Ameliorating effect of histamine on impairment of cued fear extinction induced by morphine withdrawal in histidine decarboxylase gene knockout mice.
OBJECTIVE
Histamine plays an important role in morphine addiction and memory-dependent behavior. However, little is known about the effect of histamine on the impairment of memory after morphine withdrawal. This study was designed to investigate the effect of histamine on memory impairment induced by morphine withdrawal in histidine decarboxylase knockout (HDC-KO) and wild-type (WT) mice.


METHODS
WT and HDC-KO mice were given subcutaneous morphine or saline twice daily for 5 consecutive days. The mice received a cued or contextual fear conditioning session 7 days after the last injection. During subsequent days, mice received 4 cued or contextual extinction sessions (one session per day). Western blot was used to assess extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala and hippocampus.


RESULTS
Morphine withdrawal did not affect the acquisition of cued or contextual fear responses. It impaired cued but not contextual fear extinction. The acquisition of cued and contextual fear responses was accelerated in HDC-KO mice. Histamine deficiency aggravated the impairment of cued fear extinction induced by morphine withdrawal, whereas histamine (icv, 5 μg/mouse) reversed this effect. Morphine withdrawal decreased ERK phosphorylation in the amygdala after cued fear extinction, especially in HDC-KO mice.


CONCLUSIONS
These results suggest that morphine withdrawal specifically impairs cued fear extinction and histamine ameliorates this impairment. Its action might be mediated by the modulation of ERK phosphorylation in the amygdala. Histamine should be explored for possible roles in the prevention or treatment of morphine abuse and relapse.
Department of Pharmacology, Institute of Neuroscience, Zhejiang University, Hangzhou, China.
Ying-xia
YX
Gong
Wen-ting
WT
Shou
Bo
B
Feng
Wei-ping
WP
Zhang
Hui-juan
HJ
Wang
Hiroshi
H
Ohtsu
Zhong
Z
Chen
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003463:Cues; D005108:Extinction, Psychological / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005239:Fear / Q000187:drug effects*; D006632:Histamine / Q000096:biosynthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006640:Histidine Decarboxylase / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009021:Morphine Dependence / Q000188:drug therapy / Q000201:enzymology / Q000523:psychology*; D010766:Phosphorylation; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000523:psychology*
D006632:Histamine; D048049:Extracellular Signal-Regulated MAP Kinases; D006640:Histidine Decarboxylase