Alterations of BDNF and trkB mRNA Expression in the 6-Hydroxydopamine-Induced Model of Preclinical Stages of Parkinson’s Disease: An Influence of Chronic Pramipexole in Rats

<div><p>Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson’s disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by <i>in situ</i> hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.</p></div

The influence of 6-OHDA, pramipexole and imipramine on BDNF and trkB mRNAs in the caudate-putamen.

<p>n = 9–10. For further explanations see Figs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g002" target="_blank">2</a>.</p

The influence of 6-OHDA, pramipexole and imipramine on trkB mRNA in the hippocampus.

<p>n = 9–10. For further explanations see Figs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g002" target="_blank">2</a>.</p

The influence of 6-OHDA, pramipexole and imipramine on BDNF and trkB mRNAs in mesencephalic structures.

<p>n = 5–10 (substantia nigra), n = 7–10 (ventral tegmental area). For further explanations see Figs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g002" target="_blank">2</a>.</p

The influence 6-OHDA, pramipexole and imipramine on BDNF and trkB mRNAs in the amygdala.

<p>n = 8–10. For further explanations see Figs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g002" target="_blank">2</a>.</p

The influence of 6-OHDA, pramipexole and imipramine on BDNF mRNA in the hippocampus.

<p>The results are expressed as the mean ± S.E.M. LESION—lesioned rats, IMI—imipramine, PRA—pramipexole, Q-B/pixel2—the mean optical density-background per area units, SAL—saline, SHAM—sham-operated rats, n = 7–10, differences between SHAM-SAL vs. other groups are indicated by *p≤0.05, and differences between LESION-SAL vs. other groups by #p≤0.05). For further explanations see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">Fig. 1</a>.</p

The influence of 6-OHDA, pramipexole and imipramine on BDNF mRNA in the nucleus accumbens.

<p><b>n = 9–10.</b> For further explanations see Figs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g002" target="_blank">2</a>.</p

The influence of 6-OHDA, pramipexole and imipramine on BDNF and trkB mRNAs in the caudate-putamen.

<p>n = 9–10. For further explanations see Figs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g002" target="_blank">2</a>.</p

Representative autoradiograms showing BDNF and trkB mRNAs expression in frontal sections of the brain.

<p>Regions of interest are outlined. AMG—amygdala, CP—caudate-putamen, DG—dentate gyrus, HB—habenula, NAC—nucleus accumbens, SN—substantia nigra, VTA—ventral tegmental area. AP—anterior-posterior levels according to Paxinos and Watson [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.ref045" target="_blank">45</a>].</p

The influence of 6-OHDA, pramipexole and imipramine on BDNF and trkB mRNAs in the habenula.

<p>n = 8–10. For further explanations see Figs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117698#pone.0117698.g002" target="_blank">2</a>.</p