be physiologically important. Through increasingly mechanistic studies of this 
system, it will be possible to delineate the precise molecular steps by which 
opiates regulate the expression of specific intracellular messenger proteins and, 
as a result, induce aspects of tolerance, dependence, and withdrawal in these 
neurons. 
Regulation by Cocaine. In a series of related experiments, the authors’ 
laboratory has begun to study the effects of acute and chronic cocaine on 
Fos expression in the mesolimbic dopamine system. Hope and Nestler 
(1991) and Hope and colleagues (in press) have replicated the findings of 
other groups (Graybiel et al. 1990; Young et al. 1991) showing that acute 
administration of cocaine (at a dose of 15 mg/kg intraperitoneal [IP]) induces 
Fos mRNA levels in the NAc (figure 6) and the caudate/putamen 45 minutes 
after drug administration (Hope and Nestler 1991 ; Hope et al., in press). 
Moreover, it was shown that acute cocaine elicits a similar induction in mRNA 
levels for Jun and zif. (Zif is a transcription factor that, although binding to a 
distinct response element, is regulated in several circumstances in a fashion 
similar to Fos and Jun.) As systemic administration of cocaine is known to 
inhibit a majority of neurons in the NAc (White et al. 1987), cocaine induction 
of Fos and related transcription factors represents one example, alluded to 
above, where these proteins can be induced in the absence of an increase in 
neuronal activity. One possible mechanism of cocaine action, which can be 
tested directly, is that the drug induces Fos via the indirect activation of D1- 
dopamine receptors and the subsequent activation of the cAMP pathway, 
which also exerts inhibitory effects on these cells electrophysiologically. An 
alternative possibility that the authors do not favor but cannot exclude is that 
cocaine induces Fos in the minority of neurons in the NAc that are activated 
by systemic administration of the drug. 
Chronic administration of cocaine (15 mg/kg IP b.i.d. for 14 days) almost 
completely abolishes the ability of a subsequent acute dose of cocaine 
(administered 18 hours after the previous dose) to induce Fos mRNA levels 
in these two brain regions (figure 6) (Hope and Nestler 1991; Hope et al., in 
press). A similar “desensitization” was observed for the ability of cocaine to 
induce jun and zif 
To further investigate this apparent desensitization, Hope and Nestler (1991) 
and Hope and colleagues (in press) studied acute and chronic regulation of 
AP-1 binding activity in the NAc using the gel shift assay (figure 6). It was 
found that acute cocaine dramatically induces AP-1 binding activity in this 
brain region 2 hours following drug administration, indicating that induction of 
Fos and Jun mRNA is associated with an increase in the functional activity of 
these or related transcription factors. However, chronic cocaine administration 
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