Modulation of fra‐2 and σ receptor gene and protein expression is correlated with the ability of a σ receptor antagonist to attenuate cocaine‐induced sensitization

Sigma (σ) receptors have recently been implicated in the actions of cocaine, and antagonists of these receptors prevent many acute and subchronic cocaine effects, including sensitization. However, the underling mechanisms are still unclear. An earlier study in our lab showed that acute administration cocaine can alter fra‐2 and σ receptor gene and protein expression. Based on this result, we hypothesized that cocaine‐induced changes in fra‐2 and σ receptor gene and protein expression may contribute to the development of behavioral sensitization. Mice were randomly divided into four treatment groups (Saline+Saline, Saline+Cocaine, BD1063+Cocaine, BD1063+Saline), then injected once a day for five days with a locomotor stimulatory dose of cocaine (Days 1–5), followed by a 10 day drug‐free period, and subsequently challenged with cocaine (Day 15). Locomotor activity was monitored on each day using an automated activity monitoring system. On Days 1, 3, 5 or 15, the brains of the animals were collected for subsequent measurements of fra‐2 and σ receptor mRNA and protein levels. The results showed that the σ receptor antagonist BD1063 attenuates cocaine‐induced changes in behavior, gene and protein expression. Together, the data suggest that the ability of the σ receptor antagonist to modulate fra‐2 and σ receptor gene and protein expression contributes to its ability to attenuate cocaine‐induced sensitization.