Immediate Early Gene Activation 
and Long-Term Changes in Neural 
Function: A Possible Role in 
Addiction? 
Harold A Robertson 
INTRODUCTION 
Psychostimulants such as cocaine and amphetamine have a range of 
pharmacological effects on the central nervous system (CNS). The most 
important of these effects, those related to addictive behavior, appear to 
depend on dopaminergic mechanisms (Wise 1984). Thus, a receptor for 
cocaine has been described (Ritz et al. 1987) and sequenced (Shimada et al. 
1991; Kilty et al. 1991) that appears to be a site on the dopamine transporter 
on dopamine nerve terminals. Furthermore, there is evidence from animal 
studies to suggest that dopamine function in the nucleus accumbens plays an 
Important part in intracranial self-stimulation and self-administration of cocaine 
(Roberts and Koob 1982). Finally, there is evidence that the dopaminergic 
mechanisms in the nucleus accumbens may be a final common pathway for 
many, if not all, substances that produce addictive behavior (Di Chiara and 
Imperato 1988). Therefore, it seems clear that dopaminergic mechanisms play 
a central role in the addictive properties of cocaine and other psychostimulant 
drugs. These compounds have their effects on dopamine either by increasing 
its release into the synapse (amphetamine) or by blocking the reuptake of 
dopamine from the synapse (cocaine), the net effect in either case being an 
increase in dopamine levels in the synapse. It should be noted that this 
explanation for the actions of cocaine and amphetamine is almost certainly 
incomplete. Other agents (e.g., tricyclic antidepressants, tyramine) share 
these actions and do not produce addiction. The obvious question is, What 
does the dopamine accumulation following cocaine and/or amphetamine do 
that produces addiction? It seems reasonable to assume that dopamine 
produces some sort of change in neural systems that leads to a long-term 
change in function. It is known that the changes that occur are robust and 
persistent. In animals, the sensitization and reverse tolerance produced by 
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