Chronic corticosterone exposure during adolescence reduces impulsive action but increases impulsive choice and sensitivity to yohimbine in male Sprague-Dawley rats

Abstract

Chronic stress during adolescence is associated with an increased risk for alcoholism and addictive disorders. Addiction is also associated with increased impulsivity, and stress during adolescence could alter cortical circuits responsible for response inhibition. Therefore, the present study determined the effect of chronic exposure to the stress hormone corticosterone (CORT) during adolescence on tests of impulsivity in adulthood and examined possible biochemical mechanisms. Male Sprague-Dawley rats were exposed to CORT by their drinking water during adolescence (post-natal day 30-50). The rats were then tested in adulthood to assess behavior on the 5-choice serial reaction time task (5CSRTT), stop-signal reaction time task (SSRTT), and the delay-discounting task, which differentially assess attention, impulsive action, and impulsive choice. Yohimbine-induced impulsivity on the 5CSRTT and biochemical analysis of the lateral orbital frontal cortex (lOFC) was also assessed owing to the ability of yohimbine to activate the hypothalamic-pituitary-adrenal axis and influence impulsivity. Adolescent CORT-treated rats were found to behave largely like controls on the 5CSRTT, but did show reduced premature responses when the intertrial interval was increased. Nevertheless, the CORT-treated rats tended to have more yohimbine-induced impulsive responses at low doses on this task, which was not found to be due to increased pCREB in the lOFC, but could be related to a higher expression/activity of the AMPA receptor subunit GluR1. Adolescent CORT-treated rats performed more accurately on the SSRTT, but showed greater impulsivity on the delay-discounting task, as indicated by steeper discounting functions. Therefore, adolescent CORT exposure reduced impulsive action but increased impulsive choice, indicating that chronic stress hormone exposure in adolescence can have long-term consequences on behavior.

Figure 1

Timeline of experimental events. (a) Male Sprague-Dawley rats were treated with corticosterone via their drinking water during post-natal days (PNDs) 30–50, and all behavioral testing began at PND 60, 10 days after the CORT exposure. There was no corticosterone CORT given during behavioral testing. (b) The CORT-exposed rats drank the same amount of fluid as rats drinking normal tap water throughout the CORT exposure period. (c) CORT-exposed rats did not differ from control rats in the amount of weight gained during the CORT exposure across adolescence. Data are displayed as samples throughout the exposure period. (d) The figure depicts the average dose in mg/kg of CORT that rats consumed on selected days throughout the 50-μg/ml phase of exposure.

Figure 2

Effects of chronic adolescent corticosterone (CORT) on baseline behaviors in the 5-choice serial reaction time task (5CSRTT). Chronic adolescent CORT had no significant effects on task accuracy at stable stimulus durations (a) or variable stimulus durations (b), though all rats showed decrements in performance as stimulus duration decreased. Chronic adolescent CORT also produced no significant differences in other measures of task performance including premature responses at a stable intertrial interval (ITI) (c), trial omissions (d), or perseverative responses (e).

Figure 3

Chronic adolescent corticosterone (CORT) decreases impulsivity with changing intertrial intervals (ITIs) on the 5-choice serial reaction time task (5CSRTT). Chronic adolescent CORT improved task accuracy when the ITI was switched to both 4 and 6 s (a), and produced an overall reduction in premature responses on the first day that the ITI was switched (b). The adolescent CORT-treated rats showed no significant differences in omissions (c) or perseverative responses (d) as the ITI increased. ^*p<0.05.

Figure 4

Chronic adolescent corticosterone (CORT) treatment enhances sensitivity to yohimbine-induced impulsivity on the 5-choice serial reaction time task (5CSRTT). Adolescent CORT-treated and control rats were given injections of saline and varying doses of yohimbine prior to testing on the 5CSRTT with a stable intertrial interval (ITI) and stimulus duration. Adolescent CORT-treated rats had an upward and leftward shift in the yohimbine dose–response curve, indicative of a greater sensitivity to yohimbine's effects on impulsivity (a), whereas the number of omissions on the task was not different between groups and was not significantly disrupted except at the highest dose of yohimbine (b). ^**p<0.01.

Figure 5

Chronic adolescent corticosterone (CORT) treatment does not alter expression of CREB, but increases phosphorylated GluR1 in the lateral orbital frontal cortex (lOFC). Phosphorylation of CREB in the lOFC is associated with yohimbine-induced impulsivity on the 5-choice serial reaction time task (5CSRTT) (Sun et al, 2010), but adolescent CORT treatment did not alter the expression of phospho-CREB at ser133, total CREB, or the ratio of phospho- to total CREB in the lOFC (a). Adolescent CORT treatment did significantly increase phosphorylation of the AMPA receptor subunit GluR1 at the protein kinase A (PKA) site ser845, with a trend toward increasing overall GluR1 expression, p=0.08. However, the ratio of phosphorylated to total GluR1 was not different, indicating a likely overall increase in protein expression that is maintained in the phosphorylated state (b). All bands were normalized to GAPDH and representative blots are below the graphical quantification, ^*p<0.05.

Figure 6

Chronic adolescent corticosterone (CORT) improves accuracy on the SSRTT. Adolescent CORT-treated rats demonstrated better stop accuracy across increasing stop signal delays (SSDs), but were not different from controls at baseline stop accuracy with zero delay (a). Adolescent CORT treatment did not affect accuracy on go trials at any SSD (b). CORT treatment did not affect the mean reaction time (MRT) on go trials at any delay (c). CORT treatment did not significantly alter the estimated stop-signal reaction time (d), ^*p<0.05.

Figure 7

Chronic adolescent corticosterone (CORT) increases impulsive choice on the delay-discounting task. When the range of delays to the larger reinforcer were long (maximum 60 s), there was no significant difference between adolescent CORT-treated and control rats on the discounting function either early (a) or late (b) in training. However, when the range of delays to large reinforcement were short (maximum 15 s), adolescent CORT treatment caused steeper discounting functions both early (c) and late (d) in training at the new delays, indicating an increased impulsive choice, ^*p<0.05, ^**p<0.01.