Long-Term Potentiation (LTP) in the Central Amygdala (CeA) is enhanced after prolonged withdrawal from chronic cocaine and requires CRF₁ receptors

The amygdala is part of the brain reward circuitry that plays a role in cocaine-seeking and abstinence in animals and cocaine craving and relapse in humans. Cocaine-seeking is elicited by cocaine-associated cues, and the basolateral amygdala (BLA) and CeA are essential in forming and communicating drug-related associations that are thought to be critical in long-lasting relapse risk associated with drug addiction. Here we simulated a cue stimulus with high-frequency stimulation (HFS) of the BLA-CeA pathway to examine mechanisms that may contribute to drug-related associations. We found enhanced long-term potentiation (LTP) after 14-day but not 1-day withdrawal from 7-day cocaine treatment mediated through N-methyl-D-aspartate (NMDA) receptors (NRs), Ltype voltage-gated calcium channels (L-VGCCs), and corticotropin-releasing factor (CRF)₁ receptors; this was accompanied by increased phosphorylated NR1 and CRF₁ protein not associated with changes in NMDA/AMPA ratios in amygdalae from cocaine-treated animals. We suggest that these signaling mechanisms may provide therapeutic targets for the treatment of cocaine cravings.