Enriched environment confers resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors.
We investigated, in mice, the influence of life experience on the vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a major neurotoxin that induces a Parkinson's disease-like syndrome in humans, and to cocaine, a potent psychostimulant that promotes drug addiction. Our findings show that adult C57BL/6 mice raised in an enriched environment (EE) for only 2 months are significantly more resistant to both drugs compared with mice raised in a standard environment (SE). Indeed, EE mice showed decreased locomotor activity in response to cocaine (10 and 20 mg/kg) as well as a different pattern of c-fos expression in the striatum compared with SE mice. After MPTP treatment, SE mice showed a 75% loss of dopamine neurons, whereas EE mice showed only a 40% loss. The dopamine transporter plays a key role in mediating the effects of both drugs. We thus investigated the regulation of its expression. EE mice showed less dopamine transporter binding in the striatum and less dopamine transporter mRNA per dopamine neuron at the cellular level as demonstrated by in situ hybridization. In addition, enriched environment promoted an increase in the expression of brain-derived neurotrophic factor in the striatum. These data provide a direct demonstration of the beneficial consequences that a positive environment has in preventing neurodegeneration and in decreasing responsiveness to cocaine. Furthermore, they suggest that the probability of developing neurological disorders such as Parkinson's disease or vulnerability to psychostimulants may be related to life experience.
Bezard
Erwan
E
Basal Gang, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5543, Université Victor Segalen, 33076 Bordeaux Cedex, France.
Dovero
Sandra
S
Belin
David
D
Duconger
Sophie
S
Jackson-Lewis
Vernice
V
Przedborski
Serge
S
Piazza
Pier Vincenzo
PV
Gross
Christian E
CE
Jaber
Mohamed
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000517:prevention & control; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity; D050483:Dopamine Plasma Membrane Transport Proteins; D004351:Drug Resistance / Q000502:physiology*; D004777:Environment; D005106:Exploratory Behavior / Q000187:drug effects; D006133:Growth Substances / Q000378:metabolism*; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D009498:Neurotoxins / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000517:prevention & control; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
D015415:Biomarkers; D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D006133:Growth Substances; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D016760:Proto-Oncogene Proteins c-fos; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003042:Cocaine