The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice

Addict Biol. 2010 Oct;15(4):403-12. doi: 10.1111/j.1369-1600.2009.00202.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / toxicity*
  • Amphetamine-Related Disorders / genetics*
  • Amphetamine-Related Disorders / physiopathology
  • Animals
  • Carrier Proteins / genetics*
  • Cell Survival / drug effects
  • Cell Survival / genetics*
  • Cell Survival / physiology
  • Conditioning, Classical / drug effects*
  • Conditioning, Classical / physiology
  • Corpus Striatum / drug effects*
  • Corpus Striatum / physiopathology
  • Cytokines / genetics*
  • Dopamine / metabolism*
  • Glial Fibrillary Acidic Protein / metabolism
  • Gliosis / chemically induced
  • Gliosis / physiopathology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Motivation / drug effects*
  • Motivation / physiology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiopathology
  • PC12 Cells
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Carrier Proteins
  • Cytokines
  • Glial Fibrillary Acidic Protein
  • pleiotrophin
  • Amphetamine
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Dopamine