The time course of unconditioned morphine-induced psychomotor sensitization mirrors the phosphorylation of FADD and MEK/ERK in rat striatum: role of PEA-15 as a FADD-ERK binding partner in striatal plasticity.
Drugs of abuse induce behavioral neuroadaptations whose molecular mechanisms, partly known, are crucial to understanding drug addictions. The multifunctional adaptor Fas-associated protein with death domain (FADD) was recently associated with the induction of neuroplasticity. This study investigated the modulation of FADD and MAP kinase signaling, as well as their interactions with PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) and Akt1 pathways, during the expression of unconditioned morphine-induced psychomotor sensitization. In morphine-pretreated rats (10mg/kg during 5 days), a challenge dose of the opiate induced a robust psychomotor sensitization at early withdrawal (3 days, SW 3), but not after a prolonged abstinence period (14 days), which was coincident with an accelerated dopamine turnover in the striatum. Marked concomitant increases in the content of p-FADD (48%) and the activation of MEK-ERK (46-79%) were quantified during the short-term expression of morphine sensitization (SW 3, in the absence of morphine challenge). At SW 3, p-PEA-15, a FADD-ERK binding partner, was also upregulated (51%) as well as the activation of its phosphorylating Akt1 kinase (49%). Notably, the MEK inhibitor SL 327 attenuated (58%) the expression of morphine-induced psychomotor sensitization (SW 3) and fully prevented the upregulation of p-FADD, p-PEA-15 and p-Akt1 at SW 3. The results indicate that the activation of MEK/ERK, the upregulation of p-FADD and that of the linking partners PEA-15/Akt1 have a major role in mediating the short-lasting expression of unconditioned psychomotor sensitization induced by morphine in rats.
Ramos-Miguel
Alfredo
A
Laboratorio de Neurofarmacología, IUNICS, Universitat de les Illes Balears, and Red Temática de Investigación Cooperativa en Salud (Trastornos Adictivos), Palma de Mallorca, Balears, Spain.
Esteban
Susana
S
García-Sevilla
Jesús A
JA
D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004334:Drug Administration Schedule; D004563:Electrochemistry / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
D004791:Enzyme Inhibitors; D053200:Fas-Associated Death Domain Protein; D009294:Narcotics; D009419:Nerve Tissue Proteins; C424127:SL 327; D000607:Aminoacetonitrile; D009020:Morphine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases