THE RESPONSE OF SUBTHALAMIC NUCLEUS NEURONS TO DOPAMINE-RECEPTOR STIMULATION IN A RODENT MODEL OF PARKINSONS-DISEASE

Overactivity in the subthalamic nucleus (STN) is believed to contribut e to the pathophysiology of Parkinson's disease, It is hypothesized th at dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular si ngle unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal p athway (a model of Parkinson's disease), As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal cond itions and were decreased by the nonselective dopamine receptor agonis ts apomorphine and L-3,4-dihydroxyphenylalanine (L-DOPA), STN firing r ates were also decreased by the D2 receptor agonist quinpirole when ad ministered after the D1 receptor agonist nyl-2,3,4,5-tetrahydro-(1H)-3 -benzazepine-7,8-diol (SKF 38393). Results of the present study challe nge the prediction that dopaminergic agonists reduce STN activity pred ominantly through actions at striatal dopamine D2 receptors. Firing ra tes of STN neurons were not altered by selective stimulation of D2 rec eptors and were increased by selective stimulation of D1 receptors. Mo reover, there was a striking difference between the responses of the S TN to D1/D2 receptor stimulation in the lesioned and intact rat; apomo rphine inhibited STN firing in the lesioned rat and increased STN firi ng in the intact rat. These findings support the premise that therapeu tic efficacy in the treatment of Parkinson's disease is associated wit h a decrease in the activity of the STN, but challenge assumptions abo ut the roles of D1 and D2 receptors in the regulation of neuronal acti vity of the STN in both the intact and dopamine-depleted states.