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Published in final edited form as: Psychopharmacology (Berl). 2012 Sep 15;225(3):569–577. doi: 10.1007/s00213-012-2844-4

Persistent effects of prior chronic exposure to corticosterone on reward-related learning and motivation in rodents

Peter Olausson 1, Drew D Kiraly 1, Shannon L Gourley 1, Jane R Taylor 1
PMCID: PMC3546199  NIHMSID: NIHMS408130  PMID: 22983097

Abstract

Repeated or prolonged exposure to stress has profound effects on a wide spectrum of behavioral and neurobiological processes, and has been associated with the pathophysiology of depression. The multifaceted nature of this disorder includes despair, anhedonia, diminished motivation and disrupted cognition, and it has been proposed that depression is also associated with reduced reward-motivated learning. We have previously reported that prior chronic corticosterone exposure to mice produces a lasting depressive-like state that can be reversed by chronic antidepressant treatment. In the present study, we tested the effects of prior chronic exposure to corticosterone (50 µg/ml) administered to rats or to mice in drinking water for 14 days followed by dose-tapering over 9 days. The exposure to corticosterone produced lasting deficits in the acquisition of reward-related learning tested on a food-motivated instrumental task conducted 10–20 days after the last day of full dose corticosterone exposure. Rats exposed to corticosterone also displayed reduced responding on a progressive ratio schedule of reinforcement when tested on day 21 after exposure. Amitriptyline (200 mg/ml in drinking water) exposure for 14 days to mice produced the opposite effect, enhancing food-motivated instrumental acquisition and performance. Repeated treatment with amitriptyline (5 mg/kg, ip; bid) subsequent to corticosterone exposure also prevented the corticosterone-induced deficits in rats. These results are consistent with aberrant reward-related learning and motivational processes in the depressive states and provide new evidence that stress-induced neuroadaptive alterations in corticolimbic-striatal brain circuits involved in learning and motivation may play a critical role in aspects of mood disorders.

Keywords: Depression, Stress, Corticosterone, Antidepressant, Learning, Reward

INTRODUCTION

Among the wide array of symptoms observed in depressed individuals, such as dysphoria, anhedonia, insomnia and weight loss, is a severely reduced engagement in rewarding activities (Gotlib & Joormann, 2010). This decrease may be related to the complex disturbances in the emotional, motivational and cognitive domains that are associated with depression. One possibility is that alterations in reward-related learning, whereby behavioral responses or cues become associated with rewarding stimuli, fails to appropriately guide or motivate subsequent behavior. These forms of incentive learning depend on several factors, including reward processing, motivation and the neuroplasticity underlying formation of new or strengthened memories. Another possibility is that changes in motivation reduce both new reward-motivated learning as well as the behavioral response to previously established reinforcers. Both processes are likely altered in depression and may together exacerbate the clinical symptoms, or delay recovery. However, little is known about reward-motivated learning in animal models that aim to reproduce a depressive-like phenotype.

Prolonged or repeated exposure to stressful events has been associated with depression in humans (Kendler et al., 1999). Repeated stress exposure also produces depressive-like behaviors in rodent models (Willner, 2005). The link between stress and depression is strengthened by a substantial number of clinical studies that have demonstrated dysregulation of the stress hormone status in a large sub-population of depressed individuals (Southwick et al., 2005). As a critical component of the normal stress response, cortisol, or the rodent analog corticosterone, may be responsible for producing some of the neurobiological and behavioral changes in response to stress. Animals subjected to certain chronic stress paradigms have also been shown to exhibit deficits in reward-related learning (e.g., Matthews & Robbins, 2003; Dias-Ferreira et al., 2009), suggesting it impairs neuroplasticity. Chronically stressed animals show marked decreases in the activity of plasticity-associated proteins required for learning and memory formation, such as brain derived neurotrophic factor (BDNF) and the transcription factor cAMP Response Element Binding protein (CREB) (Nibuya et al., 1995; Smith et al., 1995a; b; Nibuya et al., 1996). On the other hand, chronic treatment of rodents with clinically effective antidepressants promotes neuroplasticity and reverses the stress-induced depressive-like behaviors (Nibuya et al., 1995; Nibuya et al., 1996; Shirayama et al., 2002).

We have previously demonstrated that chronic exposure to low doses of corticosterone in drinking water to rats or mice for 20 days produces a lasting depressive-like state characterized by behavioral despair, reduced motivation and anhedonia when tested 2–4 weeks of discontinuation. These behavioral changes were concurrent with decreased levels of BDNF and ERK activity in hippocampus, as well as with dysregulated ionotropic glutamate receptor levels in the PFC (Gourley et al., 2008b; Gourley et al., 2009). Finally, both the behavioral and neurobiological alterations could be reversed by chronic treatment with tricyclic or SSRI antidepressants (Gourley et al., 2008a; Gourley et al., 2008c; Gourley & Taylor, 2009). Therefore, prior chronic corticosterone exposure is a novel pharmacology-based model of depression in experimental rodents with potential face, construct, and predictive validity.

Preclinical research on stress and depression has emphasized the effects of experimental manipulations on the response to aversive stimuli and events, and the effects of chronic stress on acquisition of reward-motivated behavior largely remain to be described. This is the first study to examine the long-term consequences of chronic corticosterone exposure made prior to training on a task of reward-related learning. The current experiments complement our earlier studies in mice where corticosterone was administered only after instrumental performance had been acquired (Gourley et al., 2008a). This study was designed to achieve several goals: First, we examined the effect of prior chronic corticosterone exposure on the acquisition of reward-motivated learning where an instrumental response becomes associated with the availability of food. Second, we tested whether the administration of the tricyclic antidepressant amitriptyline, alone or in conjunction with corticosterone exposure, would influence the acquisition of food-motivated instrumental responding and/or prevent the effects of corticosterone on this behavior. Third, we tested whether changes in motivation may contribute to any observed changes in acquisition, and fourth, we performed the core experiment in both rats and mice to establish that these effects could be generalized across species as has been previously shown for anhedonic- and helplessness-like behavior (Gourley et al., 2008b; Gourley et al., 2009).

MATERIALS AND METHODS

1. Animals and animal care

All animal use was conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and was approved by the Yale University Animal Care and Use Committee.

1.1 Rats

Experimentally naïve male Sprague-Dawley rats (n=58; Charles River, USA) were housed in pairs under constant cage temperature (20°C), humidity (40–50%) and a controlled 12/12 h light-dark cycle (light on at 7 a.m. and off at 7 p.m.), and were allowed 7 days to adjust to the housing facilities prior to any study. The rats had access to water and food as detailed below.

1.2 Mice

Male C57Bl/6 mice (n=24) were housed in groups (n=4–5) under constant cage temperature (20°C), humidity (40–50%) and a controlled 12/12 h light-dark cycle (light on at 7 a.m. and off at 7 p.m.) had free access to water at all times and limited access to food as detailed below.

1.3 Food access

During the five days prior to the start of training, animals were limited to 90 min access to food per day as required by the experimental protocol. During the testing period, food pellets were intermittently available in the operant chambers according to the behavioral task protocol (see below) as well as in the home cage for 60 min, beginning 30 min after the daily testing session. During this time, the food was available in excess to eliminate any competition between cage mates and to allow each subject to reach their individual satiety level. This food access paradigm has proven to support normal growth rates while establishing the motivational state required for training.

2. Drugs

In the rat experiments, corticosterone hemisuccinate (Steraloids, USA) was dissolved in tap water and administered in the drinking bottle, and amitriptyline (Sigma, USA) was dissolved in physiological saline (0.9%) and injected intraperitoneally (ip) at a volume of 2 ml/kg. In mouse experiments, both corticosterone and amitriptyline were dissolved in 2% saccharin (to mask the flavor of amitriptyline) and administrated in the drinking fluids. In this experiment, 2% saccharin was used as a control solution such that all animals had access to a sweetened solution.

3. Behavioral Procedures

Instrumental conditioning was tested using standard aluminum operant chambers for rats (l=30 cm, w=20 cm, h=25 cm) or mice (l=16 cm, w=14 cm, h=13 cm) with grid floors controlled (Med Associates Inc., USA). Each chamber was housed in a sound attenuating outer chamber equipped with a white noise generator and a fan to reduce external noise. The chamber was illuminated by house light mounted on the back wall. A pellet dispenser delivered food pellets (20 or 45 mg; Bio-Serv, USA) as the reinforcer into the magazine. Head entries were detected by a photocell mounted above the reinforcer receptacle. In this magazine was a stimulus light. For rats, two levers were placed on each side of the magazine. For mice, three nose poke apertures were placed on the back wall of the chambers (i.e., opposite to the reinforcer magazine).

Animals were initially food restricted and trained to consume grain-based food pellets (mice: 20 mg; rats: 45 mg) in their home cages. All animals are subsequently habituated to the testing apparatus for two days with unlimited food pellets available in the reinforcer magazine. Beginning on the next day, the subjects received daily training sessions for 10 consecutive days. Responding for food was tested based on our previously published instrumental conditioning procedures (Olausson et al., 2006). Responding on the correct (i.e. active) lever/nose poke or lever was reinforced, whereas responding on the other (inactive) lever/nose poke had no programmed consequences. Completion of the response requirement (see below) resulted in a simultaneous offset of the house light and onset of the stimulus light, followed 2-sec later by delivery of a single food pellet. One second later the stimulus light was turned off and the house-light turned on. The first ten (10) reinforcers were obtained after successful completion of responding according to a fixed ratio (FR1) schedule, following which pellets were available after responding on a variable ratio (VR2) schedule. The session lasted for 15 min. The position of the active nose pokes/lever (left/right) was balanced for all experimental groups. The procedures used here were similar to those of Gourley et al., (2008a) but in contrast to the previous experiments, here a short cue was associated with reinforcer delivery based on the instrumental conditioning paradigm originally developed by Kelley and colleagues (Smith-Roe & Kelley, 2000; Baldwin et al., 2002).

In the final experiment, rats were also tested on a progressive ratio schedule of reinforcement after completion of regular training. In this test, training was preformed using a FR1 schedule to minimize differences between the experimental group during acquisition of the instrumental task. In the progressive ratio test, the response requirement to obtain food was initiated as a FR1 schedule but progressively increased by 2 to obtain a subsequent reinforcer (i.e. 1,3,5,7…,X+2 responses). All other parameters were kept identical to the training procedure detailed above, i.e., auditory and visual cues signaled reinforcement delivery. The test was terminated when no active response had been made for 5 min.

Locomotor activity was measured using automated activity meters (Digiscan animal activity monitor, Omnitech Electronics, USA). The activity meters were equipped with two parallel rows of infrared photosensors, each row consisting of 16 sensors placed 2.5 cm apart. The activity meters were controlled by and data from the activity meters collected by a PC using the Micropro software (Omnitech Electronics, USA). Animals were placed in transparent plastic boxes that were fitted into the activity meters and locomotor activity was then recorded for 60 min. All experiments were performed between 8 a.m. and 6 p.m.

4. Experimental design

4.1 Mouse Experiment

In Experiment 1, mice were randomly divided into three experimental groups and received corticosterone (50 µg/ml, free-base), amtriptyline (200 µg/ml), or 2% saccharin for 14 consecutive days. Animals were subsequently weaned off the drug solutions (3 days corticosterone 25 µg/ml or amitriptyline 100µg/ml, 3 days corticosterone 12.5 µg/ml or amitriptyline 50 µg/ml) prior to the initiation of any experiment. After 3 days of complete withdrawal, all mice were habituated to the behavior testing equipment and trained on the instrumental conditioning task for 10 consecutive days.

4.2 Rat Experiment

In this Experiment, rats were randomly divided into four experimental groups and received tap water or corticosterone (50 µg/ml, free-base) for 15 consecutive days. At the same time, rats were injected with saline or amitriptyline (5 mg/kg, ip; twice daily) during the course of treatment yielding the following experimental groups: H2O + saline, corticosterone + saline, H2O + amitriptyline, and corticosterone + amitriptyline. Animals were subsequently weaned off the corticosterone solution over the course of 6 days (3 days 25 µg/ml, 3 days 12.5 µg/ml) prior to the initiation of any experiment. After 3 days of complete washout, all rats were habituated to the behavior testing equipment and trained on the appetitive-learning task for 10 consecutive days according to the procedures described above. In

5. Statistics

The data from all experiments were evaluated using a one or two-way analysis of variance (ANOVA) followed by post hoc tests with correction for multiple comparisons when appropriate. A probability value (p) equal to, or less than, 0.05 was considered statistically significant.

RESULTS

A. Effect of Prior Chronic Corticosterone and Amitriptyline on Instrumental Conditioning in Mice

Here, we tested the effects of corticosterone and amitriptyline on acquisition of reward-motivated instrumental performance in mice: chronic corticosterone exposure was given prior to the initiation of training to specifically examine effects on learning. Average dose over the course of the exposure period was 7.9 mg/kg/day (per oral) for corticosterone and 15.6 mg/kg/day (per oral) for Amitriptyline. There were 8 subjects included in all experimental groups, for a total of 24 animals in this experiment. A two-way ANOVA analysis of active nose poke responding (see Fig 1A) showed a significant Treatment × Training Day interaction (F18,162=4.718; p≤0.0001) along with main effects of both Treatment (F2,18=12.329; p≤0.001) and Training Day (F9,162=139.691; p≤0.0001). Post hoc analyses showed that animals that had received prior chronic corticosterone exposure were consistently lower (p≤0.001) and amitriptyline-exposed mice consistently higher (p≤0.01) than control animals.

Fig 1.

Fig 1

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Effect of prior repeated corticosterone (50 µg/ml) or amitriptyline (200 µg/ml) exposure to mice on training on instrumental conditioning. A) Active responses, B) Number of reinforcers, C) Inactive responses. Symbols represent mean responses +/− SEM.

There were also parallel effects seen in the number of rewards earned (see Fig 1B) Treatment × Training Day interaction (F9,18=4.045; p≤0.0001), Treatment (F2,18=9.580; p≤0.01) and Training Day (F9,162=157.218; p≤0.0001). There was a main effect of Training Day (F9,162=2.851; p≤0.01) on the number of inactive responses made, which decreased progressively during training (Fig 1C). There was no effect of Treatment on this measure assessing inactive lever responses. At the beginning of testing there was no significant difference in the weights between the experimental groups (F2,29=0.818; n.s.), showing that the behavioral alterations were not attributed to significant changes in appetite or ability to consume food in the home cage at the initiation of testing.

B. Effect of Prior Chronic Corticosterone and Amitriptyline on Instrumental Conditioning in Rats

Rats were tested on the acquisition of a food-motivated instrumental response following prior chronic exposure to corticosterone and/or amitriptyline (see above for details). There were 8 subjects included in all experimental groups, for a total of 32 animals in this experiment. Average dose over the course of the exposure period was 6.2 mg/kg/day (per oral) for corticosterone. Active lever responses (see Fig 2A) were evaluated with a three-way ANOVA using Treatment 1 (H2O vs corticosterone), Treatment 2 (saline vs amitriptyline) and Training Day as the independent variables. These analyses demonstrated a significant interaction (F18,324=3.34; p≤0.001) as well as main effects of both corticosterone (F1,36=4.46; p≤0.05) and amitriptyline (F1,36=12.19; p<0.001) exposure, and a significant effect of Training Day (F9,28=51.16; p≤0.0001). Post hoc analysis with Bonferroni-Dunn correction for multiple comparisons revealed that animals exposed to corticosterone alone displayed lower levels of responding than controls (corticosterone vs H2O p≤0.01). Chronic treatment with amitriptyline increased responding in corticosterone-exposed animals (corticosterone vs. corticosterone + amitriptyline p≤0.0001). Chronic exposure to amitriptyline alone increased food-motivated responding above normal levels in both animals that received prior corticosterone exposure (p≤0.01) and in those that were corticosterone-naïve (p≤0.01). Consequently, there was no statistical difference between the two amitriptyline-exposed groups (p=0.7953).

Fig 2.

Fig 2

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Effect of prior repeated corticosterone (50 µg/ml) exposure in combination with Vehicle or Amitriptyline (5 mg/kg, ip; twice daily) in rats on training on instrumental conditioning in rats. A) Active responses, B) Number of reinforcers, C) Inactive responses. Symbols represent mean responses +/− SEM.

The same differences were observed in the number of rewards obtained (see Fig 2B). This measure showed a significant Treatment 1 × Treatment 2 × Training Day interaction (F18,324=2.47; p=0.001) as well as main effects of both corticosterone (F1,35=4.457; p≤0.05) and amitriptyline (F1,35=12.186; p=0.001) exposure and Training Day (F9,28=165.535; p≤0.0001). A three-way ANOVA, using Treatment 1 (H2O vs corticosterone), Treatment 2 (saline vs amitriptyline) and Training Day demonstrated a significant interaction (F18,315=2.46; p≤0.001) as well as significant effects of amitriptyline exposure (F1,36=12.19; p≤0.001) and Training Day (F9,28=10.61; p≤0.0001) (Fig 2), showing that overall the inactive responses decreased with training in all groups (see Fig 2C). Post hoc analysis with Bonferroni-Dunn correction for multiple comparisons revealed that animals exposed to corticosterone displayed lower levels of responding than controls (corticosterone vs H2O p≤0.01) which could also reflect motivational deficits. Notably, at the beginning of testing there was no significant difference in the weights between the experimental groups (F3,3=1.119; n.s.) showing that the behavioral alterations were not attributed to changes in appetite or motivation to consume food in the home cage at the initiation of testing. There was also no difference in locomotor activity when tested in a separate group of animals that had been subjected to the identical corticosterone exposure paradigm (F1,14=0.919; n.s.).

Five subjects were excluded from the final analysis of the data as none of them acquired the instrumental response by the end of training using a criterion of ≤3 active responses/session on training days 8–10. These animals were approximately evenly distributed among experimental conditions and belonged to the following groups: H2O + saline (2), corticosterone + saline (1) and H2O + amitriptyline (2). The total number of animals included in the experimental analyses were H2O + saline (n=6), corticosterone + saline (n=7) and H2O + amitriptyline (n=6) and corticosterone + amitriptyline (n=8) for a total of 27 subjects.

Effect of Prior Chronic Corticosterone Exposure on Responding on a Progressive Ratio Schedule of Reinforcement in Rats

To directly investigate motivation we subsequently tested rats on a progressive ratio schedule of reinforcement on day 11 (see Fig 3A–D). Here, prior corticosterone exposure produced a significant reduction in instrumental performance when the number of responses required to obtain a reinforcer was progressively increased. A two-way ANOVA using Treatment 1 (H2O vs corticosterone) and Treatment 2 (saline vs amitriptyline) as the independent factors revealed an interaction both on breakpoints (F3,22=4.93; p≤0.01; Fig 3A) and active lever responses (F3,22=3.63; p≤0.05; Fig 3B). In addition, there was a significant main effect of Treatment 1 on measures of breakpoints (F1,25=9.44; p≤0.01; Fig 3A), active responses (F1,25=6.62; p≤0.05; Fig 3B) and on inactive lever responses (F1,25=5.40; p≤0.05; Fig 3C). There was also a main effect of Treatment 2 on breakpoints (F1,25=4.94; p≤0.05; Fig 3A), along with a trend for active responses (F1,25=3.49; p≤0.07; Fig 3B). Post hoc analysis with Bonferroni-Dunn correction show that the breakpoint was lower in rats that had received prior corticosterone exposure compared to rats that received H2O + saline, H2O + amitriptyline or that received the combination of corticosterone + amitriptyline (p≤0.05, all groups). Similarly, the active responses and the inactive response were also lower in rats that had chronic corticosterone exposure than the other experimental groups (p≤0.01). One rat was excluded from the analyses because responses were more than 2 STD below the mean. The total number of animals included in the experimental analyses were H2O + saline (n=7), corticosterone + saline (n=6) and H2O + amitriptyline (n=6) and corticosterone + amitriptyline (n=7) for a total of 26 subjects.

Fig 3.

Fig 3

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Effect of prior repeated corticosterone (50 µg/ml) exposure in combination with Vehicle or Amitriptyline (5 mg/kg, ip; twice daily) in rats on instrumental responding using a Progressive Ratio schedule of reinforcement in rats. A) Breakpoint, B) Active responses, C) Inactive responses, D) Number of Reinforcers. Bars represent mean responses +/− SEM. * p≤0.05, * p≤0.01

DISCUSSION

Prior chronic corticosterone exposure produces a persistent depressive-like state in rodents and has been proposed as a novel animal model of depression (Gourley and Taylor, 2009). The present experiments were designed to examine the effects of prior chronic corticosterone exposure on the acquisition of reward-motivated operant behavior. Here we demonstrate that exposure to corticosterone for 20 days via exogenous administration in drinking water produces a long-lasting deficit in the subsequent acquisition of a food-reinforced instrumental response. Treatment with the tricyclic antidepressant amitriptyline prevented the corticosterone-induced deficits when tested in rats. Interestingly, amitriptyline increased instrumental performance compared to control animals both in corticosterone-naïve and corticosterone-exposed rats. This may suggest that chronic exposure to amitriptyline per se facilitates this form of reward-related learning.

Our data are consistent with the notion that chronic corticosterone exposure is sufficient to recapitulate multiple core symptoms of depression in rodents (Gourley & Taylor, 2009). The new results extend our previous findings (Gourley et al., 2008a; Gourley et al., 2008b) that found a reduction in progressive ratio responding when corticosterone exposure was given after instrumental training had been established. In these earlier studies, establishing instrumental performance prior to corticosterone exposure ensured that there was no effect on baseline acquisition of the instrumental response before the progressive ratio test. In the present study we found that prior chronic corticosterone exposure given before instrumental conditioning impaired both the acquisition of reward-related learning as well as subsequent progressive ratio responding when tested in rats. It is likely that the motivational deficit is one of the factors also responsible for the reduced instrumental responding observed in the acquisition phase of the instrumental conditioning. Since this pattern of behavior was observed both in rats and in mice, prior low dose corticosterone produces a reproducible impairment in instrumental conditioning that could be explored in a variety of preclinical models aimed at understanding the neurobiology of depression and/or investigating new treatments for these disorders.

The observation that animals exposed to corticosterone both reach asymptote at lower levels of responding and display reduced break points when tested on the progressive ratio schedule suggests that the neurobiological changes and changes in motivation induced by a short period of corticosterone exposure are persistent, lasting for at least 21 days following discontinuation. These long-lasting effects of chronic corticosterone exposure on reward-motivated learning are also in line with the impairment of Pavlovian autoshaping after exposure to repeated maternal separation stress (Matthews & Robbins, 2003), an experimental manipulation that has also been argued to produce a lasting depressive-like state. Of particular relevance to our interpretation is the finding that chronically stressed animals exhibit an anhedonic phenotype in responding to rewards such as sucrose (Willner, 1997). Using the current model we have previously shown that prior corticosterone exposure also produces a lasting decrease in sucrose consumption and preference when compared to controls (Gourley & Taylor, 2009). These same animals show reduced motivation when subsequently subjected to a food-reinforced progressive ratio task. It is therefore likely that the motivational value of natural reinforcers are reduced by prior chronic corticosterone, resulting in lower levels of responding at the end of training. This possibly explains why, by the end of the training period, the corticosterone treated animals had very low levels of overall responding.

Mice that acquire instrumental responding before any corticosterone exposure display reduced progressive ratio responding but do not show changes in baseline instrumental performance (Gourley et al., 2008a; Gourley et al., 2008c). This raises the possibility that corticosterone impairs animals’ ability to learn the consequences of their actions and to respond flexibly when response contingencies change – such as on a progressive ratio schedule of reinforcement. Such impairments have been reported previously after chronic stress exposure (Matthews & Robbins, 2003; Dias-Ferreira et al., 2009). Similar deficits could contribute to the behavioral phenotype reported here, and future experiments will attempt to disentangle effects of prior chronic corticosterone exposure on stimulus-response vs. response-outcome associative learning and the role of alterations in primary and conditioned motivation.

Prior chronic treatment with amitriptyline produced a lasting increase in instrumental acquisition and performance in corticosterone-naïve animals. As antidepressant primarily are used to reverse the symptoms of depression, little has been done to examine their effects on reward-motivated behaviors in “normal” subjects with the exception of animal models used for screening antidepressant activity. The pharmacodynamic effects of tricyclic antidepressants include inhibition of serotonin, norepinephrine and in some cases also dopamine reuptake, a pharmacological profile shared by psychostimulant drugs of abuse that have also been shown to enhance the acquisition of instrumental performance and increased progressive ratio responding (Olausson et al., 2006). Therefore, the resulting enhancement of monoamine neurotransmission produced by amitriptyline and other reuptake inhibitors causes a host of neurobiological changes believed to facilitate neuroplasticity within multiple brain circuits, including those involved in acquisition of Pavlovian approach behavior. It may thus not be entirely unexpected that chronic exposure to amitriptyline also has the ability to promote reward-motivated learning in otherwise experimentally naive animals. However, there are also differences compared to the effects of psychostimulants that may be of interest. Given that the effect of amitriptyline enhanced acquisition, but not progressive ratio responding, the processes involved in memory consolidation and/or retrieval may be more sensitive to the effects of amitriptyline than those modulating primary motivation. This observation is supported by the instrumental performance on the final day of training (Day 10) where there was no difference between rats exposed to amitriptyline, with or without corticosterone preexposure, and that of controls. However, amitriptyline was able to reverse both the impaired acquisition, and the reduced motivation, in animals that had been exposed to corticosterone. Future experiments will need to further clarify these effects on acquisition of instrumental performance and progressive ratio responding.

The exact neurobiological substrate for the corticosterone-induced impairments in instrumental conditioning requires further investigation. While their role in the pathophysiology of depression remain controversial, two of the targets that have been well studied in animal models of depression and antidepressant activity are the transcription factor CREB and its downstream target BDNF. Chronically stressed animals display changes in both BDNF and CREB-regulated gene transcription (Nibuya et al., 1995; Smith et al., 1995a; b) and chronic treatment with antidepressants increases CREB activity and BDNF levels throughout cortico-limbic-striatal regions (Nibuya et al., 1995; Nibuya et al., 1996) in non-stressed animals. Additionally, manipulations that alter CREB or BDNF function in mesolimbic dopamine systems can induce a depressive-like state (Berton et al., 2006; Wallace et al., 2009; Krishnan and Nestler 2010). Abnormalities in these neuroplasticity-associated proteins or their down-stream targets could thus underlie the deficits in reward-related learning observed here following chronic corticosterone exposure. However, post mortem studies performed in humans have failed to establish a strong correlation between the levels of BDNF and depressive symptoms (Gorgulu and Caliyurt, 2009) and the role of these targets in depression or in the clinical effects of antidepressants in humans remain unclear. Chronic stress has also been shown to induce more specific dendritic reorganizations in the medial prefrontal cortex in animals (e.g., Wellman, 2001; Radley et al., 2004; Radley et al., 2006; Liu & Aghajanian, 2008; Dias-Ferreira et al., 2009), and lesion of the prelimbic subregion decreases instrumental performance (Corbit & Balleine, 2003) and progressive ratio responding (Gourley et al., 2008c). Together these findings suggest that long-term exposure to corticosterone may result in deficits in synaptic plasticity and organization concurrent with impaired reward-related learning.

In summary, our results show that prior chronic corticosterone exposure produces a significant and persistent impairment in reward-motivated instrumental learning in both mice and rats, and progressive ratio responding in rats. These data suggest that prior corticosterone affects acquisition of instrumental responding through reductions in motivation, which we previously observed in mice (Gourley et al., 2008a; Gourley et al., 2008b; Gourley et al., 2008c). These data may parallel the decreased emotional responses to previously rewarding experiences seen clinically in depressed patients (Gotlib & Joormann, 2010). While reward-related learning and motivational function has received little attention in basic and translational clinical research these symptoms are an integral and crippling part of depression. Our results are encouraging in that these deficits induced by corticosterone were prevented by treatment with antidepressants. By using this model we may be able to better understand the neurobiological changes that occur and aid in the development of novel treatment approaches.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the valuable technical assistance of Dr. Dilja Krueger, Ms. Victoria Stewart and Ms. Jessica Johnson. The study was supported by PHS grants AA017537, MH066172 and NARSAD Young Investigator Award.

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