The Temporal Sequence of Changes in Gene Expression by Drugs of Abuse - Drugs of Abuse: Neurological Reviews and Protocols - page 2

the nucleus accumbens and ventral mesencephalon. However, about 5 yr ago
studies emerged from both the animal literature and neuroimaging of drug
addicts indicating that the expression of addicted behaviors such as sensitiza-
tion and craving involved regions of the cortex and allocortex (4-7) . In this
regard, two regions that have come to be closely associated with addiction are
the amygdala and frontal cortex (including the anterior cingulate and ventral
orbitofrontal cortex). In addition, the last decade of research has revealed a
variety of enduring changes in gene expression produced by repeated exposure
to drugs of abuse, notably psychostimulants (3 , 8) . The most long-lasting
neuroadaptations that would be expected to underlie enduring behaviors
associated with addiction appear to be concentrated in the nucleus accumbens
and in cortical regions providing input to the nucleus accumbens, such as
the prefrontal cortex. These studies are outlined and integrated with the
corticostriatal circuitry postulated to be critical for the expression of behavioral
characteristics of psychostimulant addiction, such as sensitization and craving.
2. Temporal and Anatomical Sequence of Changes
in Gene Expression
A variety of studies using different addictive drugs, given in different
dosing regimens and employing different withdrawal periods, have shown that
repeated administration of addictive drugs produced short, intermediate, and
enduring changes in gene expression. Figure 1 illustrates the sequence of
changes in gene expression associated with repeated cocaine administration.
Five categories of cocaine-induced changes in gene expression are outlined,
ranging from increases in immediate early gene (IEG) expression that diminish
with repeated injections to changes in gene expression that appear only after
a period of withdrawal. The data outlined in Fig. 1 are specifi c for cocaine-
induced changes in gene expression, and using these data as a guide certain
temporal patterns of drug-induced changes in gene expression can be discerned
from the extant literature. Similarly, anatomical patterns of gene expression
related to various times during the chronic injection and withdrawal periods
can be shown. However, there are exceptions in the anatomical discretion, and,
importantly, in many brain nuclei relevant to addiction, notably the amygdala,
very little data have been collected regarding changes in gene expression.
3. Rapid Response and Tolerance, Widespread
in Dopamine Terminal Fields
The earliest changes in gene expression that are measurable shortly after
acute drug administration occur in many brain regions, the most well studied
being dopamine terminal fi elds such as the striatum, nucleus accumbens, and
prefrontal cortex. These genes include classic IEG transcription factors such