Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences.

L M Depoy,S L Gourley,A G Allen

doi:10.1038/tp.2016.150

Abstract

Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called ‘reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, ‘stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in ‘stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure.

Highlights

Cocaine addiction is characterized by maladaptive decisionmaking and a loss of control over drug consumption; these changes may reflect the combination of preexisting behavioral characteristics and the effects of repeated drug exposure on prefrontal cortical neurobiology that further exacerbate disease psychopathology.[1,2]
Adolescents are vulnerable to drugs of abuse—for example, adolescence is characterized by both high rates of experimental drug use and heightened susceptibility to the development of dependence.[3,4]
We focused on dendritic spines within the prefrontal cortex, so-called ‘reward seeking’ following abstinence, and the development of habit-like response strategies, considered an etiological factor in the maintenance of drug seeking in cocaine-abusing individuals.[2]

Summary

INTRODUCTION

Cocaine addiction is characterized by maladaptive decisionmaking and a loss of control over drug consumption; these changes may reflect the combination of preexisting behavioral characteristics and the effects of repeated drug exposure on prefrontal cortical neurobiology that further exacerbate disease psychopathology.[1,2] Adolescents are vulnerable to drugs of abuse—for example, adolescence is characterized by both high rates of experimental drug use and heightened susceptibility to the development of dependence.[3,4] Adolescentemergent drug use is associated with increased likelihood of abuse and dependence in adulthood, as well as decreased likelihood of seeking treatment.[5,6] a better understanding of the effects of adolescent cocaine exposure on prefrontal cortical-dependent decision-making is critical In both humans and rodents, adolescents and adults appear to be differentially sensitive to cocaine,[7] but investigations into the long-term consequences of adolescent drug exposure are lacking. The mice with a history of adolescent cocaine self-administration (7.5 μg ml − 1) were placed in the chambers in which they had originally

MATERIALS AND METHODS

RESULTS

Findings

CONFLICT OF INTEREST