Expression changes of hippocampal energy metabolism enzymes contribute to behavioural abnormalities during chronic morphine treatment.
Dependence and impairment of learning and memory are two well-established features caused by abused drugs such as opioids. The hippocampus is an important region associated with both drug dependence and learning and memory. However, the molecular events in hippocampus following exposure to abused drugs such as opioids are not well understood. Here we examined the effect of chronic morphine treatment on hippocampal protein expression by proteomic analyses. We found that chronic exposure of mice to morphine for 10 days produced robust morphine withdrawal jumping and memory impairment, and also resulted in a significant downregulation of hippocampal protein levels of three metabolic enzymes, including Fe-S protein 1 of NADH dehydrogenase, dihydrolipoamide acetyltransferase or E2 component of the pyruvate dehydrogenase complex and lactate dehydrogenase 2. Further real-time quantitative PCR analyses confirmed that the levels of the corresponding mRNAs were also remarkably reduced. Consistent with these findings, lower ATP levels and an impaired ability to convert glucose into ATP were also observed in the hippocampus of chronically treated mice. Opioid antagonist naltrexone administrated concomitantly with morphine significantly suppressed morphine withdrawal jumping and reversed the downregulation of these proteins. Acute exposure to morphine also produced robust morphine withdrawal jumping and significant memory impairment, but failed to decrease the expression of these three proteins. Intrahippocampal injection of D-glucose before morphine administration significantly enhanced ATP levels and suppressed morphine withdrawal jumping and memory impairment in acute morphine-treated but not in chronic morphine-treated mice. Intraperitoneal injection of high dose of D-glucose shows a similar effect on morphine-induced withdrawal jumping as the central treatment. Taken together, our results suggest that reduced expression of the three metabolic enzymes in the hippocampus as a result of chronic morphine treatment contributes to the development of drug-induced symptoms such as morphine withdrawal jumping and memory impairment.
State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Xiao-Lan
XL
Chen
Gang
G
Lu
Ying-Xia
YX
Gong
Liang-Cai
LC
Zhao
Jie
J
Chen
Zhi-Qiang
ZQ
Chi
Yi-Ming
YM
Yang
Zhong
Z
Chen
Qing-lin
QL
Li
Jing-Gen
JG
Liu
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000235:genetics / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology
D000701:Analgesics, Opioid; D007506:Iron-Sulfur Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D012965:Sodium Chloride; D009020:Morphine; D007770:L-Lactate Dehydrogenase; C409676:lactate dehydrogenase 2; D009245:NADH Dehydrogenase; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D005947:Glucose