Miller, Courtney

Substance use disorders (SUDs) are perpetuated by the formation of drug-associated memories. Methamphetamine (METH)-associated memories undergo immediate and long-lasting disruption after treatment with blebbistatin (blebb), a nonmuscle myosin II (NMII) inhibitor, but cocaine (COC) associated memories do not. This suggests that the mechanisms of METH and COC-associated memories are different. To visualize these potential differences, RNA-sequencing was conducted. Crhr2, a gene that encodes corticotropin releasing factor receptor 2 (CRF2), was uniquely upregulated in the BLA after METH learning. Action upon CRF2 after memory consolidation did not have an effect. However, pretreating brains with CRF2 antagonist Astressin-2B (AS2B) prevented blebb’s ability to disrupt established METH-associated memories. Additionally, overexpressing CRF2 in the basolateral amygdala (BLA) plus providing its ligand UCN3 during conditioning, and then administering blebb resulted in disruption of COC-associated memory. CRF2 is the first upstream regulator of NMII inhibition of METH-associated memory to be identified.

Methamphetamine (METH) is addictive and associated with a high rate of relapse. One relapse trigger is re-experiencing drug-associated contextual associations. Therefore it is possible that, by targeting METH-associated contextual memories, drug seeking behavior can be inhibited. Recent evidence has suggested that memory formation relies on actin polymerization, which allows dendritic spines to undergo structural and functional plasticity, key components of memory. To see if actin polymerization could be a target for the extinction of METH seeking memories we inhibited actin polymerization in animals that had been trained in either METH or food associated conditioned place preference. Pretest inhibition of actin cycling in the basolateral amygdala complex produced immediate and persistent extinction of METH seeking behavior. Additionally, inhibiting actin polymerization 24hrs before testing disrupted seeking behavior for METH but not food. These results indicate that METH-associated memories are selectively vulnerable to disruption through inhibition of actin dynamics.