Differential Regulation of the Period Genes in Striatal Regions following Cocaine Exposure

Edgardo Falcon,Angela Ozburn,Colleen A Mcclung,Kole Roybal,Shibani Mukherjee,Xiaoxi Zhuang

doi:10.1371/journal.pone.0066438

Abstract

Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (Npas2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2.

Highlights

Drug addiction is associated with major disruptions in circadian rhythms
Expression levels of Clock and Brain and Muscle ARNT-like protein 1 (Bmal1) were not significantly altered by cocaine in these regions following these treatment paradigms (Figure 1). These results suggest that chronic cocaine treatment selectively affects the expression of Neuronal PAS Domain Protein 2 (Npas2) in striatal regions
The Period genes are differentially induced by cocaine in striatal regions Both NPAS2 and CLOCK regulate the expression of the Per genes (Per1and 2) and Cry genes (Cry1 and 2) [19,28]

Summary

Introduction

Drug addiction is associated with major disruptions in circadian rhythms. For example, drug addicts are commonly reported to have disruptions in their sleep/wake cycle, activity cycles, eating habits, as well as, blood pressure, hormone secretion and body temperature rhythms [1,2]. A study by Lynch et al found that seven days of cocaine self-administration lead to a significant upregulation of a number of circadian and circadian-associated genes in the dorsal striatum, including Clock, Brain and Muscle ARNT-like protein 1 (Bmal1), Per, and Cryptochrome (Cry1), among others [9]. These studies suggest that psychostimulants have selective effects on the expression of these genes in striatal regions. It is important to examine the expression of these genes throughout a 24 hour period in order to distinguish changes in rhythm amplitude or phase from specific drug-induced timepoint-dependent effects

Methods

Results

Conclusion