Inhibition of the lateral habenular CaMKⅡ abolishes naloxone-precipitated conditioned place aversion in morphine-dependent mice.

Addictive substances mediate positive and negative states promoting compulsive drug use. However, substrates for aversive effects of drugs are not fully understood. We found that inactivation of the lateral habenula (LHb) by microinjection of tetrodotoxin (TTX) abolished naloxone-precipitated conditioned place aversion (CPA) in morphine-dependent mice. We also found that lateral habenular administration of KN-62, a specific inhibitor for calcium/calmodulin dependent protein kinase II (CaMKII), abolished naloxone-precipitated CPA in morphine-dependent mice. Furthermore, we found chronic morphine treatment induced overexpression of CaMKII in the LHb. In conclusion, our results suggest that the increased expression of CaMKII in the LHb is instrumental for morphine-driven aversive behaviors.