| The globus pallidus occupies a very important position in the basal ganglia. Orexin is a member of neuropeptides family which was first identified in the hypothalamus. Much evidence has shown that central orexinergic systems are closely related to Parkinson’s disease. The globus pallidus receives orexinergic innervation arising from the hypothalamus. Morphological studies have shown the expression of both orexin-1 and orexin-2 receptors in the globus pallidus. Object: To elucidate the modulation of endogenous orexin on the spontaneous firing activity of the globus pallidus neurons and the possible involvement in Parkinson’s disease. Methods: In vivo extracellular single unit recordings, 6-hydroxydopamine(6-OHDA)-lesioned parkinsonian rats, lateral hypothalamus area(LHA) lesions model rats, haloperidol rigidity rats, cannula implantation, elevated body swing test(EBST) were performed in the present study. Results: 1. In the globus pallidus of normal rats, 33 pallidal neurons were recorded. Micropressure ejection of the specific OX1 receptor antagonist, SB-334867(0.1μM), decreased the basal firing rate from 15.78±3.03 Hz to 11.48±2.45 Hz(P<0.001) in 22 out of the 33 neurons. The average decrease was 35.64±4.01%, which was significantly different(P<0.001) from that of vehicle(normal saline) injection. Further analysis of firing pattern showed that SB-334867 increased both CV(basal: 0.74±0.11; SB-334867: 0.87±0.12; P<0.05) and FF(Basal: 0.27±0.11; SB-334867: 0.64±0.29; P<0.05), suggesting that SB-334867 change the firing pattern with reducing the regularity of the spontaneous firing. A positive correlation between SB-334867-induced change in firing rate and the basal firing level was observed in globus pallidus neurons(r=0.519, P<0.05). 2. Micropressure ejection of 0.01 n M, 1n M, 0.1μM, 0.01 m M and 0.1m M SB-334867 decreased the basal spontaneous firing rate by 18.11±3.92%, 25.20±5.74%, 35.64±4.01%, 21.60±4.48% and 17.62±3.20%, respectively. 3. In the globus pallidus of normal rats, micropressure ejection of the specific OX2 receptor antagonist, TCS-OX2-29(0.1μM), changed the basal firing rate from 16.23±1.98 Hz to 16.48±2.02 Hz in 11 neurons recorded. The average change was 0.90±0.03%. Further firing pattern analysis showed that TCS-OX2-29 did not change the CV(basal: 0.41±0.09; TCS-OX2-29: 0.45±0.08; P>0.05) and FF(basal: 0.039±0.022; TCS-OX2-29: 0.038±0.020; P>0.05). 4. In rats with LHA lesioning, micropressure ejection of 0.1μM SB-334867 did not change the basal firing rate significantly(basal: 15.91±1.93 Hz; SB-334867: 16.33±2.04 Hz) in 20 our of the 29 pallidal neurons. The average change was 2.61±2.13%, which was significantly different(χ2=7.839, d.f.=1, P<0.01) from that of normal rats. 5. In the globus pallidus of normal rats, micropressure ejection of 0.1μM SB-334867+0.01 m M orexin-A increased the average firing rate by 11.06±4.00% in 8 pallidal neurons. However, micropressure ejection of 0.01 m M orexin-A alone increased the average firing rate by 38.08±10.99% in the some 8 neurons, which was significantly different(P<0.05) from that of co-application of SB-334867 and orexin-A. Furthermore, micropressure ejection of 0.1μM TCS-OX2-29+0.01 m M orexin-A changed the basal firing rate from 13.74±2.45 Hz to 15.58±2.69 Hz. The average increase was 14.85±2.02%, which was significantly weaker than that of orexin-A alone(P<0.05). 6. In 6-OHDA parkinsonian rats, micropressure ejection of 0.1μM SB-334867 decreased the basal firing rate from 13.48±2.72 Hz to 10.79±2.38 Hz(P<0.001) in 16 pallidal neurons on the unlesioned side. The average decrease was 26.66±4.40%, which was significantly different(P<0.001) from that of vehicle(normal saline) injection. In 15 pallidal neurons on the lesioned side, micropressure ejection of 0.1μM SB-334867 decreased the basal firing rate from 17.87±2.32 Hz to 16.14±2.20 Hz(P<0.001). The average decrease was 10.79±1.25%(P<0.001 compared with vehicle), which was significantly weaker than that of unlesioned side). 7. In EBST, unilateral microinjection of orexin-A into the globus pallidus increased the percent of contralateral-biased swing(89.0±4.0%, n=8), which was significantly different compared to that of control group(48.0±2.0%, n=5, P<0.001). Unilateral microinjection of SB-334867 into the globus pallidus induced ipsilateral-biased swing(92.0±2.8%, n=9, P<0.001 compared to that of control). 8. In haloperidol-induced rigidity rats, unilateral microinjection of SB-334867 into the globus pallidus induced ipsilateral deflection, which was significantly different compared to that of control group(P<0.001). Conclusion: The present in vivo electrophysiological studies provided evidence that SB-334867 decreased the spontaneous firing of pallidal neurons in both normal and 6-OHDA lesioned parkinsonian rats, suggesting the involvement of endogenous orexinergic systems in the activity of globus pallidus mainly through orexin-1 receptors. Pallidal orexinergic systems may modulate the motor behavior in rats. The present studies may provide further rational and experimental basis for investigations into the potential of endogenous orexinergic systems in the treatment of Parkinson’s disease. |
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