Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats

Abstract

Rationale: Environmental challenges during adolescence, such as drug exposure, can cause enduring behavioral and molecular changes that contribute to life-long maladaptive behaviors, including addiction. Selectively bred high-responder (bHR) and low-responder (bLR) rats represent a unique model for assessing the long-term impact of adolescent environmental manipulations, as they inherently differ on a number of addiction-related traits. bHR rats are considered "addiction-prone," whereas bLR rats are "addiction-resilient," at least under baseline conditions. Moreover, relative to bLRs, bHR rats are more likely to attribute incentive motivational value to reward cues, or to "sign-track."

Objectives: We utilized bHR and bLR rats to determine whether adolescent cocaine exposure can alter their inborn behavioral and neurobiological profiles, with a specific focus on Pavlovian conditioned approach behavior (i.e., sign- vs. goal-tracking) and hippocampal neurogenesis.

Methods: bHR and bLR rats were administered cocaine (15 mg/kg) or saline for 7 days during adolescence (postnatal day, PND 33-39) and subsequently tested for Pavlovian conditioned approach behavior in adulthood (PND 62-75), wherein an illuminated lever (conditioned stimulus) was followed by the response-independent delivery of a food pellet (unconditioned stimulus). Behaviors directed toward the lever and the food cup were recorded as sign- and goal-tracking, respectively. Hippocampal cell genesis was evaluated on PND 77 by immunohistochemistry.

Results: Adolescent cocaine exposure impaired hippocampal cell genesis (proliferation and survival) and enhanced the inherent propensity to goal-track in adult bLR, but not bHR, rats.

Conclusions: Adolescent cocaine exposure elicits long-lasting changes in stimulus-reward learning and enduring deficits in hippocampal neurogenesis selectively in adult bLR rats.

Keywords: Adolescence; Cocaine; Hippocampus; Neurogenesis; Pavlovian conditioning.

Fig. 1

Experimental design. PND: post-natal day; ST: sign-track; GT: goal-track.

Fig. 2

Locomotor response to novelty in (a) bLR and (b) bHR rats. Data represents mean ± SEM of locomotion (total activity, which is the sum of lateral and rearing movements) on post-natal day (PND) 25 (Baseline, n=10 per group) and PND 59 following adolescent (PND 33–39) repeated treatment with cocaine (15 mg/kg, 7 d, n=10) or saline (n=10) for each phenotype. A repeated measures two-way ANOVA with Age (PND 25 vs. PND 59) and Treatment (saline vs. cocaine) as factors showed that there was an overall effect of Age on total locomotion for bLR and bHR rats. At least *p < 0.01 for PND 59 vs. PND 25.

Fig. 3

Adolescent cocaine exposure produces behavioral sensitization in bHR but not bLR rats. Mean ± SEM mm of (a, c) crossover bouts and (c, d) head-waving bouts for bLR (a–b) and bHR (c–d) rats following acute (D1: PND 33) and repeated (D7: PND 39) saline (Sal, n=10) or cocaine treatment (Coc, 15 mg/kg, n=10). Although cocaine treatment increased psychomotor activity as measured by crossover bouts relative to saline controls (on D1 and D7) for both phenotypes, only bHR rats showed evidence of sensitization (ψp < 0.01; Effect of day: D1 vs. D7). ***p < 0.001 and *p < 0.05 as compared to Sal-treated control group.

Fig. 4

Adolescent cocaine exposure does not alter sign-tracking behavior in either bHR or bLR rats, but enhances goal-tracking behavior in adult bLR rats only. Food cup-directed behavior (goal-tracking) and lever-CS directed behavior (sign-tracking) across 14 days (PND 62–75) of Pavlovian conditioning approach training for bLR (a–c) and bHR (d–f) rats treated with cocaine (n=10) or saline (n=10) during adolescence (PND 33–39). Data are expressed as the mean ± SEM of (a, d) the number of contacts, (b, e) the probability of approach and (c, f) the latency of first approach to the lever-CS or the food cup. **p < 0.01 and *p < 0.05 as compared to Sal-treated control group (Linear mixed-effects models followed by Bonferroni post hoc pairwise comparisons).

Fig. 5

(a) Adolescent cocaine exposure reduces the difference in the probability to approach the lever-CS vs. the food cup in bLR rats treated with cocaine (n=10) or saline (n=10) during adolescence (PND 33–39). (b) Adolescent cocaine exposure did not alter the response pattern of bHR rats. Data are expressed as the mean ± SEM probability of approach to the lever-CS minus the probability of approach to the food cup (scale from 0 to −1 or 0 to +1). *p < 0.05 as compared to Sal-treated control group (Student’s t-test). (c) Effect of adolescent treatment (Sal vs. Coc) on response topography (proportion of Cup trials, Lever Trials or None trials) across sessions 1–14 in adult bLR rats (Student’s t-test, p < 0.05, Sal vs. Coc for Cup trials and None trials). (d) Adolescent cocaine exposure did not change the response topography across sessions 1–14 in adult bHR rats.

Fig. 6

Adolescent cocaine exposure reduces hippocampal cell genesis in adult bLR rats. Quantitative analysis of Ki-67+ and BrdU+ cells by area (mm²) in the left dentate gyrus of the hippocampus of bLR (a) and bHR (b) rats expressed as the mean ± SEM of the total number of quantified cells by area. Groups of treatment: Sal (n=10/phenotype) and Coc (n=10/phenotype). *p < 0.05 as compared to bLR-Sal-treated control group (Student’s t-test). Representative IHC of Ki-67+ (left panels, brown labeling in blue granular cell layer) and BrdU+ (right panels, dark brown labeling in light brown granular layer) cell labeling following treatment (Sal vs. Coc) during adolescence (PND 33–39) in bLR (c) and bHR (d) rats. For each treatment group, an image was taken with a light microscope using a 63× objective lens to identify individual cells. Scale bar: 30 µm.