of catecholamine neurotransmitters. These adaptations require chronic 
exposure to the opiates and are blocked by concomitant adminstration of 
an opiate receptor antagonist, indicating that persistent activation of opiate 
receptors is involved. 
The up-regulation of adenylate cyclase and cAMP-dependent protein kinase 
can be viewed as a compensatory, homeostatic response of LC neurons to 
persistent opiate inhibition of the cells (figure 1) (Nestler and Tallman 1988). 
According to this view, up-regulation of the cAMP system increases the intrinsic 
excitability of LC neurons and thereby accounts, at least in part, for opiate 
tolerance, dependence, and withdrawal. That is, in the opiate-dependent state, 
the combined presence of the opiate and the up-regulated cAMP system would 
return LC firing rates to control levels, whereas removal of the opiates would 
leave the up-regulated AMP system unopposed, which would lead to withdrawal 
activation of the neurons. Several lines of evidence support this scheme. 
First, cAMP and agents that elevate cAMP levels excite LC neurons via the 
activation of cAMP-dependent protein kinase and the subsequent activation 
of the slowly depolarizing Na + channel (Wang and Aghajanian 1990). In fact, 
the basal firing rate of LC neurons appears to be entirely dependent on the 
activity of the cAMP system and of this channel (Alreja and Aghajanian 1991). 
Second, the time course by which certain components of the up-regulated 
cAMP system revert to normal during opiate withdrawal parallels the time 
course by which withdrawal activation of LC neurons and various behavioral 
signs of withdrawal recover (Rasmussen et al. 1990). Third, recordings from 
LC neurons in brain slices in vitro, where most synaptic connections of the 
neurons have been severed, have indicated that LC neurons from dependent 
animals exhibit basal firing rates more than twofold greater than those from 
control animals (Kogan et al. 1992). This finding establishes that intrinsic 
mechanisms contribute to opiate dependence in these cells. Moreover, LC 
neurons from dependent animals show a dramatically greater maximal 
responsiveness to cAMP analogs, providing functional evidence for an up- 
regulated cAMP system during dependence (Kogan et al. 1992). Taken 
together, these findings demonstrate that up-regulation of the cAMP system 
represents one mechanism by which opiates induce addiction in these neurons. 
Opiate-induced up-regulation of the cAMP system in the LC occurs at both the 
level of protein and messenger RNA (Nestler et al. 1989; Guitart et al. 1990; 
Nestler 1992), consistent with the possibility that the changes arise through the 
regulation of gene expression. As described below, opiate regulation of these 
proteins offers a model system in which to study the mechanisms by which 
opiates alter gene expression and produce addictive changes in target neurons. 
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