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Dopaminergic presynaptic modulation of nigral afferents: its role in the generation of recurrent bursting in substantia nigra pars reticulata neurons.

de Jesús Aceves J, Rueda-Orozco PE, Hernández R, Plata V, Ibañez-Sandoval O, Galarraga E, Bargas J - Front Syst Neurosci (2011)

Bottom Line: No action of D(1)-class agonists was found on pallidonigral synapses.The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models.These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism.

View Article: PubMed Central - PubMed

Affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México Distrito Federal México, México.

ABSTRACT
PREVIOUS WORK HAS SHOWN THE FUNCTIONS ASSOCIATED WITH ACTIVATION OF DOPAMINE PRESYNAPTIC RECEPTORS IN SOME SUBSTANTIA NIGRA PARS RETICULATA (SNR) AFFERENTS: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D(1)-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D(1)- and D(2)-class receptors where D(1)-class receptor activation enhances and D(2)-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D(2)-class receptors (D(3) and D(4) types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D(1)-class agonists was found on pallidonigral synapses. In contrast, administration of D(1)-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D(3) and D(4) type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D(1)- and D(2)-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism.

No MeSH data available.


Related in: MedlinePlus

Biphasic concentration–response relationship of D1-agonist. (A) 5 μM SKF 81297 decreased IPSCs evoked from striatonigral terminals. (B) 5 μM SKF 81297 decreased IPSCs evoked from pallidonigral terminals. Record 3 in each frame is the superimposition of representative records 1 and 2 after normalization of the first IPSC to better appreciate the PPR change when it is present. (C) Concentration–response relationship (C–R plot) showed a biphasic response on striatonigral responses: once 3 μM are surpassed, IPSCs decay with increasing concentrations. Ascending C–R plot was fitted with the Hill equation finding a submicromolar EC50.
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Figure 3: Biphasic concentration–response relationship of D1-agonist. (A) 5 μM SKF 81297 decreased IPSCs evoked from striatonigral terminals. (B) 5 μM SKF 81297 decreased IPSCs evoked from pallidonigral terminals. Record 3 in each frame is the superimposition of representative records 1 and 2 after normalization of the first IPSC to better appreciate the PPR change when it is present. (C) Concentration–response relationship (C–R plot) showed a biphasic response on striatonigral responses: once 3 μM are surpassed, IPSCs decay with increasing concentrations. Ascending C–R plot was fitted with the Hill equation finding a submicromolar EC50.

Mentions: Therefore we were forced to infer that reports about D1-mediated inhibition of striatonigral terminals (Miyazaki and Lacey, 1998) were either involving a non-specific action, a pallidal contamination, or both. To test this hypothesis we used larger micromolar concentrations of the D1-agonist while evoking IPSCs from both pathways. Figures 3A,B show that 5 μM SKF 81297 decreased IPSCs evoked from both set of terminals. Striatonigral IPSC decreased 82 ± 13% (n = 18; P < 0.001) and pallidonigral responses decreased by 35 ± 15% (n = 6; P < 0.005). These actions could not be blocked by micromolar concentrations of SCH 23390 (not shown), suggesting that they were not specific. In view of these results we built a concentration–response relationship (C–R plot) using a wide range of SKF 81297 concentrations while stimulating striatonigral afferents. This C–R plot can be seen in Figure 3C: it is biphasic. When the Hill equation was fitted to the ascending (specific part) EC50 was 440 ± 60 nM and the Hill coefficient 1.6 ± 0.2, suggesting cooperativity and a specific action at submicromolar concentrations. Moreover, the fact that pallidonigral inputs are also affected when they do not respond when submicromolar concentrations of agonists are used confirmed non-specific actions.


Dopaminergic presynaptic modulation of nigral afferents: its role in the generation of recurrent bursting in substantia nigra pars reticulata neurons.

de Jesús Aceves J, Rueda-Orozco PE, Hernández R, Plata V, Ibañez-Sandoval O, Galarraga E, Bargas J - Front Syst Neurosci (2011)

Biphasic concentration–response relationship of D1-agonist. (A) 5 μM SKF 81297 decreased IPSCs evoked from striatonigral terminals. (B) 5 μM SKF 81297 decreased IPSCs evoked from pallidonigral terminals. Record 3 in each frame is the superimposition of representative records 1 and 2 after normalization of the first IPSC to better appreciate the PPR change when it is present. (C) Concentration–response relationship (C–R plot) showed a biphasic response on striatonigral responses: once 3 μM are surpassed, IPSCs decay with increasing concentrations. Ascending C–R plot was fitted with the Hill equation finding a submicromolar EC50.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3039203&req=5

Figure 3: Biphasic concentration–response relationship of D1-agonist. (A) 5 μM SKF 81297 decreased IPSCs evoked from striatonigral terminals. (B) 5 μM SKF 81297 decreased IPSCs evoked from pallidonigral terminals. Record 3 in each frame is the superimposition of representative records 1 and 2 after normalization of the first IPSC to better appreciate the PPR change when it is present. (C) Concentration–response relationship (C–R plot) showed a biphasic response on striatonigral responses: once 3 μM are surpassed, IPSCs decay with increasing concentrations. Ascending C–R plot was fitted with the Hill equation finding a submicromolar EC50.
Mentions: Therefore we were forced to infer that reports about D1-mediated inhibition of striatonigral terminals (Miyazaki and Lacey, 1998) were either involving a non-specific action, a pallidal contamination, or both. To test this hypothesis we used larger micromolar concentrations of the D1-agonist while evoking IPSCs from both pathways. Figures 3A,B show that 5 μM SKF 81297 decreased IPSCs evoked from both set of terminals. Striatonigral IPSC decreased 82 ± 13% (n = 18; P < 0.001) and pallidonigral responses decreased by 35 ± 15% (n = 6; P < 0.005). These actions could not be blocked by micromolar concentrations of SCH 23390 (not shown), suggesting that they were not specific. In view of these results we built a concentration–response relationship (C–R plot) using a wide range of SKF 81297 concentrations while stimulating striatonigral afferents. This C–R plot can be seen in Figure 3C: it is biphasic. When the Hill equation was fitted to the ascending (specific part) EC50 was 440 ± 60 nM and the Hill coefficient 1.6 ± 0.2, suggesting cooperativity and a specific action at submicromolar concentrations. Moreover, the fact that pallidonigral inputs are also affected when they do not respond when submicromolar concentrations of agonists are used confirmed non-specific actions.

Bottom Line: No action of D(1)-class agonists was found on pallidonigral synapses.The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models.These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism.

View Article: PubMed Central - PubMed

Affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México Distrito Federal México, México.

ABSTRACT
PREVIOUS WORK HAS SHOWN THE FUNCTIONS ASSOCIATED WITH ACTIVATION OF DOPAMINE PRESYNAPTIC RECEPTORS IN SOME SUBSTANTIA NIGRA PARS RETICULATA (SNR) AFFERENTS: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D(1)-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D(1)- and D(2)-class receptors where D(1)-class receptor activation enhances and D(2)-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D(2)-class receptors (D(3) and D(4) types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D(1)-class agonists was found on pallidonigral synapses. In contrast, administration of D(1)-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D(3) and D(4) type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D(1)- and D(2)-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism.

No MeSH data available.


Related in: MedlinePlus