sequence of changes involving secretion of neurotrophic factors and 
synaptic reorganization, culminating in a permanent alteration in the 
susceptibility of this part of the brain to seizures. 
DOPAMINE AND IEG ACTIVATION 
The neurotransmitter dopamine appears to play a pivotal role in regulation 
of movement by the striatum. Loss of dopamine-containing neurons of 
the substantia nigra leads to a profound loss of motor control as seen in 
Parkinson’s disease. Dopamine is also thought to play a similar role in 
higher functions, and disorders of dopaminergic neurotransmission are 
generally assumed to lie behind the schizophrenias and may also contribute 
in large part to the disturbances of both thought and movement seen in 
Huntington’s chorea. The dopaminergic system also appears to play a 
central role in cocaine and amphetamine addiction (Roberts and Koob 1982; 
Koob and Bloom 1988; Di Chiara and Imperato 1988). Activation of c -fos in 
an animal model for Parkinson’s disease was first demonstrated using the 
antiparkinsonian drug L-dopa (the immediate precursor of dopamine) and 
drugs selective for the DI -dopamine receptor (Robertson et al. 1989a, 1989b, 
1991b; Paul et al., in press). After L-dopa or a DI -dopamine agonist, c-Fos 
protein was found only in the regions of the brain (striatum) that were 
experimentally depleted of dopamine and where dopamine receptors were 
known to be supersensitive. Significantly, activation of lEGs appears 
to be a DI -dopamine receptor-linked function (Robertson et al. 1989b). 
Compounds that act indirectly to release dopamine (such as cocaine and 
amphetamine) also increase expression of c -fos and other lEGs in striatum 
via DI dopamine receptors (Robertson et al. 1989b; Graybiel et ai. 1990; 
Young et al. 1991 ; Moratalla et al. 1992). It is most important to note that, 
whereas amphetamine and cocaine activate lEGs in naive, untreated animals, 
directly acting DI dopamine receptor agonists only induce IEG transcription in 
supersensitive tissue. Thus, even high doses of a DI agonist or apomorphine 
will not produce IEG expression in animals that have not been depleted of 
their dopamine content. 
Although D2 dopamine agonists apparently have little effect on IEG activation, 
it is significant that the combination of a DI and a D2 dopamine agonist has 
synergistic effects on induction of c -fos, c-jun, jun-B, and NGFI-A (Paul et al. 
1990, in press; Robertson et al. 1991b) reminiscent of the synergism seen in 
studies on locomotion in animal models for Parkinson’s disease (Robertson 
and Robertson 1986, 1989). Moreover, although c- fos activation in the 
striatum following DI agonist stimulation is spread over the entire striatum, 
the combination of DI and D2 agonists produces a pattern that reveals the 
compartmentalization of this brain region (Paul et al. 1990; Robertson et al. 
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