The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson's disease.
Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson's disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway (a model of Parkinson's disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine and L-3, 4-dihydroxyphenylalanine (L-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (+/-)- 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson's disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.
Kreiss
D S
DS
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1406, USA.
Mastropietro
C W
CW
Rawji
S S
SS
Walters
J R
JR
D000818:Animals; D015259:Dopamine Agents / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004594:Electrophysiology; D008297:Male; D009474:Neurons / Q000502:physiology*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology*; D013787:Thalamic Nuclei / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
D015259:Dopamine Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine