Dopamine receptor supersensitivity in rat subthalamus after 6-hydroxydopamine lesions.
The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta, but the importance of this input in the pathophysiology of parkinsonism remains to be determined. We used whole-cell patch-clamp recordings in brain slices to study presynaptic dopaminergic modulation of synaptic inputs to the STN in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. Here, we report that dopamine was more potent for inhibiting GABA IPSCs and glutamate EPSCs in the STN ipsilateral to the lesion, and was less potent for suppressing IPSCs and EPSCs in the STN contralateral to the lesion, compared with the effects of dopamine in control STN. Dopamine reduced IPSCs with an IC50 value of 20.9 +/- 3.6 microM in control STN, whereas IC50 values were 0.83 +/- 0.15 and 55.1 +/- 11.1 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Dopamine also inhibited EPSCs with an IC50 value of 12.8 +/- 2.8 microM in control STN, whereas IC50 values were 4.5 +/- 0.9 and 41.6 +/- 9.8 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Results with paired stimuli to evoke EPSCs and IPSCs suggest that endogenous dopamine acts presynaptically to inhibit transmitter release in the STN. These results show that chronic dopamine denervation significantly alters the regulation of synaptic input to the STN. Our results also suggest that the STN may be an important target for levodopa therapy in Parkinson's disease.
Shen
Ke-Zhong
KZ
Department of Neurology, Oregon Health and Science University, Portland, OR 97239 USA.
Zhu
Zi-Tao
ZT
Munhall
Adam
A
Johnson
Steven W
SW
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007839:Functional Laterality; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000473:pathology; D013565:Sympatholytics; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D011954:Receptors, Dopamine; D013565:Sympatholytics; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D016627:Oxidopamine; D014633:Valine; D004298:Dopamine