FIGURE 1 8. Diagrammatic representation of the induction and suppression 
ofc-fos expression by repeated cocaine injections. The 
induction process is triggered by excess dopamine at the 
synapse secondary to blockade of reuptake by cocaine. 
The effect is mediated by D1 receptors positively linked 
to adenylate cyclase. This effect is transient but is 
accompanied by a concurrent activation of the suppression 
process. The mechanism(s) of suppression are not presently 
known but appear to taper off slowly. The suppression 
cumulates markedly with repeated cocaine administration, 
thereby resulting in a prolonged uncoupling of dopaminergic 
gene regulation from dopaminergic neurotransmission. 
Pretreatment with antagonists of the D1 and D2 subtypes of dopamine 
receptors demonstrated that the c -fos induction in response to cocaine was 
blocked by the D1 antagonist. The D1 receptor is linked in a positive fashion to 
adenylate cyclase, which suggests that c -fos gene expression is activated by a 
cAMP-dependent process. In support of this, many in vitro studies have shown 
that c ^os expression can be activated by stimulation of the cAMP second- 
messenger system (for review, see Montminy et al. 1990). Furthermore, one 
or more cAMP-responsive c/'s-acting elements are present in the promoter of 
the c -fos gene. In these studies, sequences at -60 in the c -fos promoter confer 
cAMP-dependent inducibility on a c -fos promoter-reporter construct in transient 
expression assays (Sassone-Corsi et al. 1988). Deletions or mutations in the 
cAMP response element (CRE) at -60 eliminate cAMP responsiveness in the 
transient expression assay. The CRE is a binding site for a transcription factor 
called CREB (Hoeffler et al. 1988), which is a member of the activating 
transcription factor (ATF) family of leucine zipper trans- acting factors (Hai et al. 
205 
