Opiate withdrawal induces dynamic expressions of AMPA receptors and its regulatory molecule CaMKIIalpha in hippocampal synapses.
Adaptive changes in brain areas following drug withdrawal are believed to contribute to drug seeking and relapse. Cocaine withdrawal alters the expression of GluR1 and GluR2/3 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in nucleus accumbens or amygdala, but the influence of drug withdrawal on hippocampus is little known. Here, we have examined the expression of GluR1 and GluR2/3 in hippocampal membrane and synaptic fractions following repeated morphine exposure and subsequent withdrawal. Repeated morphine exposure for 12 d increased GluR1 and GluR2/3 in synaptosome but not in membrane fraction. Interestingly, CaMKIIalpha, known to be able to regulate the function of AMPA receptors, was decreased in synaptosome but not in membrane fraction; pCaMKIIalpha, the phosphorylated form of CaMKIIalpha, was increased in both fractions. However, during opiate withdrawal, GluR1 was generally reduced while GluR2/3 was prominently increased in both fractions; pCaMKIIalpha was strongly decreased immediately after withdrawal, but detectably increased in late phase of morphine withdrawal in both fractions. Importantly, the opiate withdrawal-induced increase in GluR2/3 was dependent on the activation of glucocorticoid receptors and NMDA receptors, as it was prevented by the glucocorticoid receptor antagonist RU38486, or intrahippocampal injection of the NMDA receptor antagonist AP-5 or the antagonist to NR2B-containing NMDA receptors, Ro25-6981. These findings indicate that opiate withdrawal induces dynamic expression of GluR1 and GluR2/3 subunits of AMPA receptors in hippocampal synapses, possibly revealing an adaptive process of the hippocampal functions following opiate withdrawal.
Zhong
Weixia
W
Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310006, PR China.
Dong
Zhifang
Z
Tian
Meng
M
Cao
Jun
J
Xu
Tianle
T
Xu
Lin
L
Luo
Jianhong
J
D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis*; D002462:Cell Membrane / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009020:Morphine / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013315:Stress, Psychological / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
D000701:Analgesics, Opioid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008565:Membrane Proteins; D009020:Morphine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C104722:glutamate receptor ionotropic, AMPA 2