investigation. Ultimately, similar types of experiments could be carried out 
using transgenic animals, where the constructed genes would be introduced 
into all somatic cells, including the relevant neurons through germ line 
transmission. At very early stages of investigation, these examples illustrate 
how the precise mechanisms by which drugs of abuse regulate gene 
expression can be delineated using molecular biological techniques. 
CONCLUSIONS 
This chapter described the experimental strategy that the authors’ laboratory is 
using to investigate the role of changes in gene expression in the development 
of opiate and cocaine addiction. The strategy involves the study of discrete 
brain regions that are known to contribute to behavioral aspects of drug 
addiction and in which electrophysiological studies provide insight into the 
functional changes at the neuronal level that underlie the addictive behaviors. 
This makes it possible to understand biochemical and molecular actions of the 
drugs within a functional context. The focus is on identifying intracellular 
signaling proteins that are regulated by chronic drug treatments at the level 
of gene expression. These target proteins are then used to investigate the 
mechanisms by which the drugs of abuse alter the expression of the genes 
encoding them. To date, it has been possible to identify alterations in G 
proteins and the cAMP system in specific regions of the CNS in response to 
chronic opiates and/or chronic cocaine. Of particular interest is the up- 
regulation of the cAMP system observed in the LC in response to chronic 
opiates (biochemical adaptations shown to contribute to opiate tolerance, 
dependence, and withdrawal exhibited by these neurons) and a similar up- 
regulation of the cAMP system observed in the mesolimbic dopamine system 
in response to chronic opiates and chronic cocaine, which could be related to 
drug reinforcement or craving mediated via this neural pathway. Current 
studies are aimed at investigating opiate and cocaine regulation of transcription 
factors in these discrete brain regions. Ultimately, it will be possible to expand 
on the correlative data resulting from these studies with more direct analyses 
that make use of in vivo methods for detecting changes in target gene 
expression. Together, these studies of opiate and cocaine action will help 
define the precise mechanisms, at the molecular level, by which these drugs 
of abuse alter the expression of specific genes in particular neuronal cell types 
and thereby produce physical and psychological aspects of addiction. 
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Aghajanian, G.K. Tolerance of locus coeruleus neurones to morphine and 
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Ill 
