psychostimulant drugs last many weeks and perhaps months. In humans, the 
effects of psychostimulant use are still evident after years of abstinence (Koob 
and Bloom 1988). 
The mechanism underlying long-term changes in the brain is unknown. The 
phenomenon of long-term potentiation is interesting but, in general, only lasts 
for a few weeks at the most and decays over that period. By contrast, the 
phenomenon of kindling in animals is generally regarded as representing a 
permanent change in neuronal function. However, the biological basis of 
kindling is largely unknown, although there are suggestions that it could 
involve activation (or inhibition) of gene expression in parts of the limbic 
system, including the hippocampus. Kindling is a process whereby repeated 
subthreshold stimulation (electrical or chemical) will lead to a gradual increase 
in response. Thus, repeated subconvulsant doses of a chemical convulsant 
agent will also induce kindling (for reviews on kindling, see Goddard 1983 
and Cain 1989). In the case of kindled seizures, this process culminates 
in a major motor seizure. Most importantly, once an animal is kindled, it 
apparently remains in the kindled state for the remainder of its life (about 
33 months is the longest known duration). Moreover, the kindled state, unlike 
long-term potentiation, appears to depreciate little with time (for a review, see 
Cain 1989). 
Kindling can also be induced chemically by agents such as cocaine. The 
kindling-like effects of cocaine have been known longer than researchers 
have been aware of kindling (Downs and Eddy 1932). Post and colleagues 
(1975) drew attention to the idea that the local anesthetic actions of cocaine 
might produce a process of “pharmacological kindling” during repeated high- 
dose drug administration. In many ways, electrophysiological kindling was 
reminiscent of the behavioral sensitization that is characteristic of cocaine. 
Cocaine-induced behavioral sensitization is longlasting and shows cross- 
sensitization to other stimuli and shows, at least in part, a dependence on 
the interval between injections just as kindling does (Post and Contel 1981 ; 
Post and Weiss 1988). The search for a mechanism to explain the persistent 
changes that are characteristic of electrophysiological kindling led to a 
consideration of the possible role of gene activation in this process. Since 
electrophysiological kindling is a permanent change in neuronal function, it 
was reasoned that the genetic material might be involved. Experiments 
demonstrated that the immediate early gene (IEG) c-fos was rapidly and 
transiently expressed in the dentate gyrus and other parts of the hippocampus 
after a kindling stimulus (Dragunow and Robertson 1987a) or following 
induction of seizure activity by chemical convulsants (Morgan et al. 1987; 
Dragunow and Robertson 1987b). Subsequent work has shown that induction 
of lEGs is a consequence of neuronal activation in many parts of the CNS 
55 
