Elsevier

Neuroscience

Volume 119, Issue 3, 4 July 2003, Pages 767-775
Neuroscience

Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine

https://doi.org/10.1016/S0306-4522(03)00099-XGet rights and content

Abstract

It is widely recognized that methamphetamine enhances the release of dopamine at dopaminergic neuron terminals of the mesolimbic system, which induces dopamine-related behaviors. Brain-derived neurotrophic factor (BDNF), a neurotrophin, binds to and activates its specific receptor tyrosine kinase, TrkB. BDNF has been shown to influence the release of dopamine in the mesolimbic dopamine system. The present study was designed to investigate roles of BDNF and TrkB in the expression of methamphetamine-induced dopamine release in the nucleus accumbens and dopamine-related behaviors induced by methamphetamine in rats. Methamphetamine (1 mg/kg, s.c.) produced a substantial increase in the extracellular levels of dopamine and induced a progressive augmentation of dopamine-related behaviors such as rearing and sniffing. In contrast, both the stimulation of dopamine release and induction of dopamine-related behaviors by methamphetamine were significantly suppressed by pretreatment with intra-nucleus accumbens injection of either BDNF (2.0 μl/rat, 1:1000, 1:300 and 1:100) or TrkB (2.0 μl/rat, 1:1000 and 1:100) antibody. Furthermore, the basal level of dopamine in the nucleus accumbens was not affected by treatment with both BDNF and TrkB antibodies. These findings provide further evidence that BDNF/TrkB pathway is implicated in the methamphetamine-induced release of dopamine and the induction of dopamine-related behaviors.

Section snippets

Experimental procedures

The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals, Hoshi University, as adopted by the Committee on Animal Research of Hoshi University, which is accredited by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Histological analysis

Fig. 1 shows the placement of microdialysis probes in the nucleus accumbens. Guide cannulas were localized above the nucleus accumbens. Only data from the rats in which the probes were inserted accurately into the nucleus accumbens were used for the subsequent statistical analysis.

Effect of pretreatment with bdnf or trkb antibody into the nucleus accumbens on the meth-induced enhancement of da release and decreasing of dopac and hva in the nucleus accumbens

Table 1 shows basal levels of DA. Compared with the saline-pretreated group, basal levels of DA in the nucleus accumbens were not changed in rats that received intra-nucleus accumbens BDNF-antibody (2.0 μl,

Discussion

The nucleus accumbens has been shown to be the key brain region that underlies the action of psychostimulants and opioids such as METH, cocaine and morphine. Various studies provide evidence that METH and d-amphetamine significantly release DA in the nucleus accumbens (Di Chiara and Imperato, 1988; Zhang et al., 2001; for review see Seiden et al., 1993), which results in the expression of their DA-related actions, including drug dependence. It is also well recognized that rearing and sniffing

Conclusion

We demonstrated here that the microinjection of either BDNF or TrkB antibody into the nucleus accumbens significantly decreases the substantial elevation of extracellular DA levels by METH without any changes in the basal DA level, resulting in a significant decrease in METH-induced DA-related behaviors. These findings imply that BDNF/TrkB pathway may be involved in the expression of METH-induced DA release and its related pharmacological actions.

Acknowledgements

This work was supported in part by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology of Japan. We wish to thank Ms Naoko Kuzumaki and Ms Kaori Shibui for their expert technical assistance.

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