Decrease of morphine-induced reward effects and withdrawal symptoms in mice overexpressing gamma-aminobutyric acid transporter I.
Morphine addiction has been shown to result from neural adaptations produced by repeated drug exposure, but the mechanism is still unclear. In the present study, we found that gamma-aminobutyric acid (GABA) uptake was increased in mouse brain 120 min after, but not 20 min after, morphine (10 mg/kg, s.c.) injection. We generated GABA transporter I (GAT1)-overexpressing mice to investigate whether the GABAergic system and GABA transporter are involved in morphine-induced reward effects and withdrawal symptoms. Our results revealed that the rewarding effects induced by morphine were significantly decreased in GAT1-overexpressing mice as measured by the conditioned place preference (CPP) paradigm. Moreover, both somatic and vegetative signs of naloxone-induced morphine withdrawal symptoms were substantially reduced in GAT1-overexpressing mice. In addition, the decreased morphine rewarding in transgenic mice could be recovered when mice were coinjected with NO-711 (a GAT1 selective inhibitor) in the CPP paradigm. These findings suggest that the GABAergic system plays an important role in morphine addiction and point to the possibility of developing drugs that target GAT1 and extend the clinical application of opiates.
Hu
Jia-Hua
JH
Laboratory of Molecular Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Yang
Na
N
Ma
Ying-Hua
YH
Zhou
Xiao-Gang
XG
Zhang
Xu-Ying
XY
Jiang
Jie
J
Mei
Zhen-Tong
ZT
Fei
Jian
J
Guo
Li-He
LH
D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003213:Conditioning, Psychological; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009021:Morphine Dependence / Q000235:genetics / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D027361:Organic Anion Transporters; D010091:Oximes / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012054:Reinforcement, Psychology; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002352:Carrier Proteins; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009292:Narcotic Antagonists; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010091:Oximes; D017450:Receptors, Opioid, mu; C493414:Slc6a1 protein, mouse; C078793:NNC 711; D009270:Naloxone; D005680:gamma-Aminobutyric Acid