Inhibitory effect of knockdown Piccolo on methamphetamine-induced behavioral changes via dopamine/GABA release in the nucleus accumbens of mice

抄録

Methamphetamine (METH) is one of the stimulants and distributed worldwide. It is known that the number of repetitive users doesn't decrease and that they develop abuse and dependence in many cases, however the medication for METH addiction is not effective. Therefore, searching for new effective molecules related to METH addiction is important. We found "PCLO" as a molecule which increases the expression in the nucleus accumbens (NAc) of mice continuously administered METH. Piccolo, a protein encoded by PCLO, reported that it is involved in dopaminergic neurons, single nucleotide polymorphism of PCLO is involved in addiction related-diseases, and that PCLO itself is involved in many psychiatric diseases. However, as relation to METH dependence has not been reported yet. We investigated the physiological function of Piccolo against the pharmacological action of METH by suppressing the expression of Piccolo in the NAc that is important a brain region for drug dependence.

We generated the Piccolo-specific knockdown mice (miPiccolo mice) and Mock mice by injecting adeno-associated virus (AAV) vector including Piccolo miRNA and AAV-mock. Using these mice, we performed several behavior tests such locomotor activity test, conditioned place preference (CPP) test, to investigate the effects on pharmacological actions of METH. Furthermore we measured GABA and dopamine changes in NAc using in vivo microdialysis methods.

METH-induced locomotor activity of miPiccolo mice were reduced compared with Mock mice. METH-induced CPP formation was also decreased in miPiccolo mice. In microdialysis experiments, the basal level of dopamine in the NAc was significantly decreased in miPiccolo mice. Furthermore the amount of extracellular GABA from NAc tended to decrease in miPiccolo mice.

These results suggested that Piccolo in the NAc regulates dopaminergic- / GABAergic-neuron system and METH dependence related-behavior. Our findings might develop a novel clinical methods for METH dependence, especially since GABA system has not been mentioned. We will much more study to clarify the detail mechanism of interaction between dopamine and GABA.