intracellular messenger proteins exist in the VTA-NAc pathway of Lewis and 
Fischer 344 rats. Lewis rats self-administer opiates, cocaine, and alcohol at 
much higher rates than Fischer rats (George and Goldberg 1989; Suzuki et al. 
1988) and also develop greater degrees of conditioned place preference to 
morphine and to cocaine (Terwilliger et al. 1991 b). Interestingly, the NAc of 
Lewis vs. Fischer rats contains lower levels of G,, higher levels of adenylate 
cyclase and cAMP-dependent protein kinase, and lower levels of tyrosine 
hydroxylase, whereas the VTA of Lewis vs. Fischer rats contains higher levels 
of tyrosine hydroxylase and lower levels of neurofilaments (Beitner-Johnson 
et al. 1991; Guitart et al. 1991; Terwilliger et al. 1991b). In each case, levels 
of these specific intracellular signaling proteins in the VTA-NAc pathway of 
Lewis rats, compared with Fischer rats, resemble morphine- and cocaine- 
induced changes in these proteins in outbred Sprague-Dawley rats. 
The common chronic actions of morphine and cocaine in the mesolimbic 
dopamine system are particularly striking since the two drugs exert opposite 
electrophysiological effects on VTA neurons acutely (Henry et al. 1989), yet 
both are clearly addicting. Therefore, the common chronic actions could 
represent a general mechanism by which these drugs of abuse exert some of 
their long-term reinforcing actions in this neural pathway. The findings in Lewis 
and Fischer rats raise the additional, exciting possibility that similar mechanisms 
may contribute to individual genetic vulnerability to drug addiction (Nestler, in 
press). 
GENETIC MECHANISMS UNDERLYING BIOCHEMICAL ADAPTATIONS IN 
THE CAMP SYSTEM 
General Scheme 
Based on the knowledge of opiate and cocaine action in specific brain regions 
and of the mechanisms underlying the regulation of gene expression, one can 
formulate a working scheme to explain how these drugs of abuse might alter 
the expression of genes for specific target proteins in particular neuronal cell 
types. Two possible regulatory mechanisms involving the CREB and Fos/Jun 
families of transcription factors are shown in figure 3. These two mechanisms 
are not mutually exclusive, nor are they the only types of mechanisms that 
could be involved, because any of the transcription factors, or a combination 
of factors, shown in table 1 could conceivably play a role. However, evidence 
for neurotransmitter regulation of transcription factors is best established for 
the CREB and Fos/Jun families. Moreover, several of the known target genes 
for opiates and cocaine (e.g., cAMP-dependent protein kinase, tyrosine 
hydroxylase, neurofilaments) are known to contain cAMP and/or AP-1 
response elements (Cambi et al. 1989; Reeben et al. 1991; S. McKnight, 
personal communication, September 1990). 
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