Prelimbic medial prefrontal cortex has bidirectional control over the expression of behavioral sensitization to 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) depending on the context of drug administration

Behavioral sensitization to MDMA is observed in the vast majority of rats if tested in the same environment in which previous MDMA exposure occurred, but not if tested in a novel, unpaired context. Previous studies have revealed a critical role for the prelimbic region of medial prefrontal cortex (PL) in the expression of sensitization to MDMA, but these studies assessed sensitization only in MDMA-paired environments. Given that PL activity can both facilitate and suppress behavior depending on context, we tested the hypothesis that PL has bidirectional control over the expression of locomotor sensitization to MDMA depending on the context of drug administration. Rats were treated with either saline or MDMA (5.0 mg/kg) twice daily for 5 days, in either their home cages (unpaired groups) or the activity monitors that were used for tests of sensitization on challenge days (paired groups). Prior to MDMA challenge injections (2.5 mg/kg; at ∼ 2 weeks of withdrawal), rats received bilateral PL microinjections of either lidocaine (100 μg/0.5 μl/side) or physiological saline (0.5 μl/side). Locomotor activity in response to MDMA challenge was unaffected by PL inactivation in saline pretreated rats. However, PL inactivation caused a decrease in locomotion to the challenge injection in MDMA/paired rats and an increase in locomotion in MDMA/unpaired rats. These results establish a novel role for PL in suppressing the expression of behavioral sensitization when subjects are challenged in a drug-unpaired context, adding to the literature implicating PL activity in both the expression and inhibition of other drug-related behaviors.