to reveal a main significant between-groups effect (F(2,37) = 1.947, p = 0.157), a significant day treatment interaction (F(8,148) = 2.203, p = 0.047) was found. One-way ANOVAs for single days revealed a main significant effect by antidepressant treatment only for the second day of extinction training (F(2,39) = 3.47, p = 0.033; all other F 6 2.210; all p P 0.124). While imipramine-treated rats did not differ from vehicle treated controls (p = 0.852), animals treated with citalopram exhibited marginally a higher number of beambreaks compared to vehicle treated controls (p = 0.080) as was shown by the post hoc Dunnett’s t-test (Fig. 2A). Due to the absence of food reinforcement, the inter-response time (Fig. 2B) steadily increased as extinction progressed (F(4,148) = 89.216, p < 0.001), without any main between-groups difference (F(2,37) = 2.329; p = 0.112) or interaction effect (F(8,148) = 1.037, p = 0.411). Complementary, the number (F(4,148) = 104.781, p < 0.001) and duration (F(4,148) = 45.242, p < 0.001) of explorations of the food cup (Fig. 2C and D) and sign-trackings (number: F(4,148) = 15.335, p < 0.001, duration: F(4,148) = 10.728, p < 0.001; Fig. 3A and B) decreased over the extinction trials and were not modulated by antidepressant treatment, as revealed by the statistical analysis (between groups: all F(2,37) 6 2.578, all p P 0.087; interaction: all F(8,148) 6 1.387, p P 0.207). As for the behavior shown by the animals during extinction, the number and duration of groomings (number: F(4,148) = 4.773, p = 0.01, duration: F(4,148) = 16.024, p < 0.001) and times the animal spent quiet increased (number: F(4,148) = 11.383, p < 0.001, duration: F(4,148) = 3.424, p = 0.010), but, again, were not influenced by the antidepressant treatment (between groups: all F(2,37) 6 1.649, all p P 0.206; interaction: all F(8,148) 6 1.458, p P 0.177; data not shown). Significant differences between the treatment groups were found for rearing behavior. Although all groups showed a decrease in the number (F(4,148) = 41.946, p < 0.001) and duration (F(4,148) = 33.902, p < 0.001) of rearings from the first to the last day of extinction, without any interaction effect (both F(4,148) 6 1.222, both p P 0.209), vehicle treated rats exhibited a higher level of rearing behavior (number: F(2,37) = 5.778, p = 0.007, duration: F(2,37) = 6.892, p = 0.003). Post hoc Dunnett’s t-test revealed that vehicle treated rats reared significantly more often compared to the imipramine group (p = 0.003; citalopram: p = 0.203, Fig. 3C), and also with a longer duration compared to, both, the imipramine group (p = 0.002) and the citalopram group (p = 0.041) group (Fig. 3D). 3.1.4. Re-acquisition Unlike during the extinction trials, the antidepressant treatment had no significant influence on the assessed behaviors during the single re-acquisition session (all F(2,37) 6 2.092, all p P 0.138).
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Fig. 2. Mean (+SEM) (A) number of beam-breaks and (B) inter-response time (s) as well as number (C) and duration (D) of explorations of the food cup during extinction and re-acquisition (RA) in the operant chamber. p < 0.05 main between-groups treatment effect.
3.2. Runway behavior 3.2.1. Acquisition On the average, all animals needed 59.99 s (±6.10 SEM) to reach the goal food cup in the runway on the first day of acquisition without any substance application. Over the course of this acquisition phase, the runway-time significantly decreased to a level of 3.44 s (±0.327 SEM; F(6,114) = 30.034; p < 0.001) and remained stable over the 3 days of acquisition with treatment (F(2,34) = 1.802; p = 0.180). Moreover, repeated measures ANOVA failed to reveal any between-groups treatment (F(2,17) = 0.720; p = 0.501) or interaction-effect (F(4,34) = 0.717; p = 0.587), indicating that there were no a priori differences between the groups in acquisition preceding drug treatment. 3.2.2. Extinction The data of the behavior during extinction training are depicted in Figs. 4 and 5. Over the course of extinction the time to reach the food cup (Fig. 4A) steadily increased (F(4,68) = 5.491; p = 0.001). The repeated-measures ANOVA revealed that antidepressant treatment had a significant impact on the time to reach the goal (F(2,17) = 8.887; p = 0.002; interaction: F(8,68) = 0.885; p = 0.534). While animals treated with imipramine exhibited a significantly higher level throughout extinction training compared to vehicletreated controls (p = 0.001; post hoc Dunnett’s t-test), such an effect failed to reach significance for the citalopram-treated group (p = 0.069; post hoc Dunnett’s t-test). Similarly, a significant increase in the average distance to the goal was detected by the re-
peated-measures ANOVA (F(4,68) = 7.233; p < 0.001), indicating that animals stayed further away from the food cup as extinction progressed. Moreover, while no interaction effect was found by the ANOVA (F(8,68) = 0.575; p = 0.795), again, a main effect by antidepressant treatment was found (F(2,17) = 10.257; p = 0.001). Likewise to the runway time, the vehicle-treated rats exhibited the smallest distance to the food cup (Fig. 4B), which, however, did not differ from the citalopram-treated group (p = 0.259; post hoc Dunnett’s t-test), but was significantly different from the animals treated with imipramine, which stayed furthest away from the food cup (p = 0.001, post hoc Dunnett’s t-test). Interestingly, although vehicle-treated rats stayed near to the food cup throughout extinction training, they moved longer distances over the course of extinction (Fig. 4C). However, repeated measures ANOVA revealed only a trend for a significant main between-groups effect (F(4,68) = 3.258; p = 0.063), without any interaction (F(8,68) = 1.118; p = 0.363), but a significant within-subjects effect (F(4,68) = 20.583; p < 0.001). Post hoc Dunnett’s t-tests showed, that vehicle treated rats moved significantly longer distances compared to the imipramine(p = 0.039) but not citalopram- (p = 0.198) treated group. As can be seen in Fig. 5, rearing behavior (Fig. 5A and B) significantly decreased over extinction trials (number: F(4,68) = 7.406; p < 0.001; duration: F(4,68) = 7.126; p < 0.001) and was strongly influenced by antidepressant treatment (number: F(2,17) = 4.939; p = 0.020; duration: F(2,17) = 8.158; p = 0.003), without any interaction effect (number: F(8,68) = 1.312; p = 0.253; duration: F(8,68) = 0.758; p = 0.640). Akin to the results found for the operant chamber, above, during extinction in the runway, vehicle treated animals
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Fig. 3. Mean (+SEM) number and duration of sign tracking (A and B) and rearings (C and D) during extinction and re-acquisition (RA) in the operant chamber. : p < 0.01 and : p < 0.05 compared to vehicle-treated controls.
showed the highest level of rearing behavior. Post hoc Dunnett’s ttest revealed that, compared to the imipramine group, the vehicletreated rats reared significantly more often (p = 0.014) and with a longer duration (p = 0.002). Such an effect in comparison to the citalopram-treatment group was also found for the duration of rearings (p = 0.018), but reached only nearly significance for the number of rearings shown (p = 0.055). The repeated measures ANOVA (F(4,68) = 0.753; p = 0.559) revealed a change in the duration (F(4,68) = 4.484; p = 0.003), but not number of groomings ANOVA (F(4,68) = 0.753; p = 0.559). Similarly, only a trend for a main between-groups effect was detected for the number of groomings (F(2,17) = 3.119; p = 0.070; Fig. 5C) but a significant effect was found for the duration of grooming (F(2,17) = 6.854; p = 0.007; Fig. 5D). Here, the citalopram-treated group exhibited the longest duration of grooming, which differed significantly from that of the vehicle-treated animals (p = 0.030, post hoc Dunnett’s t-test), whereas no such difference was found between the vehicle-treated and imipramine-treated groups (p = 0.678, post hoc Dunnett’s t-test). Interaction effects failed to reach statistical significance (number: F(8,68) = 1.094; p = 0.378; duration: F(8,68) = 1.500; p = 0.173). In line with this, no significant change in the number of times the animal spent quiet (Fig. 5E) during extinction was shown by the repeated measures ANOVA (F(4,68) = 1.234 p = 0.305) and no day treatment interaction (F(8,68) = 0.393; p = 0.921). However, the number of times the animal spent quiet was significantly influenced by the antidepressant treatment (F(2,17) = 8.216; p = 0.003). Post hoc statistical analysis by Dunnett’s t-tests revealed that vehicle treated animals exhibited
the lowest number that differed significantly not only from the imipramine- (p = 0.002), but also from the citalopram- (p = 0.043) treated group. On the contrary, a significant shift in the duration of quiescence was shown by the repeated measures ANOVA (F(4,68) = 5.298; p = 0.001), along with a significant modulation by the treatment (F(2,17) = 13.206; p < 0.001, Fig. 5F) as well as a day x treatment interaction (F(8,68) = 2.133; p = 0.044). As can be seen in Fig. 5F, animals treated with imipramine showed the longest duration of quiescence, which increased over extinction trials and differed significantly from that shown by the vehicle treated group (post hoc Dunnett’s t-test: p < 0.001), while citalopram-treated rats showed a similar duration of quiescence compared to vehicletreated controls (post hoc Dunnett’s t-test: p = 0.387). One-way ANOVAs for single days revealed a main significant effect by antidepressant treatment for nearly all days of extinction training (all F P 4.026; all p 6 0.037) except day 1 (F(2,17) = 3.556, p = 0.051) and day 3 (F(2,17) = 2.530, p = 0.109). On all days during extinction no difference was revealed by the post hoc Dunnett’s t-test between the vehicle-treated and the citalopram-treated groups (all p P 0.424) however, imipramine-treated animals were significantly longer quiet compared to vehicle-treated controls on nearly all days (all p 6 0.036), except on day 3 of extinction testing (p = 0.068). 3.2.3. Re-acquisition Extinction testing in the runway was followed by another two days of re-acquisition training, where food reward was reinstated. The data of the time to reach the food cup averaged over the four
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Fig. 4. Mean (+SEM) (A) time to the goal food cup during extinction and re-acquisition days (RA1, RA2), (B) goal gradient and (C) distance moved exhibited by vehicle, citalopram- and imipramine-treated groups during extinction in the runway. : p < 0.01 and : p < 0.05 compared to vehicle-treated controls; §: p < 0.1 compared to vehicletreated controls; #: p < 0.05 main between-groups treatment effect.
trials per testing day are shown in Fig. 4A. On the first day of re-acquisition training, animals treated with the vehicle needed on the average 14.83 s (±5.20 SEM) to reach the goal food cup, whereas citalopram treated rats were much faster and needed about 5.46 s (±1.71 SEM), while imipramine treated animals required the longest time of 27.86 s (±8.01 SEM). On the second day of re-acquisition training the time to reach the food cup decreased strongly in all groups to a level below 5.25 s. Given the low running times, no other behavioral measures were taken during this experimental phase. Repeated measures ANOVA revealed a significant decrease in the time to reach the food cup (F(1,17) = 16.910, p < 0.001), along with a main influence by the treatment (F(2,17) = 3.871, p = 0.041) as well as a day treatment interaction (F(2,17) = 4.445, p = 0.028). However, post hoc Dunnett’s t-tests failed to detect any significant difference between the vehicle and treatment groups (citalopram: p = 0.467, imipramine: 0.220). One-way ANOVAs for single days revealed a main significant effect by antidepressant treatment only for day 1 of re-acquisition training (F(2,17) = 4.157, p = 0.034) but not for the second day (F(2,17) = 1.319, p = 0.293). Again post hoc Dunnett’s t-test failed to reach significance, when the time to reach the food cup of the vehicle treated animals was compared to the citalopram and imipramine treated groups (all p > 0.214).
4. Discussion In the present study we sought to determine behavioral indices of extinction-induced depression in two different operant tasks.
We reasoned that extinction-related behaviors that are modulated by antidepressant treatment could qualify as such potential behavioral markers. Extinction after cued free-reward delivery in an operant chamber and after food-reinforced runway behavior resulted in changes of operant as well as other behaviors. In the operant chamber, both antidepressants reduced rearing behavior selectively during extinction. Such effects were not found during the preceding or subsequent acquisition phases (for an overview of the results see Table 1). Similarly, rearing was also attenuated by antidepressant treatment during extinction in the runway, suggesting rearing behavior as a marker of vertical withdrawal behavior during extinction. Moreover, in the runway both antidepressants attenuated operant behavior, i.e. the time to reach the goal, as well as influencing a number of other behaviors.
4.1. Operant learning All animals learned the tasks, as indicated by the progressive decrease in the inter-response time and the number of beambreaks in the cued reward task and the decrease in time-to-goal in the runway. Neither, the SSRI citalopram, nor the TCA imipramine influenced operant behavior during acquisition in either task. In line with a previous study (Komorowski et al., 2012), these antidepressants affected neither the inter-response time nor the number of beam-breaks during acquisition. Also, in the runway task, pre-trial administration had no effect on operant behavior, in accord with findings of other studies (Barr & Phillips, 1998; Egan, Earley, & Leonard, 1979; Nikiforuk & Popik, 2009). Thus, possible
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Fig. 5. Mean (+SEM) number and duration of rearings (A and B), groomings (C and D) and quiescence (E and F) during extinction in the runway. compared to vehicle-treated controls.
group differences during acquisition due to drug treatment cannot account for the results found during extinction trials. Antidepressants have been reported to either have no effects, or to improve, but most likely to impair learning and memory parameters in humans (for review see Amado-Boccara, Gougoulis, Poirier, Galinowski & Lôo, 1995) and rodents (for review see Monléon, Vinader-Caerlos, Arenas & Parra, 2008). 4.2. Extinction The omission of reward during the extinction trials resulted in a progressive increase of inter-response times, i.e. the latency to the first beam-break at the food cup after onset of the cue-lights in the
: p < 0.01 and : p < 0.05
operant chamber and time-to-goal in the runway. This was accompanied by a decrease in exploration of the food cup and sign tracking in the operant chamber. During extinction trials, a progressive increase in beam-break latency, and, accordingly, a decrease in the number of beam-breaks, refer to learning that onset of cue-lights no longer predict food delivery, thus decreasing sign-tracking (see also Komorowski et al., 2012). Reinstatement of food reward during re-acquisition re-established approach behavior towards the former reward source. The TCA desipramine, but not the SSRI fluoxetine, delayed (increased resistance to) extinction of escape behavior in a negatively reinforced Morris water maze task (Schulz et al., 2007a; Schulz et al., 2007b) On the other hand, in a progressive ratio schedule
B. Topic et al. / Neurobiology of Learning and Memory 98 (2012) 329–340 Table 1 Overview of the results for the acquisition, acquisition-treatment and extinction phase in the operant chamber and the runway. The table presents the within-subject effects of repeated measures ANOVAs for the three periods. Acquisition
Acquisition-treatment
Extinction
Operant chamber Operant response Inter response time Number of beam-breaks
; ;
; ?
" ;
Food cup exploration Number Duration
n.m. n.m.
; "
; ;
Sign tracking Number Duration
n.m. n.m.
" "
; ;
Rearing Number Duration
n.m. n.m. n.m.
; ;
;⁄ ;⁄
Grooming Number Duration
n.m. n.m.
"⁄ "
" "
Quiescence Number Duration
n.m. n.m.
" ?
" "
Runway Operant response Time to goal Distance to goal Distance moved
; n.m. n.m.
? n.m. n.m.
"⁄ "⁄ ;0
Rearing Number Duration
n.m. n.m.
n.m. n.m.
;* ;*
Grooming Number Duration
n.m. n.m.
n.m. n.m.
? "
Quiescence number duration
n.m. n.m.
n.m. n.m.
? "*
Arrows indicate the direction of the changes." increase, ? stable, ; decrease, n.m. = not measured in this phase, * = significant main between-groups difference;0 = trend for main between-groups difference as indicated by ANOVA.
of reinforcement, SSRIs, but not the tricyclic desipramine, inhibited response decrement upon reinforcer downshift (Nikiforuk & Popik, 2009), while neither antidepressant influenced choices of delay of reinforcement (Evenden & Ryan, 1996). Here, like in our previous studies using either a two-compartment chamber (Huston et al., 2012) or an elongated operant chamber (Komorowski et al., 2012), neither class of antidepressants influenced operant behavior during extinction, suggesting, that operant behavior in the Skinner box may not be sensitive to antidepressant treatment. On the other hand, in the runway, imipramine and marginally also citalopram, attenuated operant behavior (running times during extinction), resulting in a reduced resistance to extinction. Furthermore, while in our former study with the elongated operant chamber, vehicle treated animals stayed furthest away from the former source of reward (Komorowski et al., 2012), here in the runway, the vehicle treated animals stayed closest to the food cup during extinction, while imipramine treated rats stayed furthest away and the citalopram treated animals ranged in the middle. This opposite effect deserves further discussion. In the operant chamber, food delivery is made contingent either upon the emission of an operant response (such as lever-pressing, see Huston et al., 2012) or passage of time together with a discriminative stimulus (Komorowski et al., 2012). Thus, the operant response is influenced by the actions of the reinforcer and indexes the animal’s motivation to maintain reinforcement (Ettenberg & Geist, 1993). Conversely, it has been
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suggested that in the runway paradigm, the impact of manipulation on motivational vs. reinforcement processes can be dissociated. Run-times on a given trial indicate the motivation to seek the reinforcer on that trial, whereas changes in run-times from one to the next trial represent the impact of reinforcement, and in our case, loss of reinforcement, on subsequent motivation (for review see Ettenberg, 2009). In fact, a more detailed look at the runway extinction data showed that the antidepressant-treated groups did not differ from vehicle treated animals on the first extinction trial on each day, and that slower run-times and increases in the goal gradient in the antidepressant groups emerged only on the subsequent trials on a given extinction day (data not shown), ruling out the possibility of potential sedative effects of antidepressants having confounded the results. Moreover, they suggest that the antidepressants modulated extinction/reinforcement processes by alleviating the aversive consequences of absence of reward, resulting in slower run times on subsequent trials on a given day. In line with such reasoning, the vehicle treated control animals showed a higher level of locomotor activity in the runway, potentially due to the aversive effects of the reward omission, although they stayed closest to the food cup. It is well known that loss or omission of reward is aversive to organisms (for review see: Papini, 2003), resulting in a number of behavioral effects, such as aggressive behavior (Azrin et al., 1966; Dantzer et al., 1980; Huston et al., 2012), increases in general activity (Flaherty, 1982; Flaherty et al., 1979), anxiety-like behavior (Komorowski et al., 2012) or escape responses (Bentosela et al., 2008; Daly, 1974; Huston et al., 2012; Komorowski et al., 2012; Norris et al., 2009, for review see: Papini & Dudley, 1997). We found a suppressive effect of antidepressants upon rearing behavior during extinction in the operant chamber as well as the runway. Suppressant effects of antidepressants on rearing during extinction were also found in one of our previous studies using a two compartment chamber, which was accompanied by less withdrawal behavior (Huston et al., 2012). Usually, rearing behavior in rodents is considered to be an index of vertical exploratory behavior, reflecting spatial exploration (Crusio & Schwegler, 1987), information-gathering (Topic et al., 2005) or attention (Aspide, Fresioello, de Filippis, Gironi Carnevale & Sadile, 2000; Aspide, Gironi Carnevale, Sergeant & Sadile, 1998; Ruocco, Sadile & Gironi Carnevale, 2009) in novel environments, which decreases as the animal becomes more familiar with the environment. On the other hand, rearing has also been associated with motivational state and arousal level (Sadile, 1995) as well as emotionality (Gironi Carnevale, Vitullo & Sadile, 1990). Elevated levels of rearing were also found in other animal models of depression (Schulz, Mirrione & Henn, 2010; Slotkin et al., 1999; van Riezen & Leonard, 1990) and shown to be sensitive to antidepressant treatment (Van Riezen & Leonard, 1990). Higher rearing activity in the open field has been related to higher anxiety levels in the elevated plus maze (Borta & Schwarting, 2005), and treatment with parachloroamphetamine (PCA), known to increase anxiety levels, selectively enhanced rearing in the open field, which could be counteracted by citalopram treatment (Tonissar et al., 2008). Moreover, it has been suggested that rearing may also represent an escape response (Lever, Burton & O’Keefe, 2006). Electrical stimulation of the dorsal periaqueductal gray matter, a brain region known to be involved in panic disorders (Graeff & Zangrossi, 2010), elicits rearing (Sandner, Schmitt, & Karli, 1987) as one part of a complex defensive reaction and escape response (Silveira & Greaff, 1992). Proactive coping as a behavioral category in other stress paradigms also involves rearing (Paul et al., 2011), and rearing behavior is considered to represent an index of ‘explorative escape attempts’ in the defensive burying paradigm (de Boer & Koolhaas, 2003). Although in the present study a decrease in rearing behavior was shown by all groups over the course of extinction, indicating further familiarization/habituation with
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the testing environment, the vehicle-treated animals exhibited a higher level compared to antidepressant-treated groups. Together with these and other findings assessing rearing behavior (for review see: Lever, Burton, & O’Keefe, 2006), our results of a higher level of rearing in vehicle-treated rats selectively during extinction in both tasks, suggests that it reflects an avoidance/escape reaction, and thus, indicates this measure as a useful marker of vertical withdrawal behavior in both variants of instrumental extinction. Operant extinction is stressful and results in activation of the HPA-axis (Coe, Stanton, & Levine, 1983; Coover et al., 1971; Kawasaki & Iwasaki, 1997). Grooming behavior in rats and mice has been closely linked to activation of the HPA-axis (e.g. Dunn, Berridge, Lai, & Yachabach, 1987; for review see: Kruk et al., 1998). Besides its well known function in body care and thermoregulation, it has been interpreted as a form of displacement activity functioning to reduce stress or reflecting de-arousal due to the termination of, or habituation to, a stressful situation (Spruijt, van Hooff, & Gispen, 1992) and, thus, used as a behavioral marker of stress in rodents (e.g. File, Mabbutt, & Walker, 1988; Kalueff & Tuohimaa, 2005; Kyzar et al., 2011; Nakazato, 2012). In the cued free-reward delivery paradigm, the TCA impramine reduced grooming behavior only during acquisition, which is in line with another study showing inhibitory effects of imipramine on spontaneous grooming (Skuza, Rogoz, & Zak, 1989). However, neither antidepressant influenced grooming during the extinction trials. Surprisingly, during extinction in the food-reinforced runway, the SSRI citalopram enhanced the duration of grooming. Increases in grooming can be found in high and low stress situations (File et al., 1988), which may point to a higher or lower level of stress in the citalopram treated group. However, contrasting effects of antidepressants on grooming behavior have been found depending on pattern analysis (Enginar, Hatipoglu, & Firtina, 2008), and in other animal models of depression, a decrease in grooming behavior was found (Willner, 2005), which could be reversed by antidepressant treatment (Yalcin, Belzung, & Surget, 2008). Given the behavioral pattern found for the vehicle- and citalopram-treated groups during extinction in the runway, it seems that the high level of rearing and locomotor activity found in vehicle-treated rats, might have inhibited or dominated over grooming behavior, since neither differed with respect to the duration of quiescence. It has been suggested that low ‘priority’ behavior, such as grooming, may become disinhibited when high priority ‘reactive’ behavior systems, such as escape, do not dominate (Spruijt et al., 1992), indicating that the higher grooming behavior found in citalopram-treated rats here may reflect a behavioral response in terms of displacement activity to reduce the arousal or stress (Van Erp, Kruk, Meelis, & Willekens-Bramer, 1994) of the extinction procedure. The behavioral pattern shown by the imipramine-treated rats during extinction in the runway differed from that shown by the citalopram-treated group. While both exhibited a reduction in rearing behavior, the citalopram group groomed more, whereas in the imipramine-treated group horizontal activity measures were decreased and, thus, quiescence behavior was increased. Both attenuating effects of imipramine might account for the increases found in quescience behavior. The differences in the behavioral pattern found may be related to differences in the pharmacological actions and affinities to various neurotransmitter systems of the two antidepressants (Dekeyne & Millan, 2003; Millan, 2006). Akin to this, different behavioral profiles according to antidepressant class used were also found in the forced swimming test. In this task, a reduction in immobility is a common effect of various classes of antidepressants. However, while SSRIs additionally also induce an increase in swimming behavior, noradrenaline reuptake inhibitors selectively influence climbing behavior (Detke & Lucki, 1996; Detke, Rickels, & Lucki, 1995). Such distinguishing
behavioral effects have been found also in humans with major depressive disorder. Treatment with TCAs or selective noradrenaline reuptake inhibitors are correlated with changes in psychomotor and neurovegetative symptoms, while SSRIs are initially and stronger related to changes in mood, anxiety and cognitive symptoms (Katz et al., 1994; Katz et al., 2004; Uher et al., 2009). SSRI treated rats reached the food cup faster than controls during the initial re-acquisition phase, when food reward was reinstated, which may point to deficits or a delay in re-learning in the vehicle-treated animals when food reward was reinstated. The results suggest that a broader behavioral assessment of the effects of extinction in the food-reinforced runway may provide a means to distinguish drugs with a common therapeutic use, but which act on distinct neurotransmitter systems (Detke & Lucki, 1996). 5. Conclusions Taken together, the results of the present study provide additional evidence that the procedure of extinction of operantly reinforced behavior results in a set of behavioral alterations, which are sensitive to antidepressant treatment. Although the two antidepressants distinctly influenced different sets of behaviors in these two tasks, elevated levels of rearing behavior were modulated by antidepressant treatment irrespective of task and treatment conditions, suggesting that this exploratory-related behavior may reflect vertical withdrawal behavior during extinction conditions, and, thus, provide a useful behavioral marker of extinction-induced depression. The model of extinction-induced depression mimics known symptoms of MD, such as withdrawal and avoidance behavior. It is sensitive to antidepressants and fulfills the requirements of construct and predictive validity of an animal model of depression. Acknowledgments This work was supported by a grant from the German National Science Foundation (Hu 306/27-2) and the Research Training Group GK1033-2. References Amado-Boccara, I., Gougoulis, N., Poirier, M. F., Galinowski, A., & Lôo, H. (1995). Effects of antidepressants on cognitive functions: A review. Neuroscience and Biobehavioral Reviews, 19, 479–493. American Psychiatric Association. (1994) Diagnostic and Statistical Manual of Mental Disorders (4th ed.). American Psychiatric Press Aspide, R., Fresiello, A., de Filippis, G., Gironi Carnevale, U. A., & Sadile, A. G. (2000). Non-selective attention in a rat model of hyperactivity and attention deficit: Subchronic methylphenidate and nitric oxide synthesis inhibitor treatment. Neuroscience and Biobehavioral Reviews, 24, 59–71. Aspide, R., Gironi Carnevale, U. A., Sergeant, J. A., & Sadile, A. G. (1998). Noonselective attention and nitric oxide in putative animal models of attentiondeficit hyperactivity disorder. Behavioural Brain Research, 95, 123–133. Azrin, N. H., Hutchinson, R. R., & Hake, D. F. (1966). Extinction induced aggression. Journal of Experimental Analysis of Behavior, 9, 191–204. Barr, A. M., & Phillips, A. G. (1998). Chronic mild stress has no effect on responding by rats for sucrose under a progressive ratio schedule. Physiology and Behavior, 64, 591–597. Bentosela, M., Barrera, G., Jakovcevic, A., Elgier, A. M., & Mustaca, A. E. (2008). Effect of reinforcement, reinforcer omission and extinction on a communicative response in domestic dogs (Canis familiaris). Behavioral Processes, 78, 464–469. Borta, A., & Schwarting, R. K. W. (2005). Inhibitory avoidance, pain reactivity, and plus-maze behaviour in Wistar rats with high versus low rearing activity. Physiology and Behavior, 84, 387–396. Carvalho, J. P., Trent, L. R., & Hopko, D. R. (2011). The impact of decreased environmental reward in predicting depression severity: Support for behavioral theories of depression. Psychopathology, 44, 242–252. Coe, L. C., Stanton, M. E., & Levine, S. (1983). Adrenal responses to reinforcement and extinction: Role of expectancy versus instrumental responding. Behavioral Neuroscience, 97, 654–657. Coover, G. D., Goldman, L., & Levine, S. (1971). Plasma corticosterone increases produced by extinction of operant behavior in rats. Physiology and Behavior, 6, 261–263.
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