Behavioral sensitization to cocaine in rats: Evidence for temporal differences in dopamine D ₃ and D ₂ receptor sensitivity

Rationale Cocaine-induced changes in D ₂ receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D ₃ receptors is less clear. Objectives To characterize the effects of repeated cocaine administration on the sensitivity of rats to D ₂- and D ₃-mediated behaviors, as well as the binding properties of ventral striatal D ₂-like and D ₃ receptors. Methods Pramipexole was used to assess the sensitivity of rats to D ₃/D ₂ agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D ₂-like and D ₃ receptors (24 h and 42 days) were also evaluated. Results Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h-42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose-response curve. Cocaine treatment also decreased Bmax and K _d for D ₂-like receptors and increased D ₃ receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists. Conclusions These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D ₃ and D ₂ receptors, with enhancements of D ₃-mediated behavioral effects observed within 72 h and enhancements of D ₂-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D ₃ receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.