Quantitative Mapping of Cocaine-Induced ΔFosB Expression in the Striatum of Male and Female Rats

Satoru M Sato,Anne Marie Wissman,Catherine S Woolley,Andrew F Mccollum,Fabien Tell

doi:10.1371/journal.pone.0021783

Abstract

ΔFosB plays a critical role in drug-induced long-term changes in the brain. In the current study, we evaluated locomotor activity in male and female rats treated with saline or cocaine for 2 weeks and quantitatively mapped ΔFosB expression in the dorsal striatum and nucleus accumbens of each animal by using an anti-FosB antibody that recognizes ΔFosB isoforms preferentially. Behavioral analysis showed that while there was little difference between males and females that sensitized to cocaine, nonsensitizing rats showed a large sex difference. Nonsensitizing males showed low behavioral activation in response to cocaine on the first day of treatment, and their activity remained low. In contrast, nonsensitizing females showed high activation on the first day of treatment and their activity remained high. Western blot and immunohistochemical analyses indicated that basal levels of ΔFosB were higher in the nucleus accumbens than the dorsal striatum, but that the effect of cocaine on ΔFosB was greater in the dorsal striatum. Immunostaining showed that the effect of cocaine in both the dorsal striatum and nucleus accumbens was primarily to increase the intensity of ΔFosB immunoreactivity in individual neurons, rather than to increase the number of cells that express ΔFosB. Detailed mapping of ΔFosB-labeled nuclei showed that basal ΔFosB levels were highest in the medial portion of the dorsal striatum and dorsomedial accumbens, particularly adjacent to the lateral ventricle, whereas the cocaine-induced increase in ΔFosB was most pronounced in the lateral dorsal striatum, where basal ΔFosB expression was lowest. Sex differences in ΔFosB expression were small and independent of cocaine treatment. We discuss implications of the sex difference in locomotor activation and regionally-specific ΔFosB induction by cocaine.

Highlights

Drug abuse gives rise to long-term changes in brain function
Upon the initial injection (D1), locomotor activity was significantly greater in cocaine- than saline-treated rats; responses to cocaine increased during the first week and remained high during the second week (Wk2: F1,56 = 171.5, p,0.001)
Averaged across the treatment period, cocaine-treated females showed significantly more locomotor activity than cocaine-treated males, while no sex difference was observed in saline-treated rats

Summary

Introduction

DFosB, a truncated and long-lasting form of the immediate-early gene FosB, has been studied extensively as a mediator of long-term structural and functional changes within the reward circuitry of the brain, especially in response to psychostimulants [1]. The nucleus accumbens is further divided into core and shell, based on chemorachitecture [5,6,7] and function [8]. Striatonigral MSNs express D1 dopamine receptors, Substance P and dynorphin (Dyn), whereas striatopallidal cells express mostly D2 receptors and enkephalin. These classes of MSNs are largely distinct in the dorsal striatum [10,11], but less so in the NAc [12]. DFosB accumulation varies subregionally with different drugs [15] and over time during the course of drug administration and withdrawal [13]

Methods

Results

Discussion

Conclusion