Altered attention and prefrontal cortex gene expression in rats after binge-like exposure to cocaine during adolescence

Abstract

Illicit use of drugs frequently begins and escalates during adolescence, with long-term adverse consequences. Because it is increasingly accepted that neural development continues through adolescence, addiction research has become more invested in understanding the behavioral and molecular consequences of early exposure to drugs of abuse. In a novel binge administration paradigm designed to model the pattern of human adolescent drug use, we administered ascending doses of cocaine or saline during a 12-d developmental period [postnatal day 35 (P35) to P46] corresponding to human adolescence. During adulthood (P70), rats treated with this regimen displayed increased responsiveness to the stimulant effects of cocaine. Adult rats also displayed abnormally rapid shifts in attention when performing an attentional set-shifting task, which measures the ability to shift attention between stimuli and whose performance requires an intact prefrontal cortex (PFC). Treatment with cocaine during adolescence also caused acute alterations in the expression of genes encoding cell adhesion molecules and transcription factors within the PFC. Furthermore, we observed decreases in histone methylation, which may indicate a role for chromatin remodeling in the observed changes in gene expression patterns. These findings suggest that exposure to cocaine during adolescence has far-reaching molecular and behavioral consequences in the rat PFC that develop over time and endure long after drug administration has ceased.

Figure 1.

Figure 1. Performance during 1 h habituation sessions in rats treated during adolescence with cocaine and saline and tested 10 d (cocaine, n = 7; saline, n = 9) and 24 d (cocaine, n = 9; saline, n = 8) after treatment. A, Total distance traveled. B, Vertical rear counts. Values represent the mean + SEM. *p ≤ 0.05; **p ≤ 0.005.

Figure 2.

Figure 2. Performance during 1 h cocaine and saline challenge sessions in rats treated during adolescence with cocaine and saline and tested 10 d (cocaine, n = 7; saline, n = 9) and 24 d (cocaine, n = 9; saline, n = 8) after treatment. A, Total distance traveled. B, Vertical rear counts. Values represent the mean + SEM. *p ≤ 0.05; **p ≤ 0.005.

Figure 3.

Figure 3. A priori comparisons of the trials to reach criterion during IDS versus EDS phases of the ASST in rats treated during adolescence with cocaine and saline. A, Performance 10 d after treatment (cocaine, n = 12; saline, n = 11). B, Performance 24 d after treatment (cocaine, n = 11; saline, n = 10). Values represent the mean + SEM. The criterion was as follows: six consecutive trials correct. *p ≤ 0.05.

Figure 4.

Figure 4. Trials to reach criterion performance for all phases of the ASST in rats treated during adolescence with cocaine and saline. A, Performance 10 d after treatment (cocaine, n = 12; saline, n = 11). B, Performance 24 d after treatment (cocaine, n = 11; saline, n = 10). Values represent the mean + SEM. The criterion was as follows: six consecutive trials correct.

Figure 5.

Figure 5. Western blot analysis of two methylation sites of histone H3 in medial PFC tissue of rats 22 h after cocaine treatment (P47). A, Immunoblot analysis with antibodies against trimethylated (Lys⁴) (K4) histone H3 and trimethylated (Lys²⁷) (K27) histone H3. Actin was used as a loading control. B, Average levels of both modified histones corrected for loading errors. Values represent the mean + SEM of six saline- and eight cocaine-treated animals. *p ≤ 0.05; **p ≤ 0.01.