CNS development requires a complex coordination of genetic factors 
and environmental forces that direct brain maturation and shape infant 
development in a reproduceable, yet individualized manner. The cellular 
events underlying these processes require differential gene transcription. 
The authors hypothesize that the toxic developmental effects of substances 
of abuse may be mediated via perturbations of normal patterns of gene 
expression. To address this question, we have conducted experiments in 
an animal model, exposing developing rat brain to cocaine, permitting 
identification and characterization of some of the earliest cellular events 
(and targets) mediating drug effects. This analysis focuses on a class of 
immediate early genes (lEGs) that act as transcription factors (lEGs c-fos, 
c-jun, and zif 268) that may subserve one mechanism by which substances 
of abuse alter genetic programs during development. 
IMMEDIATE EARLY GENES 
The molecular mechanisms underlying the neuronal response to cocaine 
exposure remain elusive. Recently, I EG response has been used as a 
marker of neuronal activation in various CNS stimulation paradigms, including 
models of seizure (Morgan et al. 1987; Sonnenberg et al. 1989), nociceptive 
stimulation (Draisci and ladarola 1989; Naranjo et al. 1991), and circadian 
neurobiology (Aronin et al. 1990). lEGs are called proto-oncogenes because 
they represent the normal cellular homologues of transforming viral oncogenes 
(Morgan and Curran 1991). Nuclear proto-oncogenes function in cellular signal 
transduction as transcription factors binding to the promoters of target genes, 
thereby influencing transcription of specific gene products. Drug-induced 
alterations in IEG expression can modify gene expression during development 
and thereby alter cellular identity and neuronal repertoire. The lEGs c -fos, 
c-jun, and zif/26 8 are of particular interest because they demonstrate rapid 
and dramatic induction in specific brain areas of adult rats exposed to cocaine 
or amphetamine (see other chapters in this volume). In most cell types, basal 
levels of c -fos and c-jun mRNA and of c-Fos and c-Jun protein are relatively 
low (Morgan and Curran 1991). In contrast, certain cells maintain relatively 
high basal levels of zif ! 268 mRNA and Zif/268 protein (Worley et al. 1991). 
The induction of c -fos, c-jun, and zif / 268 in response to novel stimuli in 
neurons follows a similar pattern; mRNA transcription occurs within 5 minutes 
and continues for approximately 20 minutes, with peak steady-state mRNA 
levels at 30 to 45 minutes and peak protein synthesis at about 2 hours 
poststimulation (not shown). 
162 
