kn-62 and Substance-Withdrawal-Syndrome

Alcoholics often experience hyperalgesia, especially during abstinence, yet the underlying cellular and molecular bases are unclear. Recent evidence suggests that 5-HT type 2 receptors (5-HT

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Central Nervous System Depressants; Enzyme Inhibitors; Ethanol; Excitatory Postsynaptic Potentials; Glutamic Acid; Habenula; Neurons; Nociception; Rats; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin, 5-HT2; RNA, Messenger; Serotonin 5-HT2 Receptor Antagonists; Substance Withdrawal Syndrome

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.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Avoidance Learning; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Conditioning, Classical; Habenula; Male; Mice, Inbred C57BL; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Substance Withdrawal Syndrome

Learning and memory have been suggested to play an important role in the development of opiate addiction. Based on the recent finding that calcium/calmodulin protein kinase II (CaMKII) is essential in learning and memory processes, the present study was performed to examine whether inhibition of hippocampal and amygdala CaMKII prevents the dependence and relapse to morphine. The results showed that inhibition of CaMKII by microinjection of specific inhibitors KN-62 into hippocampus decreased the morphine withdrawal syndromes induced by opiate antagonist naloxone. In contrast, inhibition of CaMKII in amygdala failed to do so. Microinjection of KN-62 into both hippocampus and amygdala suppressed the development of formation and reactivation of morphine conditioned place preference (CPP). However, inhibition of CaMKII in amygdala, but not in hippocampus, could attenuate the maintenance of morphine CPP. These results suggest that hippocampal CaMKII is critically involved in the development of morphine physical and psychological dependence, and amygdala CaMKII is some different from hippocampal CaMKII in regulating the dependence and relapse to opiates. Inhibition of this kinase may have some therapeutic benefit in the treatment of opiate dependence and relapse.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amygdala; Animals; Behavior, Animal; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Conditioning, Psychological; Enzyme Inhibitors; Hippocampus; Male; Microinjections; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome