Nicotine-Induced Sensitization in Mice: Changes in Locomotor Activity and Mesencephalic Gene Expression

Abstract

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.

Combined Exposure to Nicotine and Ethanol in Adolescent Mice Differentially Affects Anxiety Levels during Exposure, Short-Term, and Long-Term Withdrawal

“…Our results agree with previous studies that showed that mice are sensitive to the locomotor activating effects of nicotine (Saito et al, 2005;Ulusu et al, 2005). We were concerned that altered activity could influence anxiety measures; accordingly, in addition to using the absolute number of open arms entries as a measure of anxiety, we used the percentage of open arms entries.…”

“…In keeping with previous data (Saito et al, 2005;Ulusu et al, 2005), nicotine exposure alone elicited increased locomotor activity (NIC4VEH, Po0.02; NIC4ETOH, Po0.005; FPLSD). However, ethanol treatment reversed the nicotineinduced increase in locomotor activity as indicated by the significant difference between values for the nicotine and combined exposure groups (NIC4NIC + ETOH, Po0.002; FPLSD) and by the less-than-additive effect of NICOTINE and ETHANOL detected by the NICOTINE Â ETHANOL …”

Effects of a cannabinoid receptor (CB) 1 antagonist AM251 on behavioral sensitization to nicotine in a rat model of novelty-seeking behavior: correlation with hippocampal 5HT

“…Two independent populations of animals were used to test for two separate doses of therapeutics described in Drugs. Intermittent sensitization protocols were shown to induce strong behavioral sensitization (Robinson and Becker 1986;Vezina and Queen 2000;Kabbaj et al 2002;Saito et al 2005).…”

Ventral Tegmental Transcriptome Response to Intermittent Nicotine Treatment and Withdrawal in BALB/cJ, C57BL/6ByJ, and Quasi-Congenic RQI Mice

“…Intermittent exposure to nicotine, the major addictive agent in tobacco, produces locomotor sensitization in rodents [1,2]. Development of sensitization has been hypothesized to be involved in drug addiction and related to changes in activity of the mesolimbic circuitry [3][4][5][6].…”

“…Development of sensitization has been hypothesized to be involved in drug addiction and related to changes in activity of the mesolimbic circuitry [3][4][5][6]. Global effects of nicotine on gene expression have been studied in smokers [7,8], in rats [9] and mice [2] after intermittent nicotine treatments, in rats after chronic treatment [10][11][12][13], and using in vitro models [14][15][16].…”