those seen in control and chronically treated animals (Aghajanian 1978; Christie 
et al. 1 987). The withdrawal results in an induction of fos and jun in LC and 
several other regions of the CNS (Hayward et al. 1990). The increased firing 
of neurons within LC during withdrawal is compatible with the notion that c -fos 
is an activity-driven gene. However, 2-deoxyglucose uptake does not change 
in other brain regions where fos is also induced by opiate withdrawal, showing 
that there is not an absolute coincidence between activity, as measured by 
2-deoxyglucose, and fos induction (Wooten et al. 1982; Kimes and London 
1989; reviewed in Morgan and Curran 1991a). What role CIE genes play 
during withdrawal is not known at present. However, several possibilities 
are suggested. For example, the tyrosine hydroxylase (TH) gene can be 
regulated in some systems by Fos and Jun (Gizang-Ginsberg and Ziff 1990). 
Furthermore, the regulation of TH levels in a few highly specific regions of the 
CNS has been implicated in the physical effects of morphine (and cocaine) 
(Guitart et al. 1990; Beitner-Johnson and Nestler 1991). Indeed, morphine 
induces changes in TH in several brain regions, including LC (Hayward et al. 
1990). Thus, AP-1 complexes may provide a mechanistic link that couples 
morphine to alterations in TH levels and thereby catecholamine biosynthesis. 
Cocaine and Amphetamine Regulation of C -fos 
The psychomotor stimulants, methamphetamine and cocaine, can act indirectly 
as dopamine agonists to elevate prodynorphin-derived peptides in the striatum 
(Hanson et al. 1987; Sivam 1989). Since it had been suggested that Fos and 
Jun act in the regulation of expression of several neuropeptide genes, including 
preprodynorphin and preproenkephalin (White and Gall 1987; Draisci and 
ladarola 1989; Sonnenberg et al. 1989b), several studies have undertaken the 
analysis of immediate early (IE) gene expression following treatment with 
amphetamines and cocaine (e.g., Graybiel et al. 1990; Young et al. 1991). 
Acute cocaine induces FLI and c -fos mRNA in striatum, olfactory tubercle, the 
islands of Calleja, and nucleus accumbens. Since this induction was blocked 
by SCH 23390, it is inferred that cocaine is acting via D1 -dopamine receptors 
(Young et al. 1991). Likewise, amphetamine, as well as two D1 -dopamine 
receptor agonists, SKF 38393 and CY 208-243, induce fos in the striatum via 
the D1 -dopamine receptor (Robertson et al. 1989; Graybiel et al. 1990). 02- 
dopamine receptor agonists such as LY 171555 do not induce fos in striatum 
(Robertson et al. 1989), although this agent, like D1 -dopamine agonists, can 
elicit rotational behavior in rats bearing unilateral lesions in the substantia nigra. 
That is, activation of D1 -dopamine, but not D2-dopamine, receptors results in 
fos induction in striatum. Furthermore, rotational behavior can be separated 
from an induction of c -fos. Surprisingly, haloperidol, a neuroleptic with 
dopamine antagonist properties, also induces c -fos in striatum (Miller 1990). 
Since the action of haloperidol is blocked by the D2-dopamine receptor agonist 
44 
