1990). The second level is at the cell nucleus and involves transcriptional 
mechanisms. Recently, a group of trans - acting factors that mediate down- 
regulation of c -fos transcription had been elucidated. One of these, called 
CREM (cAMP response element modulator), can act as an inhibitory 
modulator of cAMP-induced activation of c -fos gene expression (Foulkes 
et al. 1991a, 1991b). Thus, we propose that sequential activation of CREB 
followed by CREM forms the basis of the induction and suppression of c -fos 
expression following cocaine injection. Obviously, receptor desensitization 
and transcriptional modulation can act in combination to cause IEG 
suppression. Our data suggest that the suppression of IEG expression is a 
powerful regulatory mechanism governing the production of protein from this 
class of genes expression. The fact that, with repeated drug administration, 
the suppression mechanism(s) override the induction process reinforces the 
premium that the cell places on regulation of IEG expression. IEG expression 
is allowed to reach only a certain degree and duration before it is actively 
inhibited. Thus, the effective and prolonged suppression of IEG expression 
seen with repeated cocaine administration may be viewed as providing a 
protective or homeostatic function. 
It is interesting to speculate on the meaning of some of these phenomena the 
authors have observed with cocaine administration. The data illuminate both 
the normal functioning of the dopaminergic system and its abnormal functioning 
subsequent to cocaine abuse. Normal dopaminergic functioning probably 
involves intermittent activation of c -fos and modulation of NGFI-A expression 
either up or down from the basal state of expression. In humans this may 
serve to couple positively rewarding or pleasurable stimuli to modifications in 
gene expression. Since cocaine is one of the most rewarding drugs in animal 
self-administration studies, it is tempting to suggest a relationship between 
psychological processes such as behavior modification with positive reinforcers 
and dopaminergic control of gene expression. C -fos, acting in concert with 
other transcription factors, constitutes a molecular interface between behavioral 
and environmental cues and gene regulation, whereby the lEGs integrate the 
various inputs received at the cell membrane into a coherent alteration in 
gene expression. The triggering stimulus may only briefly influence 
neurotransmission (e.g., cell depolarization, transmitter release) but may 
yield more permanent changes in neuronal biochemistry and function. A single 
intravenous injection of cocaine causing a brief “rush” fits this model very well. 
Subsequent regulation of target genes such as the dopamine D1 receptor or the 
preprotachykinin gene, both of which have AP-1 consensus elements in their 
promoter region, could lead to more permanent changes in neuronal function. 
Obviously, optimal changes in target gene expression depend on the rate of 
presentation and the intensity of the reinforcing cues to provide the optimal 
amount and duration of IEG expression. Too great an intensity at too frequent 
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