Sensitization to cocaine and dopamine autoreceptor subsensitivity in the nucleus accumbens.

It has been suggested that dopamine autoreceptor subsensitivity may play a role in cocaine-induced behavioral sensitization. In order to evaluate this hypothesis, we administered cocaine to rats daily (15 mg/kg ip x 2 days, 30 mg/kg ip x 5 days) and then monitored nucleus accumbens dopamine during the local administration (through the dialysis probe) of the D2/D3 agonist, quinpirole (0, 0.1, 1, and 10 microM). Our results indicate that, relative to saline-pretreated control animals, repeated cocaine administration impaired the ability of quinpirole to decrease extracellular dopamine 1-2 days after the last drug injection. However, quinpirole was equipotent at reducing accumbal dopamine in cocaine- and saline-treated animals following a 21-22 day withdrawal period. These results demonstrate that repeated cocaine produces a short duration functional tolerance in the capacity of autoreceptor stimulation to inhibit accumbal dopamine release.