1991 b; Paul et al., in press). This once again illustrates the fact that IEG 
activation is a potent tool for studying the anatomical organization of neuronal 
structures. 
Dopaminergic and glutamatergic mechanisms interface in the striatum as 
two control mechanisms central to regulation of striatal function (Clow and 
Jhamandas 1989). Glutamatergic neurotransmission appears to play some 
role in dopamine-mediated activation of IEG expression. N-methyl-D-aspartate 
(NMDA) receptor antagonists reverse amphetamine-induced activation of c -fos 
(Johnson and Robertson 1989; Aronin et al. 1991; Snyder-Keller 1991; Paul et 
al., in press; Berretta et al., in press), suggesting that glutamatergic and 
dopaminergic mechanisms also interact at the level of regulation of gene 
expression in striatum. 
It was known that dopamine agonists induce expression of c -fos, and it 
was at the same time surprising and potentially important to note that c -fos 
induction also occurred following administration of D2 dopamine receptor 
antagonists such as haloperidol (Dragunow et al. 1990; Miller 1990) and 
clozapine (Robertson and Fibiger 1991; Hiroi et al. 1991). These drugs are 
widely used in the treatment of mental disorders such as schizophrenia. The 
finding of IEG activation by these drugs in clinically relevant doses suggests 
the possibility that either the beneficial effects or some of the side effects of 
these drugs might be mediated by changes in gene expression. Both the 
symptoms of schizophrenia and the development of some side effects of 
these drugs have time courses consistent with alterations in gene expression. 
Thus, selective blockade of dopamine receptors may, like selective activation 
of dopamine receptors, be associated with long-term changes in neuronal 
function (table 2). The evidence at this time suggests that, although dopamine 
D1 agonists exert a stimulatory effect on c -fos expression, D2 receptors appear 
to mediate a tonic inhibitory effect on c -fos expression. 
TABLE 2. Some possible associations between drug-induced activation of 
lEGs and pathophysiological effects of dopaminergic drugs 
Effect 
IEG Activator 
Drug Class 
Reference 
Dystonias 
L-dopa 
D1 dopamine agonists 
Robertson et al. 
1989a, 1989b 
Tardive dyskinesias 
Haloperidol 
D2 dopamine antagonists 
Dragunow et al. 
1990 
Drug addiction 
Amphetamine, 
cocaine 
Psychostimulants 
Graybiel et al. 
1900; Young et al, 
1991 
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