Since cocaine increases dopaminergic transmission in the striatum (Hurd and 
Ungerstedt 1989; Moore et al. 1977), the effects of this indirect agonist on the 
mRNA levels of the striatal peptides dynorphin, substance P, and enkephalin 
using in situ hybridization histochemistry (ISHH) (Hurd et al. 1992) were 
examined. A treatment schedule was used in which rats were given unlimited 
access to intravenous cocaine for a period of 7 days to examine effects that 
may be related to the abuse of this drug. In this study, the self-administration 
of cocaine at an average daily rate of 58.8 mg/day (approximately 200 mg/kg/ 
day) resulted in significant regionally specific alterations in the levels of mRNA 
encoding the peptides dynorphin, substance P, and enkephalin in the striatum 
(table 1). Both dynorphin and substance P mRNA levels show substantial 
cocaine-induced increases in the dorsal striatum, whereas in the nucleus 
accumbens, these increases are relatively modest, particularly in the case of 
substance P (figure 1). Enkephalin mRNA is elevated only in the nucleus 
accumbens. Since dynorphin and substance P mRNA are expressed by most 
striatonigral neurons and enkephalin mRNA is expressed predominantly by 
striatopaliidal neurons (Gerfen and Young 1988), cocaine self-administration 
differentially alters gene regulation in these two striatal output systems. The 
most pronounced effect of cocaine is an elevation of both dynorphin and 
substance P mRNA levels in the dorsal striatum, whereas enkephalin mRNA 
levels are not significantly altered in this region. Thus, in the dorsal striatum 
there is a difference in gene regulation in striatonigral and striatopaliidal 
TABLE 1 . Average dynorphin , substance P, and enkephalin ISHH labeling 
(measured in arbitrary optical density units) in the dorsal striatum 
and nucleus accumbens in control, cocaine self-administering 
animals and saline-infused animals that received restricted food 
to match the weight of cocaine-treated animals 
Dynorphin ISHH Substance P ISHH Enkephalin ISHH 
Area 
Control 
(Food 
Restricted) 
Cocaine 
(Cocaine vs. 
Control) 
Control 
(Food 
Restricted) 
Cocaine 
(Cocaine vs. 
Control) 
Control 
(Food 
Restricted) 
Cocaine 
(Cocaine vs. 
Control) 
Dorsal 
154.0*1.9 
183.0* 2.1 
150.4*1.4 
173.6* 2.3 
161.9*1.1 
162.4*1.4 
striatum 
(154.9±2.3) 
+ 29.0* 
(150.2*2.1) 
+23.2* 
(164.6*1.4) 
+0.5 
Nucleus 
176.2*2.5 
192.0* 1.0 
152.4*1.0 
160.9* 0.8 
159.9*0.9 
164.3*1.1 
accumbens 
(177.6*2.3) 
+ 16.4* 
(151.0*1.1) 
+ 8.6* 
(161.3*0.9) 
+4.4* 
*p>0.05 
SOURCE: Hurd et al. 1992 
83 
