The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson's disease

Abstract

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.

Fig. 1.

Distribution of basal neuronal firing rates of STN neurons in the intact rat (left; n = 55) and in the lesioned rat (right;n = 57). Solid symbols illustrate the spontaneous firing rate of individual neurons expressed as spikes per sec. The asterisks indicate that the overall mean basal firing rate for STN neurons in lesioned rats was significantly higher than the mean basal firing rate in intact rats (p < 0.01).

Fig. 2.

Patterns of firing over a 45 sec period for STN neurons. Vertical lines represent spike events. Neurons were selected for presentation to reflect the spectrum of interspike interval coefficient of variation values (a measure of the regularity of spike events) occurring among STN cells from intact (left) and lesioned (right) rats. The firing patterns of a and d have low (10th percentile) coefficient of variation values, b ande have median coefficient of variation values, andc and f have high (90th percentile) coefficient of variation values. The firing patterns of b, c, and f are bursting. The firing rates of the presented neurons are as follows: a, 8.4 Hz;b, 3.8 Hz; c, 8.9 Hz; d, 21.9 Hz; e, 11.7 Hz; and f, 14.7 Hz.

Fig. 3.

Effects of apomorphine on firing rates of STN neurons in the intact (left) and lesioned (right) rat. Top, Histograms, each illustrating the effects of apomorphine (APO; 0.32 mg/kg, i.v.) on a single STN neuron. Haloperidol (HAL; 0.2 mg/kg, i.v.) reversed the effects of apomorphine in these two cells. Arrows indicate the time at which the drug was administered. Bottom, The mean response (bar height), SEM (error bar), and individual responses (open symbols), all expressed as a percent of basal values, after administration of saline or apomorphine (0.32 mg/kg, i.v.). Thedata point in parentheses indicates a value that exceeds the scale of the y-axis. For reference, the dashed line indicates 100% of the basal firing rate. The asterisks indicate a significant difference from the saline-treated intact group, and the number signs indicate a significant difference from the apomorphine-treated intact group (p < 0.01).

Fig. 6.

The effects of quinpirole and haloperidol on firing rates of STN neurons in the intact (left) and lesioned (right) rat. The graphs illustrate the mean response (bar height), SEM (error bar), and range of individual responses (open symbols). Data are expressed as a percent of basal values after administration of saline, quinpirole (QUIN; 0.26 mg/kg, i.v.), and haloperidol (HAL; 0.2 mg/kg, i.v.). However, data for rats administered quinpirole 10 min after SKF 38393 administration (QUIN after SKF 38393; quinpirole, 0.16 mg/kg, i.v.; SKF 38393 doses as indicated) are expressed as a percent of SKF 38393-induced firing (i.e., the 4 min immediately before administration of quinpirole). For reference, the dashed line indicates 100% of predrug and saline firing rate. Theasterisks indicate a significant difference from the corresponding saline-treated group (p < 0.01).

Fig. 4.

The effects of l-DOPA on firing rates of STN neurons in benserazide-pretreated intact (left) and lesioned (right) rats. Top, Histograms, each illustrating the effects of l-DOPA (100 mg/kg, i.v.) on a single STN neuron. Haloperidol (HAL; 0.2 mg/kg, i.v.) reversed the effects of l-DOPA in the lesioned rat. Arrows indicate the time at which the drug was administered. Bottom, The mean response (bar height), SEM (error bar), and individual responses (open symbols), all expressed as a percent of basal values, after administration of saline or l-DOPA (100 mg/kg, i.v.). For reference, the dashed line indicates 100% of the basal firing rate. The asterisk indicates a significant difference from the saline-treated lesioned group (p < 0.05), and the number sign indicates a trend toward a significant difference from thel-DOPA-treated intact group (p = 0.057).

Fig. 5.

The effects of SKF 38393 on firing rates of STN neurons in the intact (left) and lesioned (right) rat. Top, An approximate twofold increase in firing rate produced by SKF 38393 (SKF; intact, 20 mg/kg, i.v.; lesioned, 10 mg/kg, i.v.), which were reversed by SCH 23390 (SCH; 0.5 mg/kg, i.v.).Arrows indicate the time at which the drug was administered. Bottom, The mean response (bar height), SEM (error bar), and individual responses (open symbols), all expressed as a percent of basal values, after administration of saline (SAL) or SKF 38393 (SKF; 10 or 20 mg/kg, i.v.). The data point inparentheses indicates a value that exceeds the scale of the y-axis. For reference, the dashed line indicates 100% of the basal firing rate. Theasterisks indicate a significant difference from the corresponding saline-treated group (p < 0.01).