Extinction memory enhancement for cocaine relapse prevention: pharmacological, behavioral and molecular determinants using an animal model of cue exposure therapy

Initial studies in rats & monkeys used D-cycloserine (DCS) in conjunction w/ cocaine-cue extinction training & were based on prior research showing that this partial agonist at the NMDA receptor glycine site facilitated extinction memory to prevent reinstatement of fear & anxiety in both rat & human subjects. Our research was broadened over the years to include treatment during extinction training w/ glycine-transporter-1 (GlyT-1) inhibitors & exposure to brief interventions of environmental enrichment (EE) followed by measurement of selected molecular targets (e.g. the AMPA receptor subunit GluA1 & the BDNF receptor TrkB) in several regions of the brain. GlyT-1 inhibitors & EE were found to be very effective in inhibiting relapse to cocaine self-administration after combining each w/ cocaine-cue extinction training. Increased expression of GluA1 in the basolateral amygdala & of TrkB in dorsal hippocampus & ventromedial prefrontal cortex appear to be molecular changes important for deterrence of cocaine relapse w/these extinction-based strategies. Current research studies combining these pharmacological and behavioral strategies w/ cocaine-cue extinction training in rats exhibiting a high state of cocaine dependence. One important outcome to date is that the combined treatment strategy is highly effective in inhibiting relapse to cocaine self-administration in male rats but is completely ineffective in female rats. The molecular basis for sex difference is under investigation