The initiation, pleasure, and recreational use of drugs can be traced back to activation of dopamine neurons. But, with repeated chronic exposure, dopamine neuronal responses change, becoming as responsive to the cues predictive of drug use (e.g. seeing an empty heroin needle or hearing the music one always plays before smoking cannabis) as the drugs themselves. The dopamine inputs to the PFC assume a domineering role for triggering relapse. By using transgenic GFP-Fos rats and mice, we identified a sparse ensemble of activated (Fos positive) PFC neurons that become hyperactive in response to cues predictive of heroin or cocaine. Enhancing inhibition in these neurons via locally administered drugs, we were able to reverse the hyperactivity and block cued-induced relapse-like drug-seeking. Why the “learned” association between drugs and environmental cues becomes so strong and long-lasting remains unclear. But in collaboration with the Taniguchi and Cowan laboratories, we are investigating if the strengthened association reflects postsynaptic posttranslational modifications in ryanodine receptors and the calcium signaling pathways of PFC neurons. Alternatively, there may be a strengthening of presynaptic inputs to these PFC neurons. In collaboration with the Moutal and Khanna laboratories, we found that targeting a specific protein (CRMP2) to switch off the presynaptic CaV2.2 channels regulating neurotransmitter release also blocks cue-induced relapse-like behavior.