can be regulated by their binding to other molecules. An example of this would 
be inhibitory variants of transcription factors that do not bind DNA but rather 
dimerize with the active, DNA-binding forms of the protein and thereby inhibit 
their transcriptional activity. Such variant forms appear to exist for most 
transcription factors, including Fos/Jun and CREB (Yen et al. 1991; Foulkes 
et al. 1991). Fourth, the levels of transcription factors in the nucleus can be 
regulated by altering the rate at which they are translocated from the cytoplasm 
(where they are synthesized) to the nucleus. The prototypical example of this 
are the steroid hormone receptors, which are normally cytoplasmic proteins 
that, on binding their specific hormone, translocate into the nucleus where they 
act as transcription factors (Evans and Arriza 1989). These four mechanisms 
are not mutually exclusive; most transcription factors are probably regulated by 
more than one of them. This is illustrated by the steroid hormone receptors, 
which are regulated not only by hormone binding and nuclear translocation 
but also by their phosphorylation by several types of protein kinases and by 
regulation of their total amount (e.g., Evans and Arriza 1989; Hoeck et al. 1989; 
Denner et al. 1990). 
A Strategy To Identify Changes In Gene Expression That Underlie Drug 
Addiction 
The complexity of genetic regulatory mechanisms suggests that the complete 
identification of the precise steps by which drugs of abuse alter gene 
expression in the brain to produce addiction is an extremely difficult task. 
In an attempt to overcome these obstacles, the authors’ laboratory has 
followed a particular strategy to begin to understand this process. This 
strategy, summarized in the list below, involves the study of anatomically 
well-defined, discrete brain regions where behavioral pharmacological 
studies have indicated an important role in addictive behaviors and where 
*lectrophysiological studies have identified some functional changes in 
specific neurons that underlie the addictive behaviors. In this context, 
researchers at the authors’ laboratory have set out first to identify the 
specific proteins whose altered expression may underlie the functional 
changes observed electrophysiologically. These target proteins are then 
used to study the genetic mechanisms underlying their altered expression. 
The advantage of this strategy is that it focuses biochemical and molecular 
studies on phenomena that are directly relevant to drug addiction. The strategy 
for establishing the role of transcription factors in drug addiction is as follows: 
1 . Identify proteins whose altered levels of expression contribute to functional 
aspects of drug addiction in identified neuronal cell types. 
2. Study drug regulation of candidate transcription factors that could be 
involved. 
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