Neurturin effects on nigrostriatal dopamine release and content: comparison with GDNF

Abstract

Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family; and, while GDNF has been shown to increase dopamine (DA) release in normal animals, the ability of NTN to alter DA release has not been previously reported. The purpose of the present study was to determine if NTN could alter striatal DA release, and to compare the effects of NTN to GDNF. Male Fischer-344 rats were given a single injection of vehicle or 5 microg NTN or GDNF into the right substantia nigra. Three weeks later microdialysis experiments were conducted to assess striatal DA release. Basal extracellular levels of striatal DA were not affected by either NTN or GDNF. However, both NTN and GDNF led to increases in amphetamine-evoked overflow of DA from the ipsilateral striatum, and there was a trend for potassium-evoked overflow to be augmented. Postmortem tissue levels of DA were decreased by approximately 20% in the striatum, and increased by approximately 100% in the substantia nigra, on the ipsilateral side of the brain compared to the contralateral side following both NTN and GDNF injection. Thus, NTN, like GDNF, can augment striatal DA release, and the magnitude of the NTN effects are similar to those of GDNF.

Fig. 1

Dialysate levels of DA from the striatum of animals injected into the right substantia nigra with vehicle, NTN or GDNF. Microdialysis experiments were carried out 3 weeks after the injections. Excess potassium (100 mM) was included in the perfusate for 20-min starting at 0 min (horizontal bar above K⁺), and 100 μM amphetamine was included in the perfusate for 20-min starting at 120 min (horizontal bar above Amphetamine). Values shown are mean ± SEM from 7–8 animals per group

Fig. 2

Dialysate levels of DOPAC from the striatum of animals injected into the right substantia nigra with vehicle, NTN or GDNF. Microdialysis experiments were carried out 3 weeks after the injections. Excess potassium (100 mM) was included in the perfusate for 20-min starting at 0 min (horizontal bar above K⁺), and 100 μM amphetamine was included in the perfusate for 20-min starting at 120 min (horizontal bar above Amphetamine). Values shown are mean ± SEM from 7–8 animals per group. * P < 0.05 versus left side (repeated measures ANOVA; Newman-Keuls post-hoc comparisons indicated a significant difference (P < 0.01) between the left and right sides at each individual time point for both the NTN and GDNF treated groups)

Fig. 3

Dialysate levels of HVA from the striatum of animals injected into the right substantia nigra with vehicle, NTN or GDNF. Microdialysis experiments were carried out 3 weeks after the injections. Excess potassium (100 mM) was included in the perfusate for 20-min starting at 0 min (horizontal bar above K⁺), and 100 μM amphetamine was included in the perfusate for 20-min starting at 120 min (horizontal bar above Amphetamine). Values shown are mean ± SEM from 7–8 animals per group. * P < 0.05 versus left side (repeated measures ANOVA; Newman-Keuls post-hoc comparisons indicated a significant difference (P < 0.01) between the left and right sides at each individual time point for both the NTN and GDNF treated groups)

Fig. 4

Potassium-evoked (top panel) and amphetamine-evoked (bottom panel) overflow of DA from the striatum of animals injected into the right substantia nigra with vehicle, NTN or GDNF. Microdialysis experiments were carried out 3 weeks after the injections. Values shown are mean ± SEM from 7–8 animals per group. * P < 0.05 versus left side (mixed ANOVA followed by Newman-Keuls post-hoc comparisons)

Fig. 5

Postmortem tissue levels of DA from the striatum and substantia nigra of animals injected into the right substantia nigra with vehicle, NTN or GDNF. Tissue was harvested 3 weeks after the injections. Values shown are mean ± SEM from 7–8 animals per group. * P < 0.001 versus left side (mixed ANOVA followed by Newman-Keuls post-hoc comparisons)