As discussed in the introduction, CREB proteins are generally thought to be 
constitutively expressed in neurons, with their transcriptional activity regulated 
primarily via their phosphorylation by cAMP- or calcium-dependent protein 
kinases. According to the scheme shown in figure 3, opiates in the LC, via 
their initial effects on the cAMP pathway (via inhibition of adenylate cyclase) 
(Duman et al. 1988) or calcium pathway (via inhibition of neuronal firing) 
(Aghajanian 1978; Christie et al. 1987), could lead to decreases in the 
phosphorylation state of CREB and to subsequent changes in gene expression. 
Because this mechanism involves the regulation of a transcription factor that is 
already present in the neurons, it could begin to occur very rapidly (i.e., within 
minutes). The specificity for opiate action in this scheme would reside in (1) 
the presence of opiate receptors, (2) the ability of the activated receptors to 
regulate the cAMP and calcium pathways, and (3) the particular genes 
accessible to CREB, in a given neuronal cell type. 
In contrast to CREB, the Fos/Jun family of transcription factors tends to be 
expressed at low levels in neurons under basal conditions. In response to 
diverse types of extracellular signals, high levels of expression of these 
transcription factors are induced via increases in rates of transcription and 
mRNA translation (for review, see Morgan and Curran 1991). It appears that 
phosphorylation of CREB, or a CREB-like protein, by cAMP- or calcium- 
dependent protein kinases mediates the effects of such extracellular signals 
on Fos expression (Sheng et al. 1990); similar mechanisms may underlie the 
regulation of the other transcription factors in the Fos/Jun family. Thus, 
regulation of Fos and Fos-like transcription factors represents an additional 
mechanism by which opiates could regulate the expression of other genes via 
alterations in the cAMP or calcium systems (figure 3). Because this mechanism 
requires protein synthesis, it is slower than the first mechanism described 
above, with earliest changes in Fos/Jun target gene expression expected 
perhaps 30 to 60 minutes following the initial stimulus. 
The two regulatory schemes presented in figure 3 represent a first attempt to 
explain the actions of opiates on gene expression in the LC and other target 
neurons. As more is learned about the regulation of the CREB, Fos/Jun, and 
other families of transcription factors, more complete hypotheses can be 
formulated to account for the actions of opiates, cocaine, and other drugs of 
abuse on neural gene expression. 
Regulation of Specific Transcription Factors by Drugs of Abuse 
Regulation by Opiates. As an initial attempt to study the transcription 
factors that mediate opiate action in the LC, Hayward and colleagues (1990) 
studied regulation of Fos expression in response to acute and chronic opiate 
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