Abstract
Drug-induced plasticity of excitatory synapses has been proposed to be the cellular mechanism underlying the aberrant learning associated with addiction. Exposure to various drugs of abuse causes both morphological plasticity of dendritic spines and functional plasticity of excitatory synaptic transmission. Chronic activation of μ-opioid receptors (MOR) in cultured hippocampal neurons causes two forms of synaptic plasticity: loss of dendritic spines and loss of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. With use of live imaging, patch-clamp electrophysiology, and immunocytochemistry, the present study reveals that these two forms of synaptic plasticity are mediated by separate, but interactive, intracellular signaling cascades. The inhibition of Ca2+/calmodulin-dependent protein kinase II with 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine (KN-62) blocks MOR-mediated structural plasticity of dendritic spines, but not MOR-mediated cellular redistribution of GluR1 and GluR2 AMPA receptor subunits. In contrast, the inhibition of calcineurin with tacrolimus (FK506) blocks both cellular processes. These findings support the idea that drug-induced structural and functional plasticity of dendritic spines is mediated by divergent, but interactive, signaling pathways.
Footnotes
This project was supported by the National Institutes of Health National Institute on Drug Abuse [Grants T32-DA07234, R01-DA020582, K02-DA025048, P50-DA011806, R01-DA007339, R01-DA000564, R01-DA016674]; the National Institutes of Health National Institute of General Medical Sciences [Grants 5T32GM008471, P32-GM00847]; the Michael J. Fox Foundation; and the American Health Assistance Foundation.
The authors have no conflicts of interest to disclose.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- LTP
- long-term potentiation
- LTD
- long-term depression
- MOR
- μ-opioid receptor
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- CaMKII
- Ca2+/calmodulin-dependent protein kinase II
- GluR
- glutamate receptor
- DIV
- day 1 in vitro
- WT
- wild-type
- GFP
- enhanced green fluorescent protein
- CMV
- cytomegalovirus
- CTOP
- d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2
- KN-62
- 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine
- FK-506
- tacrolimus
- IEM-1460
- N,N,N,-trimethyl-5-[(tricyclo]3.3.1.13,7[dec-1-ylmethyl) amino]-1-pentanaminiumbromide
- mEPSC
- miniature excitatory postsynaptic current
- PSD
- postsynaptic density
- ANOVA
- analysis of variance
- CP
- Ca2+-permeable.
- Received February 7, 2012.
- Accepted May 17, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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