A General Role for G Proteins and the cAMP System In Opiate Addiction 
Alterations in levels of G proteins and the cAMP system may represent a 
general mechanism by which certain types of neurons within the CNS respond 
to opiates and develop addiction (Terwilliger et al. 1991a). Thus, chronic 
morphine has been shown to increase levels of (1) adenylate cyclase and 
cAMP-dependent protein kinase in dorsal root ganglion/spinal cord cocultures, 
amygdala, and nucleus accumbens and of (2) the protein kinase alone in the 
thalamus (Makman et al. 1988; Terwilliger et al. 1991a). As in the LC, up- 
regulation of the cAMP system in dorsal root ganglion/spinal cord cocultures 
could account for some of the electrophysiological changes associated with 
opiate tolerance, dependence, and withdrawal in these neurons (Crain and 
Shen 1990). 
Opiate regulation of G proteins is more regionally variable, with increased 
levels of G ia and/or G w observed in the amygdala (as seen in the LC) and 
decreased levels observed in dorsal root ganglion/spinal cord cocultures and 
nucleus accumbens (Attali and Vogel 1989; Terwilliger et al. 1991a). Whether 
levels of these G proteins increase or decrease in response to chronic morphine 
may be related to the development of homologous vs. heterologous forms of 
desensitization, respectively, in the specific neuronal cell types (Terwilliger 
et al. 1991a). 
Studies of Morphine and Cocaine Action in the Mesolimbic Dopamine 
System 
The nucleus accumbens (NAc), together with dopaminergic neurons in the 
ventral tegmental area (VTA) that innervate the NAc, is implicated in mediating 
psychological aspects of addiction, namely, drug reinforcement and craving, 
for opiates and many other drugs of abuse (Wise and Bozarth 1987; Koob 
and Bloom 1988; Clouet et al. 1988). Thus, it was of particular interest to 
test whether chronic cocaine might produce changes similar to morphine in 
G proteins and the cAMP system in the VTA-NAc pathway. Indeed, chronic 
cocaine was found to decrease levels of G^ and G oa (Nestler et al. 1990) and to 
increase levels of adenylate cyclase and cAMP-dependent protein kinase in 
the NAc (Terwilliger et al. 1991a). Morphine and cocaine regulation of these 
intracellular messenger proteins, summarized in figure 2, was not observed in 
the other major dopaminergic system in the brain, the nigrostriatal system; nor 
was such regulation seen in response to other classes of psychotropic drugs 
that lack reinforcing properties. These biochemical actions of cocaine could 
account for the supersensitivity of D1 -dopamine receptor function observed in 
this brain region in response to chronic cocaine in electrophysiological studies 
(Henry et al. 1989; Henry and White 1991). Although the electrophysiological 
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