colleagues (1991). In addition to the c-fosand c -jun induction, there is strong 
induction of the zinc-finger gene A/GF/-A (z/7/268, egr- 1) (Moratalla et al., in 
press). These differential patterns of gene induction are interesting because 
the DNA-binding proteins coded by these genes function as parts of dinners 
in conjunction with other binding proteins of the same transcription factor 
family, and these dimers in turn are parts of binding complexes that influence 
transcription. As a result, a wide range of control is in principle possible, 
depending on the particular genes that are coinduced and the levels and 
kinetics of their induction (Struhl 1991; Sheng and Greenberg 1990; He and 
Rosenfeld 1991; Morgan and Curran 1991). 
ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS BY 
PSYCHOMOTOR STIMULANTS: CLUES TO LONG-TERM CHANGES IN 
NEURAL PROCESSING 
The finding of selective patterns of I EG induction by psychomotor stimulants 
should give clues to the signaling pathways leading to the induction and, 
ultimately, to the consequences of the particular patterns found. For example, 
in PCI 2 cells it has been shown that membrane depolarization activates c -fos 
and jun- B, but not c -jun, and this pattern has been found in fibroblasts treated 
with cAMP analogs (Bartel et al. 1989; Mechta et al. 1989). The Di-like 
receptor selectivity of the psychomotor stimulant activation is probably 
responsible for the selective patterns of fos/jun induction that have been 
found (Moratalla et al., submitted for publication), because the c -fos promoter 
has a calcium-and-cAMP responsive element (Berkowitz et al. 1989; Sheng 
et al. 1988, 1990), and the jun - B promoter contains a novel repeat element 
that can be activated by protein kinase A. By contrast, protein kinase A may 
mediate an inhibition of c -jun directly or indirectly (de Groot et al. 1991 ; Chiu 
et al. 1989; Schutte et al. 1989; Ryseck and Bravo 1991). Signaling pathways 
leading from stimulation of adenylate cyclase and cAMP-dependent protein 
kinase A would then need to be considered as prime targets of the acute effects 
of psychomotor stimulant drugs. Nestler and colleagues find that molecules in 
the cAM P/protein kinase A pathway are regulated during prolonged exposure to 
cocaine and morphine (Guitart and Nestler 1989; Nestler et al. 1990; E. Nestler, 
personal communication, January 1992). The convergence of evidence for 
cAMP/protein kinase A mediation of responses to acute and long-term exposure 
to psychomotor stimulants fits well with the hypothesis that short-term induction 
of lEGs by these drugs of abuse could be implicated in the long-term responses 
that follow their repeated use (e.g., Graybiel et al. 1990; Young et al. 1991). 
What would be the characteristics of such neural modifications? For first 
analysis, the problem can be broken down into three parts: the initial signaling 
paths leading to changes in IEG induction, transcription, and translation; the 
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