Elsevier

Biological Psychiatry

Volume 61, Issue 7, 1 April 2007, Pages 890-901
Biological Psychiatry

Original Article
An Inducer for Glial Cell Line-Derived Neurotrophic Factor and Tumor Necrosis Factor–α Protects Against Methamphetamine-Induced Rewarding Effects and Sensitization

https://doi.org/10.1016/j.biopsych.2006.06.016Get rights and content

Background

There are few efficacious medications for drug dependence. We investigated the potential of Leu-Ile, which induces the expression of glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-α (TNF-α), as a novel therapeutic agent for methamphetamine (METH)-induced dependence.

Methods

The levels of GDNF and TNF-α messenger RNA (mRNA) were determined by real-time reverse transcription polymerase chain reaction. Enzyme immunoassays and immunohistochemistry were employed to determine levels of these proteins. Effects of Leu-Ile on METH-induced rewarding effects and sensitization were investigated with conditioned place preference and locomotor activity tests. Extracellular dopamine (DA) levels and DA uptake into synaptosomes were examined with an in vivo microdialysis and trititated thymidine ([3H]) DA uptake assay.

Results

Leu-Ile induced the expression of not only GDNF but also TNF-α. Pretreatment with Leu-Ile blocked the acquisition of METH-induced place preference and sensitization. Interestingly, post-treatment with Leu-Ile attenuated them even after their development. An inhibitory effect of Leu-Ile on METH-induced place preference was observed in neither GDNF heterozygous nor TNF-α knockout mice. Leu-Ile inhibited DA release in the nucleus accumbens and the decrease in synaptosomal DA uptake in the midbrain induced by repeated METH treatment.

Conclusions

These results suggest that Leu-Ile inhibits METH-induced rewarding effects and sensitization by regulating extracellular DA levels via the induction of GDNF and TNF-α expression.

Section snippets

Reagents

Glial cell line-derived neurotrophic factor and TNF-α were donated by Amgen (Thousand Oaks, California) and Dainippon Pharmaceutical (Osaka, Japan), respectively. Leu-Ile was purchased from Kokusan Chemical (Tokyo, Japan). All other materials used were of reagent grade.

Animals

Animals were housed in plastic cages and kept in a temperature-, humidity-, and light-controlled room (23° ± 1°C; 50% ± 5% humidity; 12-hour light/dark cycle starting at 8:00 am) and had ad libitum access to food and water,

Effect of Leu-Ile on METH-Induced Increase in GDNF Levels

Levels of GDNF expression induced by Leu-Ile (.037, .37, 3.7, and 37 μg/mL) were determined in the cultured neurons with the EIA method. The GDNF levels were significantly increased 24 hours after the addition of Leu-Ile (.37 μg/mL) resulting in a bell-shaped dose response curve compared with the control group [F(4,25) = 8.895, p < .05, one-way ANOVA] (Figure 2A). Therefore, a dose of .37 μg/mL was used in this experiment. The time course of GDNF mRNA expression was determined 6, 12, and 24

Discussion

There are currently few efficacious medications for drug dependence. Recently, it has been reported that an opioid κ receptor agonist, TRK-820, inhibits not only the rewarding effects of morphine and cocaine but also a mecamylamine-precipitated nicotine-withdrawal aversive effect (Mori et al 2002, Tsuji et al 2001). A DA D3 receptor partial agonist, BP897affects cocaine-associated stimulus-induced drug-seeking behavior in rats (Cervo et al. 2003). These medications should be effective even when

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