haloperidol increases striatal proenkephalin gene expression as determined 
by an elevation in striatal content of proenkephalin-derived peptides (Hong 
et al. 1978) and preproenkephalin mRNA (Tang et al. 1983). Furthermore, 
the increase in preproenkephalin gene expression seen in animals appears 
to apply also to humans. Examination of proenkephalin-derived peptides in 
cerebrospinal fluid (CSF) of human subjects treated chronically with haloperidol 
shows that they are significantly elevated (ladarola et al. 1988a), suggesting 
that the increase seen in striatal tissue in animals is reflected in an increase 
in CSF content in humans. The relevance of the striatum to CSF peptides is 
also supported by the observation of decreased CSF levels following striatal 
lesions (ladarola and Mouradian 1989). In humans, acute and, in some 
cases, permanent changes in behavior (e.g., parkinsonian-like side effects 
and tardive dyskinesia, respectively) can occur following antipsychotic drug 
therapy. Although a causal relationship between the increase in enkephalin 
biosynthesis and the development of parkinsonian-like side effects has not 
been established, the example illustrates that (1) chronic drug treatment can 
modify neuronal gene expression and (2) results obtained in dopaminergic 
neural circuits in animals may be applicable to humans. Thus, molecular 
studies of the dopamine system and the effects of cocaine in animal models 
may be particularly relevant to the human situation. 
Generally, an increase in mRNA content reflects a change in gene transcription 
and/or a modification of mRNA stability. Gene transcription is regulated, in part, 
by interactions of sequence-specific DNA-binding proteins (trans - acting factors 
or transcription factors) with binding sites on DNA (c/s- acting elements or 
enhancer). It has recently been hypothesized that one class of transcription 
factors, called cellular immediate early genes (lEGs), serves to couple synaptic 
transmission at the plasma membrane to alterations in transcription in the cell 
nucleus (for review, see Morgan and Curran 1991). It is hypothesized that 
signals transduced by receptors, via second messengers, initially activate 
transcription and translation of lEGs, which then translocate to the nucleus, 
acting there as “third messengers” to modify the expression of a set or network 
of secondary target genes. Thus, these genes may represent a requisite first 
step in long-term modification of neuronal function. In vivo and in vitro 
experiments have demonstrated that expression of lEGs is very malleable. 
Expression of c-fos, the prototypical I EG, can be altered by several types of 
highly specific stimuli in several different neuronal circuits (see other chapters, 
this volume). 
Initial experiments in spinal cord (Draisci and ladarola 1989) with c -fos and the 
prodynorphin opioid peptide gene first suggested that dopamine might be an 
activator of c -fos gene expression in striatum. In the spinal cord, a marked, 
prolonged increase in prodynorphin gene expression was observed in dorsal 
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