(for analysis of Fos mRNA levels) or 2.5 hours (for analysis of AP- 
1 binding activity) after their last injection on day 15. A: Levels 
of Fos mRNA in the NAc of control and treated rats analyzed by 
Northern blotting. B: Levels of AP-1 binding activity in the NAc 
of control and treated rats analyzed by gel shift assays. Data 
represent means±SEM (n=4 to 8). 
SOURCE: Data from Hope and Nestler 1991; Hope et al., in press 
appears to produce a persistent increase in AP-1 binding activity in the NAc: 
Levels of AP-1 binding are elevated 18 hours after the last chronic dose of 
cocaine whether or not an additional acute dose is administered. These 
observations indicate that chronic cocaine leads to a persistent increase in 
Fos- and/or Jun-like proteins. 
If confirmed, these findings suggest that chronic cocaine produces a gradual 
change in the protein composition of the AP-1 complex in NAc neurons. 
For example, chronic cocaine not only could produce a desensitization to 
Fos responsiveness but also a concomitant accumulation of various Fos- or 
Jun-related transcription factors. Such a change in the composition of the 
AP-1 complex could alter its transcriptional activity and/or specificity (e.g., 
see Ryseck and Bravo 1991) and thereby lead to some of the changes in gene 
expression seen in response to chronic cocaine in this brain region. In other 
words, such a change in the composition of the AP-1 complex could represent 
a “molecular switch” underlying some of the chronic actions of cocaine (Hope 
et al., in press). To test this possibility directly, it will be necessary to develop 
antibodies that distinguish the numerous individual members of the Fos and 
Jun family in immunocytochemical and immunoblotting studies. The 
immunocytochemical studies offer the additional possibility of identifying 
subsets of NAc and striatal neurons that exhibit differential immediate early 
gene responses to acute and chronic cocaine administration. 
As a first attempt to identify the specific proteins that account for the increased 
AP-1 binding activity observed under acute and chronic cocaine treatments, 
levels of Fos and Jun protein in the NAc by immunocytochemical techniques 
are now being studied in collaboration with Drs. Barry Kosofsky and Steven 
Hyman at Harvard. Acute cocaine treatment induces a dramatic increase in 
levels of Fos-like immunoreactivity, as seen for Fos mRNA, in the NAc and 
caudate/putamen. However, similar to the observations with northern blotting, 
preliminary evidence suggests that chronic cocaine decreases the inducibility 
of Fos-like immunoreactivity (Hope et al., in press). In the striatum, this 
desensitization in Fos induction shows an interesting medial to lateral gradiant 
109 
