Regulation of Neural Gene Expression 
in Opiate and Cocaine Addiction 
Eric J. Nestler, Clare M. Bergson, Xavier Gultart, and 
Bruce T. Hope 
INTRODUCTION 
Although some aspects of drug addiction can occur relatively rapidly in 
response to acute administration of a drug of abuse, most changes in brain 
function associated with addiction occur gradually over time in response to 
prolonged drug exposure. These gradually developing changes can persist for 
days, sometimes much longer, after cessation of chronic drug administration. 
The prominence of such delayed, progressively developing, and persistent 
adaptations in brain function during drug addiction suggests that long-term 
changes in neuronal gene expression are likely to be important in mediating 
addictive phenomena. 
Mechanisms Regulating Gene Expression 
It is increasingly apparent that the processes controlling the expression of 
neural genes, even in the fully differentiated adult brain, are extraordinarily 
complex. However, in recent years, much has been learned about the 
molecular mechanisms that control the expression of specific genes in the 
central nervous system (CNS). Attention has focused primarily on a class 
of DNA-binding proteins, termed “transcription factors," that bind to specific 
sequences of DNA (response elements) in the regulatory regions of certain 
genes and thereby increase or decrease the rate at which those genes are 
transcribed (for review, see Mitchell and Tjian 1989; Goodman 1990; Montminy 
et al. 1990; Morgan and Curran 1991). The mechanism for this transcriptional 
activation/repression is not fully understood but likely involves direct or indirect 
interactions of transcription factors with the RNA polymerase II transcriptional 
complex (Ptashne and Gann 1990). 
A large and increasing number of transcription factors are known, and these 
exhibit distinct structural, functional, and regulatory properties. A list of some 
prominent classes of transcription factors in the CNS is shown in table 1 . 
Based on the few neural genes that have been characterized to date, it would 
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