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Published in final edited form as: Behav Brain Res. 2020 Sep 17;396:112921. doi: 10.1016/j.bbr.2020.112921

Sex-dependent effects of chronic stress on reinstatement of palatable food seeking and involvement of dopamine D1-like receptors

Kevin T Ball 1,*, Brandon J Arnsberger 1, Rachel M McDonald 1
PMCID: PMC7572887  NIHMSID: NIHMS1630047  PMID: 32950608

Abstract

Recent work in our lab has shown that chronic stress exposure causes sex-dependent changes in subsequent relapse-like behavior in rats with a history of palatable food self-administration. Although these effects are mediated by dopamine D1-like receptors in male rats, such dopaminergic mechanisms have not been investigated in female animals. Thus, male and female rats were trained to respond for highly palatable food reinforcers in daily sessions. During subsequent extinction training, stress was manipulated (0 or 3 hr restraint/day for 7 days). To assess dopaminergic involvement, we administered either SCH-23390 (10.0 μg/kg), a dopamine D1-like receptor antagonist, or vehicle prior to daily treatments. Rats were then tested for cue- and pellet priming-induced reinstatement. Results showed that a history of chronic stress caused an increase in pellet priming-induced reinstatement in males and a decrease in cue-induced reinstatement in females. SCH-23390 combined with stress prevented those effects in males, but not in females. In females, a history of SCH-23390 administration caused an overall increase in responding that was apparent during cue-, but not pellet priming-, induced reinstatement testing. These results establish that both the effects of chronic stress on reinstatement of food seeking and the involvement of dopamine in those effects are dependent on biological sex. Such findings should inform the development of sex-specific interventions for dietary relapse and other stress-related health problems.

Keywords: CHRONIC STRESS, DOPAMINE, FOOD SEEKING, REINSTATEMENT, RELAPSE, SEX DIFFERENCES

Despite the decades long recognition that overweight/obesity is a leading cause of death and a public health crisis, available dietary treatment options remain relatively ineffective. A major factor contributing to poor treatment outcomes is palatable food craving, which leads to high rates of relapse to former unhealthy eating habits in dieters [1, 2]. Although both obesity and craving are associated with chronic stress in the clinical literature [3, 4], relatively few pre-clinical studies have used models of relapse that incorporate a chronic stressor. Consequently, little is known about the specific circumstances under which chronic stress increases relapse vulnerability or the mechanisms through which chronic stress exerts its effects.

We have investigated the relationship between chronic stress and relapse experimentally by adding a chronic stress component to the classical reinstatement model of relapse [5, 6]. Using this model, we found that rats with a history of chronic stress exposure displayed increased reinstatement responding relative to unstressed rats for more than 1 week after the last stress exposure [7–10]. Regarding neuropharmacological mechanisms, we found that many of the effects of chronic stress on reinstatement of palatable food seeking are mediated by dopamine D1-like receptors (D1Rs) [7, 8]. These findings, however, are based on studies of male animals, and we recently reported that chronically stressed female rats displayed decreased reinstatement of palatable food seeking [9] compared to unstressed females. Moreover, the dopaminergic mechanisms of chronic stress-induced alterations in reinstatement of food seeking in females have not been investigated. Therefore, in the present study, we used both male and female rats to determine whether sex differences exist with regard to the role of D1Rs in chronic stress-induced changes in reinstatement of palatable food-seeking behavior.

Data were collected from male and female Sprague-Dawley rats (Envigo; total n = 24 of each sex) weighing 292–327 g and 230–286 g (males and females, respectively) at the commencement of procedures. Rats were housed individually under standard laboratory conditions (12-hr light cycle from 7:00 AM to 7:00 PM) with ad libitum access to standard chow and water in their home cages and were weighed daily. All testing was conducted between 7:00 AM and 7:00 PM and occurred in standard modular operant conditioning chambers (Coulbourn Instruments, Whitehall, PA) that were housed in sound-attenuating, ventilated cubicles and connected to a PC with the Graphic State 4 software interface system (Coulbourn Instruments). Each chamber was equipped with an active and an inactive response lever. Responses on the inactive lever were recorded, but had no programmed consequences. Chambers also included a house light, a row of multicolored LED cue lamps (above active lever), a tone generator, and a food tray (between the two response levers). All procedures were in compliance with NIH guidelines and were approved by the Bloomsburg University Institutional Animal Care and Use Committee.

Rats were trained to press the lever for food reinforcers as previously described [9, 11]. Following initial training, rats responded on an FR-1 schedule during daily 3-hr sessions for 12 days. Each lever press resulted in delivery of a highly preferred [12] 45-mg food pellet containing 12.7% fat, 66.7% carbohydrate, and 20.6% protein (Catalogue # 1811155, TestDiet). Delivery of the pellet was accompanied by a tone + flashing cue light (conditioned stimuli, CS) presented for 5 s, which was followed by a 20-s time-out period signaled by illumination of the house light. See Fig. 1 for schematic of experimental design.

Fig. 1.

Fig. 1

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Schematic representation of the experimental design.

On the day following the last self-administration session, daily 2-hr extinction sessions began and continued for 12 days. During the extinction sessions, responses were recorded but had no programmed consequences (i.e., no CS or pellets). Beginning on the first day of extinction, half of the rats of each sex were randomly assigned to receive daily stress treatment. Each day, beginning approximately 1 hr after daily extinction sessions, stressed rats were placed in plastic semi-cylindrical restrainers (8.25 cm diameter × 20.32 cm length; Braintree Scientific) in an isolated room separate from other rats for 3 hr for 7 consecutive days. Chronic restraint stress is a well-established procedure that produces significant increases in plasma corticosterone levels [13, 14]. To assess dopaminergic involvement in chronic stress effects, rats received injections of SCH-23390 (0.0 or 10.0 μg/kg; i.p.; Sigma-Aldrich), a D1R antagonist, immediately prior to placement in restrainers. SCH-23390 was dissolved in physiological saline at a concentration of 10.0 μg/ml, and the dose is based on previous research [7, 8, 10, 11]. Unstressed rats were injected daily with SCH-23390 or vehicle and then returned to their home cages. Procedures began with n = 6 rats/treatment group/sex, but with the exclusion of three rats due to extinction responding that was > 3 standard deviations from the group mean on the day before cue-induced reinstatement testing (n = 2 males) and poor health (n = 1 female), this number was reduced to n = 5 in three groups.

Following the extinction sessions, animals underwent 1 day of 2-hr cue-induced reinstatement sessions. Sessions began with one non-contingent CS presentation; during the remainder of the session, conditions were identical to those of self-administration training, except that lever presses did not lead to pellet delivery. To extinguish lever pressing before pellet priming-induced reinstatement sessions, rats underwent five daily sessions of extinction training (2 hr, with cue) that were identical to self-administration sessions, except that lever presses did not lead to pellet delivery. Next, animals underwent within-session pellet priming-induced reinstatement testing. The testing consisted of three consecutive 1-h sessions in which the conditions were identical to the previous five extinction sessions except that four non-contingent pellets were delivered within the first minute of Session 3. Session 2 served as the 0-pellet baseline. Data from Session 1 were not used for the pellet priming analysis. This within-session procedure is based on previous studies with cocaine and pellet priming [9, 10, 15].

Data were analyzed using mixed factorial ANOVAs. The dependent variables were lever responses, pellets earned, pellets earned/body weight (mg/kg), and change in body weight across chronic treatment days. The between-subjects factors were stress condition (stressed or unstressed), SCH-23390 dose (0.0 or 10.0 μg/kg), and sex. The within-subjects factors were day, lever (active and inactive), session (cue-induced reinstatement session and preceding extinction session), and number of pellets (0 and 4; for pellet priming-induced reinstatement). Because the factorial ANOVAs resulted in multiple main and interaction effects, we report only significant F values that are important for interpretation. ANOVA main effects and interactions were interpreted based on observation of the figures. In some cases, Bonferroni post-tests for multiple comparisons were used to enhance clarity.

As shown in Fig. 2, despite differences in the patterns of lever responding across self-administration days [day × sex interaction, F(11, 473) = 6.67, p < .001], as well as a trend toward more lever pressing in females, overall responding was not significantly different between males and females. However, both pellets earned and pellets earned per body weight were greater in females than in males [main effect of sex for pellets earned and pellets earned/body weight; F(1, 43) = 6.36, p = .015, and F(1, 43) = 46.92, p < .001, respectively]. Inactive lever responding was very low overall [main effect of lever; F(1, 43) = 376.25, p < .001].

Fig. 2.

Fig. 2

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Palatable food-reinforced responding and pellets earned per body weight in male and female rats. (top) Mean (± SEM) active and inactive lever responses and pellets earned across 12 days of 3-hr food self-administration sessions. Rats responded on an FR-1 schedule of reinforcement, and delivery of the pellet was accompanied by a tone + flashing cue light CS presented for 5 s, which was followed by a 20-s time-out period signaled by illumination of the house light. (bottom) Mean (± SEM) adjusted pellets earned per body weight. Points without error bars indicate the SEM is too small to illustrate.

As shown in Fig. 3, top, extinction responding decreased over days for males and females [main effect of extinction day, F(11, 407) = 89.52, p < .001]. However, active, but not inactive, lever responding was lower for females than for males during the first 3 days of training [extinction day × sex interaction, F(11, 407) = 6.06, p < .001 and extinction day × sex × lever interaction, F(11, 407) = 5.30, p < .001].

Fig. 3.

Fig. 3.

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Extinction of food-reinforced responding and change in body weight during chronic treatment in male and female rats. (top) Extinction of food-reinforced responding: mean (± SEM) responses on the previously active lever. Responses had no programmed consequences (i.e., no CS or pellets). Rats received one of four treatments (saline + unstressed, SCH-23390 + unstressed, saline + stressed, or SCH-23390 + stressed) once each day (~1 hr after daily extinction sessions) during the first 7 days of extinction. (bottom) Mean (± SEM) weight change in the four chronic treatment groups. Points without error bars indicate the SEM is too small to illustrate.

Males gained more weight than females during the chronic treatment period [main effect of sex, F(1, 37) = 45.92, p < .001; see Fig. 3, bottom], especially when comparing unstressed groups [sex × stress interaction, F(1, 37) = 12.28, p = .001]. As expected, restraint was a stressor, causing weight loss in both male and female rats [main effect of stress, F(1, 37) = 127.23, p < .001]. Finally, there was a stress × SCH-23390 dose interaction [F(1, 37) = 9.04, p = .005]: In unstressed rats, SCH-23390 had no effect on weight gain in males and attenuated weight loss in females; in stressed rats, SCH-23390 exacerbated weight loss in both males and females.

Active, but not inactive, lever responding increased during cue-induced reinstatement tests compared to the last extinction session [main effect of session, F(1, 37) = 51.22, p < .001 and lever × session interaction, F(1, 37) = 43.35, p < .001; see Fig. 4, top]. However, the magnitude of reinstatement was greater for females than for males [main effect of sex, F(1, 37) = 11.57, p = .002, sex × session interaction, F(1, 37) = 7.77, p = .008, and sex × session × lever interaction, F(1, 37) = 12.30, p = .001]. Given the low reinstatement responding in male rats, a separate 2 (session) × 2 (lever) × 2 (stress) × 2 (SCH-23390 dose) ANOVA in male rats only was conducted, and it confirmed that overall active, but not inactive, lever pressing increased significantly from extinction to cue-induced reinstatement testing [main effect of session, F(1, 18) = 12.46, p = .002 and lever × session interaction, F(1, 18) = 9.70, p = .006]. Bonferroni post-tests indicated, however, that no individual treatment group met the criterion for a significant increase. Moreover, female, but not male, rats with a history of stress made less active, but not inactive, lever responses during reinstatement testing compared to their unstressed counterparts [stress × sex × session interaction, F(1, 37) = 8.75, p = .005 and stress × lever interaction, F(1, 37) = 4.22, p = .047], and Bonferroni post-tests indicated that only unstressed females displayed significant reinstatement responding relative to baseline. Finally, female, but not male, rats with a history of SCH-23390 treatment responded more during both extinction and reinstatement compared with saline-treated rats [SCH-23390 dose × sex interaction, F(1, 37) = 4.41, p = .043].

Fig. 4.

Fig. 4

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Effect of repeated SCH-23390 (10 μg/kg × 7 days) and repeated restraint stress (3 hr × 7 days) on subsequent CS- and pellet priming-induced reinstatement of palatable food seeking in male and female rats. (top) Mean (+ SEM) active lever presses during the last extinction session and CS-induced reinstatement testing. Reinstatement sessions began with one non-contingent CS presentation; during the remainder of the session, conditions were identical to those of self-administration training, except that lever presses did not lead to pellet delivery. (bottom) Mean (+ SEM) active lever presses during pellet priming-induced reinstatement testing. The testing consisted of three consecutive 1-h sessions that were identical to self-administration sessions, except that lever presses did not lead to pellet delivery, and four non-contingent pellets were delivered within the first minute of Session 3. Session 2 served as the 0-pellet baseline.

Active, but not inactive, lever responding increased as a function of pellet priming [main effect of pellets, F(1, 37) = 23.84, p < .001 and lever × pellets interaction, F(1, 37) = 61.62, p < .001; see Fig. 4, bottom]. For both male and female rats, Bonferroni post-tests indicated that responding increased significantly from the 0- to the 4-pellet condition only for the saline + stressed chronic treatment group; for females, however, this was due to lower responding during baseline (0-pellet condition), rather than higher responding during pellet priming. Given the overall low reinstatement responding in female rats, a separate 2 (pellets) × 2 (lever) × 2 (stress) × 2 (SCH-23390 dose) ANOVA in female rats only was conducted, and it confirmed that overall active, but not inactive, lever pressing increased significantly from the 0- to the 4-pellet condition [main effect of pellets, F(1, 19) = 16.38, p = .001 and lever × pellets interaction, F(1, 19) = 30.12, p < .001]. Moreover, for males, mean responding during pellet priming was significantly greater for the saline + stressed group compared to the SCH-23390 + stressed group. A separate 2 (pellets) × 2 (lever) × 2 (stress) × 2 (SCH-23390 dose) ANOVA in male rats only was conducted and yielded a 4-way interaction [F(1, 18) = 4.69, p = .044], confirming that the priming-induced increase in active lever pressing was greater in rats with a history of chronic stress, and that co-administration of SCH-23390 with the stress prevented this effect.

The present results establish that both the effects of chronic stress on reinstatement of palatable food seeking and the involvement of dopamine in those effects are dependent on biological sex. Results are consistent with our recent study showing that the magnitude of cue-induced reinstatement is significantly larger in females than males, and that a history of chronic stress causes a decrease in this type of reinstatement in females while having no effect in males [9]. We extend these findings by showing that SCH-23390 combined with stress did not prevent this stress-induced reduction in reinstatement responding in females; rather, SCH-23390 caused an overall increase in responding in females that was apparent during cue-, but not pellet priming-, induced reinstatement testing, as well as during the previous extinction session. Interestingly, male rats with a history of cocaine self-administration treated with repeated post-extinction SCH-23390 were shown to display higher levels of both extinction responding and subsequent cue-, but not cocaine-, induced reinstatement of cocaine seeking [10]. These results may reflect the action of SCH-23390 in the infralimbic region of medial prefrontal cortex (mPFC), as chemogenic activation of infralimbic mPFC was shown to reduce cue-, but not cocaine-, induced reinstatement of cocaine seeking [16]. Collectively, these results support evidence that distinct neural mechanisms underlie relapse triggered by CS (e.g., food- or drug-associated cues) vs. unconditioned stimuli (e.g., food or drug) [17, 18].

It is noteworthy that although chronic stress does not appear to increase responding for food- or cocaine-associated cues following extinction training [[9, 10]; present results], male rats with a history of chronic, but not acute, restraint stress display increased responding for food-associated cues following a period of forced home-cage abstinence (i.e., without extinction training) [11]. SCH-23390 combined with restraint prevents this effect, which is consistent with evidence that distinct neuropharmacological mechanisms underly relapse following extinction vs. forced [19] or punishment-induced [20] abstinence.

Another main finding in our study was that male, but not female, rats with a history of chronic restraint stress displayed increased responding during pellet priming-induced reinstatement tests relative to their unstressed counterparts, and that SCH-23390 combined with stress prevented this effect. These results extend our previous finding that chronic restraint stress increased pellet priming-induced reinstatement in the majority of male, but not female, rats [9] by establishing a role for D1Rs in this effect. These results also extend previous work showing that SCH-23390 combined with repeated yohimbine stress prevented later increases in pellet priming-induced reinstatement in male rats [8], and that SCH-23390 combined with repeated restraint stress during withdrawal from cocaine self-administration prevented later increases in cocaine priming-induced reinstatement in male rats [10]. Taken together, it appears that, for males, the ability of chronic stress to increase reinstatement responding triggered by unconditioned stimuli generalize across multiple categories (i.e., food and drug), and that the ability of SCH-23390 to attenuate those effects generalizes across multiple categories of stressor (i.e., restraint and yohimbine).

The sex-dependent behavioral effects of stress that we report are in line with results showing that chronic stress causes deficits in spatial working memory in males and improvements in females [21, 22]. Indeed, both reinstatement of food seeking [18] and working memory tasks [23] involve D1R engagement in mPFC. Moreover, differences in behavioral stress responses in males and females correspond to differences in mPFC engagement [24] and population activity of ventral tegmental area dopaminergic neurons [25]. Male and female rats also display opposite stress-induced dendritic changes in mPFC pyramidal neurons following chronic restraint stress—specifically, atrophy in males and hypertrophy in females [26]. IntramPFC injections of SCH-23390 combined with stress prevent these structural changes in male rats [27]. We speculate that SCH-23390 prevented such changes in male rats in the present study, thereby preventing the stress-induced increase in pellet priming-induced reinstatement.

With regard to non-dopaminergic mechanisms that might account for chronic stress’ reduction of cue-induced reinstatement in females, available evidence points to the potential involvement of nucleus accumbens (NAc) mu-opioid receptors (MORs). It is well-documented that NAc MORs modulate several aspects of food reward (for review see [28]). In fact, stimulation of MORs in NAc attenuates cue-induced reinstatement of sucrose seeking in male rats [29]. Notably, repeated early life stress was shown to cause a delayed increase in NAc MOR mRNA levels in females, but not males [30]. Thus, it is possible that sex-dependent alterations in NAc MORs due to chronic stress played a role in the cue-induced reinstatement results in the present study. Future studies will be necessary to confirm this hypothetical mechanism, as well as to determine the reason for chronic stress’ selective effects on cue- vs. pellet priming-induced reinstatement in female vs. male subjects, respectively.

Highlights.

  • Chronic stress causes sex-dependent changes in reinstatement of food seeking.

  • We assessed dopaminergic involvement in those changes in male and female rats.

  • A history of chronic stress increased food priming-induced reinstatement in males.

  • A history of chronic stress decreased cue-induced reinstatement in females.

  • D1-like receptor antagonism during stress prevented those effects in males only.

Acknowledgements:

This work was supported by the National Institutes of Health (NIDA R15 DA035432 to KTB).

Abbreviations:

CS

conditioned stimuli

D1R

dopamine D1-like receptor

mPFC

medial prefrontal cortex

MOR

mu-opioid receptor

NAc

nucleus accumbens

Footnotes

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Conflict of Interest: The authors declare no conflicts of interest.

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