t± 
30' 
t2t2f2ft 
6 hr 30' 
FIGURE 14. Multiple dosage regimen used to obtain suppression. Rats were 
injected IP with a single dose of cocaine 30 mg/kg or with four 
successive doses at 2-hour intervals. In both cases animals 
were sacrificed 30 minutes after the last dose of cocaine. We 
refer to the four successive injections as subchronic treatment. 
The interplay between the induction and suppression mechanisms is 
shown diagramatically in figure 18. In the acute situation activation of the 
induction mechanism (shown by the upward deflection) is followed very 
shortly by actuation of the suppression mechanism. The temporal kinetics 
of the two are different: The induction is potent and short lasting, whereas the 
suppression process has a longer time course, somewhat similar conceptually 
to an action potential followed by a recurrent inhibitory postsynaptic potential. 
The cumulation of the inhibition with repeated injections is shown in figure 18. 
Here the induction process is eventually overwhelmed by the suppression, 
which becomes progressively greater with each injection. The effects of the 
suppression slowly reverse over the next several days, but complete recovery 
is not achieved until 4 days postinjection. 
DISCUSSION 
The data presented show that cocaine induces a dual abnormality in 
dopaminergic regulation of IEG expression. First, an acute injection induces 
a large increase in c -fos gene expression. Second, a suppression mechanism 
is induced, which renders the system refractory to induction by a subsequent 
system. This period of refractoriness or suppression is variable and depends 
on the frequency and number of multiple injections. Also, categorizing these 
effects as “abnormalities” may be conceptually misleading. Since cocaine 
blocks dopamine reuptake, it may be more accurate to think of cocaine as 
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