Cocaine Withdrawal Causes Delayed Dysregulation of Stress Genes in the Hippocampus

M Julia García-Fuster,Huda Akil,Shelly B Flagel,S Taha Mahmood,Stanley J Watson,David A Slattery

doi:10.1371/journal.pone.0042092

Abstract

Relapse, even following an extended period of withdrawal, is a major challenge in substance abuse management. Delayed neurobiological effects of the drug during prolonged withdrawal likely contribute to sustained vulnerability to relapse. Stress is a major trigger of relapse, and the hippocampus regulates the magnitude and duration of stress responses. Recent work has implicated hippocampal plasticity in various aspects of substance abuse. We asked whether changes in stress regulatory mechanisms in the hippocampus may participate in the neuroadaptations that occur during prolonged withdrawal. We therefore examined changes in the rat stress system during the course of withdrawal from extended daily access (5-hours) of cocaine self-administration, an animal model of addiction. Tissue was collected at 1, 14 and 28 days of withdrawal. Plasma corticosterone levels were determined and corticosteroid receptors (GR, MR, MR/GR mRNA ratios) and expression of other stress-related molecules (HSP90AA1 and HSP90AB1 mRNA) were measured in hippocampal subfields using in situ hybridization. Results showed a delayed emergence of dysregulation of stress genes in the posterior hippocampus following 28 days of cocaine withdrawal. This included increased GR mRNA in DG and CA3, increased MR and HSP90AA1 mRNA in DG, and decreased MR/GR mRNA ratio in DG and CA1. Corticosterone levels progressively decreased during the course of withdrawal, were normalized following 28 days of withdrawal, and were correlated negatively with GR and positively with MR/GR mRNA ratio in DG. These results suggest a role for the posterior hippocampus in the neuroadaptations that occur during prolonged withdrawal, and point to a signaling partner of GR, HSP90AA1, as a novel dysregulated target during cocaine withdrawal. These delayed neurobiological effects of extended cocaine exposure likely contribute to sustained vulnerability to relapse.

Highlights

Cocaine withdrawal has been associated with negative emotional states such as elevations in brain reward thresholds and increases in anxiety-like behavior and depressive-like states
Basal CORT There was a significant effect of group (ND vs. LgA; F1,31 = 6.956, p,0.05), withdrawal time-point (Day 1–14–28; F2,31 = 6.079, p,0.01), and a group x time-point interaction (F2,31 = 3.564, p,0.05) for CORT levels
Anatomical level was taken into consideration at Day 1 and Day 14 of withdrawal and there were no significant group differences observed, there was evidence for increased glucocorticoid receptors (GR) mRNA in posterior DG at Day 14. These results indicate a progressive increase in GR mRNA in posterior DG during the course of cocaine withdrawal

Summary

Introduction

Cocaine withdrawal has been associated with negative emotional states such as elevations in brain reward thresholds and increases in anxiety-like behavior and depressive-like states (reviewed in [1]). Identifying key substrates for such negative emotional states will help ascertain the underlying neurobiology of cocaine withdrawal. The long-lasting molecular neural adaptations within the mesolimbic dopamine system [2] induced by chronic cocaine selfadministration (SA) and subsequent withdrawal are thought to underlie cocaine addiction and contribute to sustained vulnerability to relapse [3,4,5]. Emerging evidence has broadened our view of the neural substrates implicated in addiction beyond that of the mesolimbic reward system, showing drug-induced neuroplastic changes outside of the classical dopamine circuitry [6]. We have shown drug-induced alterations in hippocampal gene expression [9] and phenotypic differences in adult hippocampal neurogenesis in rats that are more or less prone to addictive behavior [10]

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