1989). Thus, a likely scenario for c -fos induction, and possibly induction of 
other lEGs, by cocaine might be as follows: Cocaine enhances dopaminergic 
activity via blockade of reuptake, thereby activating dopamine receptors. 
Activation of the D1 receptor increases intracellular cAMP and the activity 
of protein kinase A, which then phosphorylates susceptible substrates, one 
of which may be CREB or another member of the ATF family. These in 
turn rapidly act as positive regulators of c-fos gene expression via the c -fos 
CRE sites. CREB is known to be phosphorylated by protein kinase A, and 
phosphorylation affects the binding of CREB to the CRE in in vitro binding 
assays (for review, see Montminy et al. 1990). Furthermore, CREB is 
constitutively expressed, suggesting that no new protein synthesis is required 
for the increase in c -fos gene expression. The latter conclusion is supported 
by the authors’ data showing that the increase in c -fos mRNA still occurs in 
the presence of a high degree of protein synthesis inhibition produced by 
anisomycin. 
GBR-12909, a cocaine analog without the susceptible ester bond found in 
cocaine, was also able to rapidly induce c -fos mRNA and Fos-immunoreactive 
proteins. Both compounds increased c-fos gene expression. Thus, by 
biochemical criteria they appear similar; however, the duration of action is 
longer for GBR-1 2909. This is exemplified by the duration of behavioral 
activation. Intraperitoneal injection of GBR-12909 at 30 mg/kg produced an 
intense stereotypy that lasted for at least 60 minutes. This is nearly four times 
longer than the increase in locomotor activity produced by an equal dose 
of cocaine. Although we did not formally analyze it, GBR produced more 
stereotypy, such as intense sniffing directed at the hole for the water spout in 
the cage, rather than locomotion. In comparison, cocaine produced stereotypic 
head movements, but at most doses they were superimposed on an increase 
in locomotion. Regardless of the behavioral differences, we observed an 
abundant elevation in c -fos immunoreactivity throughout the striatum, nucleus 
accumbens, olfactory tubercle, and islands of Calleja. The accumbens, in 
particular, has been implicated in the reinforcing properties of cocaine (see 
Kuhar et al. 1991 for review and Hope et al. 1992). 
Several lines of evidence suggest cAMP-dependent mechanisms mediate 
the increase in c -fos expression seen with cocaine. Fewer data are available 
concerning the mechanisms underlying the suppression or refractoriness to 
induction seen with multiple cocaine injections. We speculate that suppression 
can be achieved at two levels of cellular organization. The first level is at the 
plasma membrane and involves receptor desensitization. In vitro studies 
with cells exposed to D1 agonists have shown acute and more prolonged 
desensitization depending on the duration of exposure to agonists of the D1 
receptor in cells that express the D1 receptor naturally (Barton and Sibley 
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