Nicotine-induced sensitization in mice: changes in locomotor activity and mesencephalic gene expression.
It is believed that drug-induced behavioral sensitization is an important process in the development of substance dependence. In order to explore mechanisms of sensitization, a mouse model of nicotine-induced locomotor sensitization was established, and effects of the sensitization process on mesencepahlic gene expression were examined. A schedule, which included 3 weeks of intermittent nicotine exposure (0.5 mg/kg, s.c.) and 3 weeks of withdrawal, resulted in locomotor sensitization. Effects of sensitization on mesencephalic expression of approximately 14,000 genes were assessed using oligonucleotide microarrays. Signal intensity differences in samples obtained from repeated nicotine- and saline-exposed animals were analyzed with z-test after False Discovery Rate (FDR) multiple test correction. Genes related to GABA-A receptors and protein phosphatases were among 68 genes showing significantly different expression levels between the saline and the nicotine groups. We hypothesize that some of the gene expression changes in the mesencephalon are involved in pathways leading to nicotine-induced sensitization. Down-regulation of GABA-A receptors induced by repeated nicotine exposure may facilitate dopaminergic neuronal transmission and may contribute to increased locomotor activity.
Saito
Mariko
M
Laboratory of Neurobehavioral Genetics, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. marsaito@nki.rfmh.org
O'Brien
Danielle
D
Kovacs
Krisztina M
KM
Wang
Ray
R
Zavadil
Jiri
J
Vadasz
Csaba
C
D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology*
D009538:Nicotine