Relapse is a defining feature of drug addiction, and despite years of research we still lack adequate treatments for this disease. Using the rodent self-administration and reinstatement model, we can study how drug exposure sets the stage for relapse vulnerability. I have used glutamate-selective biosensors to investigate the rate of glutamate uptake in animals following heroin self-administration and extinction training, and detected decreased clearance in the NAcore. I was also involved with another project where we began to closely analyze the signal transduction cascade underlying increases in dendritic spine head diameter (dh) responsible for relapse to cued cocaine seeking. We observed in these studies that activity of matrix metalloproteinases 2 and 9 are required for cued cocaine seeking (study b.) In the latest study in this line of investigation, we demonstrated that a key component in the signal transduction cascade leading to the activation of MMPs in the NAcore is the release of NO. We showed that activation of NAcore NO interneurons was sufficient to drive drug seeking even in the absence of conditioned cues, while the selective destruction of these cells inhibited drug seeking. We are currently performing recordings in freely moving animals to further analyze the relationship between glutamate and NO in drug seeking and taking.
a. Shen HW, Scofield MD, Boger H, Hensley M and Kalivas PW (2014) Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse. J Neurosci 34:5649-5657 (PMC3988415)
b. Smith AC, Kupchik YM, Scofield MD, Gipson CD, Wiggins A, Thomas CA and Kalivas PW (2014) Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. Nat Neurosci 17:1655-1657 (PMC4241163)
c. Smith AC, Scofield MD, Heinsbroek JA, Gipson CD, Neuhofer D, Roberts-Wolfe DJ, Spencer S, Garcia-Keller C, Stankeviciute NM, Smith RJ, Allen NP, Lorang MR, Griffin WC 3rd, Boger HA, and Kalivas PW (2017) Accumbens nNOS interneurons regulate cocaine relapse. J. Neurosci 37(4):742-756 (PMC5296777)