title: Methamphetamine-associated cleavage of the synaptic adhesion molecule intercellular adhesion molecule-5.
abstract: Methamphetamine (MA) is a highly addictive psychostimulant that, used in excess, may be neurotoxic. Although the mechanisms that underlie its addictive potential are not completely understood, in animal models matrix metalloproteinase (MMP) inhibitors can reduce behavioral correlates of addiction. In addition, evidence from genome-wide association studies suggests that polymorphisms in synaptic cell-adhesion molecules (CAMs), known MMP substrates, are linked to addictive potential in humans. In the present study, we examined the ability of MA to stimulate cleavage of intercellular adhesion molecule-5 (ICAM-5), a synaptic CAM expressed on dendritic spines in the telencephalon. Previous studies have shown that shedding of ICAM-5 is associated with maturation of dendritic spines, and that MMP-dependent shedding occurs with long term potentiation. Herein, we show that MA stimulates ectodomain cleavage of ICAM-5 in vitro, and that this is abrogated by a broad spectrum MMP inhibitor. We also show that an acute dose of MA, administered in vivo, is associated with cleavage of ICAM-5 in murine hippocampus and striatum. This occurs within 6 h and is accompanied by an increase in MMP-9 protein. In related experiments, we examined the potential consequences of ICAM-5 shedding. We demonstrate that the ICAM-5 ectodomain can interact with β(1) integrins, and that it can stimulate β(1) integrin-dependent phosphorylation of cofilin, an event that has previously been linked to MMP-dependent spine maturation. Together these data support an emerging appreciation of MMPs as effectors of synaptic plasticity and suggest a mechanism by which MA may influence the same.
authors.affiliation: The Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia 20007, USA. kec84@georgetown.edu
authors.forename: Katherine
authors.initials: K
authors.lastname: Conant
authors.forename: Irina
authors.initials: I
authors.lastname: Lonskaya
authors.forename: Arek
authors.initials: A
authors.lastname: Szklarczyk
authors.forename: Caroline
authors.initials: C
authors.lastname: Krall
authors.forename: Joseph
authors.initials: J
authors.lastname: Steiner
authors.forename: Kathleen
authors.initials: K
authors.lastname: Maguire-Zeiss
authors.forename: Seung T
authors.initials: ST
authors.lastname: Lim
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003720:Densitometry; D004151:Dipeptides / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D019012:Integrin beta1 / Q000096:biosynthesis; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D013131:Spine / Q000254:growth & development / Q000378:metabolism; D014162:Transfection
chemical_list: D051339:Actin Depolymerizing Factors; D015815:Cell Adhesion Molecules; D000697:Central Nervous System Stimulants; D004151:Dipeptides; C547413:ICAM5 protein, rat; D019012:Integrin beta1; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009419:Nerve Tissue Proteins; D011480:Protease Inhibitors; D008694:Methamphetamine; D020782:Matrix Metalloproteinases