1 to 2 hours and then disappears by about 4 hours postseizure. Although AP-1- 
like DNA-binding activity rises during the first hour after seizure, as would be 
expected, the levels remain elevated for at least 8 hours, despite the absence 
of Fos. This additional AP-1 activity is contributed by a series of inducible Fos- 
related proteins that appear with a delay following seizure and disappear with a 
slower kinetic (Sonnenberg et al. 1989a). This means that AP-1 complexes 
have a dynamic composition over time and suggests that the CIE gene 
response is part of a temporally regulated program that may span many hours 
following even a brief stimulus. The precise functional significance of the 
different AP-1 complexes is not known at present; however, it may provide 
a way of targeting the expression of different sets of genes over time or 
sequentially inducing and repressing a set of genes (reviewed in Morgan 
and Curran 1989). 
FOS MAPPING STUDIES OF DRUGS OF ABUSE 
These considerations have resulted in the widespread use of Fos 
immunohistochemistry as a mapping technique to identify the pathways and 
cells involved in particular responses in vivo (reviewed in Morgan and Curran 
1991a). It has even been proposed that Fos immunohistochemistry provides a 
form of activity map analogous to that obtained with 2-deoxyglucose (Sagar et 
al. 1988; Morgan and Curran 1991a). Of particular relevance has been the 
application of Fos mapping to the study of drugs of abuse. Here, the general 
concept has been that drug dependence, a long-term phenomenon, is elicited 
by repetitive administration of a stimulus (the drug) and in some senses is 
analogous to learning (i.e., do drugs of abuse induce a CIE response and could 
CIE gene products be involved in the establishment of the dependent state?). 
Morphine Regulation of C -fos 
Acute administration of morphine induces Fos-like immunoreactivity (FLI) in 
the caudate putamen of rat (Chang et al. 1988), a region rich in pi-type opiate 
receptors. In addition, FLI can be detected in the ventromedial nucleus of 
the hypothalamus (Chang and Harlan 1990); in contrast to the caudate, the 
hypothalamus contains predominantly K-type opiate receptors and few ^i-type 
receptors (Mansour et al. 1987). Thus, both classes of opiate receptors may 
be capable of transducing signals that can induce c -fos. Another morphine- 
sensitive brain structure, the locus coeruleus (LC), does not respond to acute 
administration of morphine with an induction of c -fos. This is not surprising 
since morphine depresses the firing rate of neurons in LC (Aghajanian 1978). 
However, during chronic morphine treatment, firing rates in LC recover to 
normal levels; whereafter, abrupt cessation of morphine or administration of 
naloxone precipitates a withdrawal, and firing rates increase severalfold above 
43 
