Disruption of psychostimulant-associated memories by single, low dose ketamine in rats

Cocaine and methamphetamine use disorders pose public health concerns due to the high propensity for relapse driven by persistent drug-associated memories. Output from the medial prefrontal cortex (mPFC) regulates relapse and is controlled by parvalbumin (PV) interneurons, which are surrounded by perineuronal nets (PNNs) that support precise PV neuron firing. We previously showed that removal of mPFC PNNs, which reduces PV firing, disrupted reconsolidation of a cocaine self-administration memory when rats were given a novel, but not familiar, memory retrieval session. Ketamine rapidly suppresses PV neuron output, so we tested whether a single low dose (6 mg/kg) administered before or after a familiar or novel memory retrieval session altered cocaine cue reinstatement. Ketamine given prior to the novel, but not familiar, retrieval session reduced cue reinstatement in male Sprague-Dawley rats. In addition, both ketamine treatments combined with a novel retrieval session reduced PNN intensity around PV neurons after cue reinstatement, suggesting that PNN decreases may be unrelated to reinstatement. However, ketamine reduced the number of c-Fos-activated PV neurons immediately after the novel memory retrieval session, indicating that ketamine may reduce reinstatement through reduced PV neuron function at the time of memory retrieval. Ketamine given just prior to a novel memory retrieval session also reduced cue-induced reinstatement in rats trained for methamphetamine, but not fentanyl or sucrose self-administration. Collectively, these studies show that a single, low dose of ketamine combined with a novel memory retrieval reduces psychostimulant-seeking behavior, and may help delineate the mechanisms for ketamine-reduced relapse in psychostimulant use disorders.