The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice.
Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 µM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.
Gramage
Esther
E
Laboratory Pharmacology and Toxicology, Univ. San Pablo CEU, 28668 Boadilla del Monte, Madrid, Spain.
Putelli
Alessia
A
Polanco
Maria J
MJ
González-Martín
Carmen
C
Ezquerra
Laura
L
Alguacil
Luis F
LF
Pérez-Pinera
Pablo
P
Deuel
Thomas F
TF
Herradón
Gonzalo
G
D000661:Amphetamine / Q000633:toxicity*; D019969:Amphetamine-Related Disorders / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000503:physiopathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D009042:Motivation / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology; D016716:PC12 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D002352:Carrier Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; C066845:pleiotrophin; D000661:Amphetamine; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine