horn neurons following transsynaptic activation during peripheral inflammation 
(ladarola et al. 1 986, 1 988b). The dynorphin gene codes for the protein 
precursor of the dynorphin family of opioid peptides. In an initial attempt 
to understand the transcriptional processes regulating dynorphin gene 
expression, our attention was drawn to c -fos. Fos-immunoreactivity was 
shown to be rapidly induced by nociceptive stimuli in the same regions of the 
spinal cord as was dynorphin (Hunt et al. 1987). The authors’ laboratory 
showed that an increase in dynorphin gene expression was preceded by an 
increase in c -fos mRNA (Draisci and ladarola 1989) and its protein product 
Fos, as well as several other Fos-immunoreactive proteins seen in Western 
blots of spinal cord nuclear extracts (ladarola et al. 1989). Furthermore, we 
also showed that both Fos-immunoreactive proteins and dynorphin peptide 
immunoreactivity or preprodynorphin mRNA were colocalized within the 
same spinal cord dorsal horn neurons (Noguchi et a!. 1991). Given this 
suggestive, albeit circumstantial, evidence, the authors and colleagues 
hypothesized that Fos, a known transcription factor, might be involved in the 
regulation of dynorphin gene expression. These data provided the basis for 
our prediction (Young et al. 1991) that, in striatum, the increase in prodynorphin 
gene expression seen following dopaminergic activation (Li et al. 1988; Sivam 
1989; Gerfen et al. 1991) would be preceded by an increase in c-fos expression 
(despite the disparate location and innervation of the two CNS regions). We 
observed that a single injection of cocaine induced a rapid (within 30 minutes), 
fivefold to eightfold elevation in striatal c -fos mRNA. GBR-12909, a longer 
acting dopaminergic uptake blocker, also increased c -fos mRNA and striatal 
Fos protein content. Similarly, but to a proportionately lesser extent, expression 
of the NGFI-A gene (Milbrandt 1987), which encodes a zinc finger-containing 
transcription factor, is elevated following cocaine injection. 
Single-dose studies are undeniably informative but do not provide an accurate 
model of human cocaine use in addicts (Gawin and Ellinwood 1988; Gawin 
1991; Spotts and Schontz 1980). These individuals generally administer 
cocaine by intravenous injection or by smoking “crack,” a preparation of the 
free base form of cocaine. Both routes of administration provide nearly 
equivalent blood levels (Foltin and Fischman 1991) and yield a rapid-onset 
euphoria — of relatively short duration (less than 10 minutes) but very intense — 
called a “rush” or “flash” (see case studies in Spotts and Shontz 1980). The 
cocaine user administers the drug multiple times over the course of a drug use 
session (during an evening or longer, up to several days in some cases) to 
experience the rush numerous times. Although this is a very characteristic 
human usage pattern, neurochemical or molecular studies of the effects of 
cocaine in animals generally do not try to model this pattern. The authors 
have employed a multiple administration schedule as a first approximation 
for the multiple administrations seen in human cocaine abuse. We find that 
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