Combining brief recall and ketamine treatment prevents stress-primed methamphetamine memory reinstatement via heightening mPFC GABA activity.

A brief recall of methamphetamine-associated memory combined with ketamine treatment facilitated the extinction of that memory and made it resistant to stress-triggered reinstatement in animals. The combination increased glutamate metabotropic receptor 5 (mGluR5) in GABA neurons of the medial prefrontal cortex (mPFC). Chemogenetic experiments showed that activating mPFC GABA neurons preserved extinction and prevented stress-primed reinstatement, whereas inhibiting them restored vulnerability to reinstatement. The findings suggest that exciting mPFC GABA neurons plays a key role in the effects of brief recall plus ketamine on curbing stress-provoked drug seeking.

Study at a glance

Abstract

This study aimed to assess whether brief recall of methamphetamine (MA) memory, when combined with ketamine (KE) treatment, may prevent stress-primed MA memory reinstatement. Combining 3-min recall and KE facilitated MA memory extinction and resistance to subsequent stress-primed reinstatement. Such combination also produced glutamate metabotropic receptor 5 (mGluR5) upregulation in animals' medial prefrontal cortex (mPFC) γ-amino-butyric acid (GABA) neuron. Accordingly, chemogenetic methods were employed to bi-directionally modulate mPFC GABA activity. Following brief recall and KE-produced MA memory extinction, intra-mPFC mDlx-Gi-coupled-human-muscarinic-receptor 4 (hM4Di)-infused mice receiving compound 21 (C21) treatment showed eminent stress-primed reinstatement, while their GABA mGluR5 expression seemed to be unaltered. Intra-mPFC mDlx-Gq-coupled-human-muscarinic-receptor 3 (hM3Dq)-infused mice undergoing C21 treatment displayed MA memory extinction and resistance to stress-provoked reinstatement. These results suggest that combining a brief recall and KE treatment and exciting mPFC GABA neuron may facilitate MA memory extinction and resistance to stress-primed recall. mPFC GABA neuronal activity plays a role in mediating brief recall/KE-produced effects on curbing the stress-provoked MA seeking.