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 towards 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.

Adolescent cocaine exposure enhanced negative affect following drug re-exposure in adult rats: Attenuation of c-Fos activation

“…However, most of the previous studies evaluated drug and/or pro-depressive phenotype effects on cell genesis already in adult rats and did not explore the long-term consequences following an adolescent cocaine experience. In this line of thought, two of our prior studies (García-Cabrerizo et al, 2015; García-Fuster et al, 2017b) evaluated the effects of administering cocaine on hippocampal cell genesis at the same age-window of adolescent vulnerability (PNDs 33–39) used in the present study. Although one study showed deficits in the number of adult-born precursor cells (Ki-67+) and the number of surviving mature cells (49–51 days old BrdU+), these effects were seen only for bred low-responder rats (i.e.…”

“…Although one study showed deficits in the number of adult-born precursor cells (Ki-67+) and the number of surviving mature cells (49–51 days old BrdU+), these effects were seen only for bred low-responder rats (i.e. rats bred for low novelty-induced locomotor activity), as compared with bred high-responders (high novelty-induced locomotion), and were suggested to be attributed to an altered neuroplastic response to learning (García-Fuster et al, 2017b). On the other hand, the other study, which used the same outbred rats as in the present study, showed no changes on neurogenic markers (Ki-67+ proliferating cells and 38 days old BrdU+ surviving cells) following adolescent cocaine exposure (García-Cabrerizo et al, 2015).…”

“…Videos were then analysed to obtain the baseline time spent immobile for each rat on PND 29 (Behavioral Tracker software, CA, USA). Following three days of rest, groups of rats were treated daily for seven days (PNDs 33–39) with saline (0.9% NaCl, 1 mL/kg, i.p., n =21) and cocaine (15 mg/kg, i.p., n =23), as previously described (see García-Cabrerizo et al, 2015 for the specific age-window of adolescent vulnerability; see also García-Fuster et al, 2017b for long-term effects in adulthood following the same experimental procedure in adolescence). This same paradigm of cocaine administration at this specific window of exposure induced behavioural psychomotor sensitization (see Parsegian et al, 2016).…”

Inhibition of a cortico-thalamic circuit attenuates cue-induced reinstatement of drug-seeking behavior in “relapse prone” male rats

“…The Gi DREADD was injected bilaterally into the PrL (relative to bregma: Locomotor test. After 5 days of recovery from surgery, rats underwent a 60-min locomotor test in a novel environment as previously described [51]. Cumulative locomotor movements (vertical and horizontal movements) were calculated and a median split was used to classify rats as either high (HR) or low (LR) responders.…”

Neurobiology of substance use in adolescents and potential therapeutic effects of exercise for prevention and treatment of substance use disorders

“…Lower gray matter volume in the prefrontal cortex, amygdala, and striatum have been observed in heavy chronic marijuana users (Battistella et al, ). Preclinical studies suggest adolescent cocaine exposure impairs hippocampal cell genesis (proliferation and survival) (Garcia‐Fuster, Parsegian, Watson, Akil, & Flagel, ), and adult hippocampal neurogenesis plays a role in cocaine addiction (Castilla‐Ortega et al, ). Further, substantia nigra hyperechogenicity was observed in young adults with a history of illicit stimulant use (cocaine, methamphetamine) who were currently abstinent and, such morphological changes in the substantia nigra, which may alter dopamine levels, are associated with developing Parkinson's disease later in life (Todd et al, ).…”