Inactivation of G(i) and G(o) proteins in nucleus accumbens reduces both cocaine and heroin reinforcement

The pertussis toxin (PTX)-sensitive G proteins G(i) and G(o) may be implicated in drug reinforcement and addiction, since certain reward-related dopamine and opiate receptor subtypes are coupled to these G proteins, and since chronic exposure to cocaine or morphine alters levels of these G proteins in the nucleus accumbens (NAc). As a direct test of this hypothesis, G(i) and G(o) proteins in the NAc were selectively inactivated by intra- accumbens injections of PTX in rats self-administering either cocaine or heroin. In control animals, bilateral injections of inactive PTX (0.1 μg/1 μl/side) in the NAc failed to alter baseline rates of cocaine and heroin self-administration. In contrast, the same dose of active PTX produced significant, long-lasting increases (up to 1 month) in the self- administration of both drugs, and shifted the dose-response curves to the right. These results suggest that PTX reduces or shortens the reinforcing efficacy of cocaine and heroin, leading to compensatory increases in drug self-administration. Similar NAc injections of PTX reduced the level of G(iα) and G(β) subunits as measured by both ADP-ribosylation and Western blot, without affecting levels of G(iα) or G(β) subunits. The effect of the toxin was mainly limited to the NAc, and no evidence of abnormal cell death or gliosis was observed. The onset of changes in self-administration rate coincided with the onset of changes in ADP-ribosylation, suggesting that, initially, the increased drug self-administration results directly from a reduction in functional G(i) and G(o) proteins. After 28 d, self- administration baselines began to recover while levels of G protein ADP- ribosylation and immunoreactivity remained low, suggesting that adaptive mechanisms are involved at later time points. These results provide direct support for a common role of G(i) and G(o) proteins in the NAc in the reinforcing and addictive properties of psychostimulant and opiate drugs.