| The globus pallidus is an important structure in the indirect pathway of the basal ganglia circuit. By innervating all the other basal ganglia nuclei, the globus pallidus plays a critical role in movement regulation. Morphological studies have revealed a high level of GABA and GABAA receptors in the globus pallidus. The expression of GABAA receptors in the globus pallidus was decreased under parkinsonian state, while the GABA content was increased. Early studies have revealed that microinjection of GABAA receptor antagonist, bicuculline, into the globus pallidus had marked antiparkinsonian effects. Neurotensin is a tridecapeptide which plays an important role in the central nervous system by acting either as a neurotransmitter or a neuromodulator. Systemic administration of a neurotensin analog that can cross the blood-brain barrier produced antiparkinsonian effects in 6-hydroxydopamine (6-OHDA)-lesioned rats. Morphological studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and both neurotensin type-1 and type-2 receptors are present in the globus pallidus. Object:To investigate the effects of endogenous GABA and neurotensin in the globus pallidus of normal and parkinsonian rats. Methods:in vivo extracellular recording, behavioral tests and immunohistochemistry were performed in the present studies. Results:1. In normal rats, micro-pressure ejection of GABAA receptor antagonist, gabazine, increased the spontaneous firing rate of pallidal neurons from 15.9±1.8 Hz to 19.4±2.1 Hz. The average increase was 28.3±3.3%, which was significantly different (P<0.001) from that of vehicle (normal saline) injection.2. In 6-OHDA parkinsonian rats, gabazine increased the firing rate by 46.0% on the lesioned side, which was significantly greater than that on the unlesioned side (21.5%, P<0.05), as well as that in normal rats (28.3%, P<0.05).3. A negative correlation between gabazine-induced excitation and the basal firing rate was observed in globus pallidus neurons of both normal and 6-OHDA parkinsonian rats.4. Micro-pressure ejection of GABAB receptor antagonist, CGP55845, only produced a weak increase in the firing rate of globus pallidus neurons in normal and parkinsonian rats, which was not significantly different from that of control group (P>0.05).5. In the behaving rats, unilateral microinjection of gabazine evoked consistent contralateral rotation in normal rats (P<0.001), and significantly potentiated apomorphine-induced contralateral rotations in 6-OHDA parkinsonian rats (P<0.01).6. The expression of GABAA receptor al subunit was decreased in the globus pallidus on the lesioned side of 6-OHDA lesioned rats (P<0.01).7. Micro-pressure ejection of neurotensin into the globus pallidus increased the spontaneous firing rate of pallidal neurons in normal and 6-OHDA parkinsonian rats (P<0.001). The neurotensin-induced increase in firing rate of globus pallidus on unlesioned side (95.9%) was stronger than that on lesioned side (37.3%, P<0.05) and normal rats (48.3%, P<0.05).8. Bilateral microinjection of neurotensin into the globus pallidus significantly attenuated haloperidol-induced catalepsy (P<0.05). This anticataleptic effect was completely counteracted by SR48692.9. Microinjection of neurotensin excited pallidal neurons from 11.3±1.6 Hz to 14.8±1.9 Hz in the presence of systemic haloperidol administration. The average increase was 34.9±3.2% (P<0.001). SR48692 blocked the excitatory effect induced by neurotensin.10. In normal rats, intracerebroventricular microinjection of neurotensin significantly elevated the concentration of dopamine in the striatum (P<0.01). In 6-OHDA parkinsonian rats, the striatal dopamine level on the lesioned side was significantly decreased compared with that on the unlesioned side and normal rats (P<0.001), while the turnover ratio, (DOPAC+HVA)/DA, DOPAC/DA and HVA/DA, were significantly increased (P<0.001). Furthermore, microinjection of neurotensin significantly elevated the striatal dopamine level on both sides of 6-OHDA parkinsonian rats (P<0.05).Conclusion:The present study indicated that gabazine increased the spontaneous firing rate of globus pallidus neurons and potentiated apomorphine-induced contralateral rotation in 6-OHDA lesioned rats. Therefore, blockade of GABAA receptors in globus pallidus could counteract the excessive striato-pallidal activity under parkinsonian state. Neurotensin increased the activity of globus pallidus neurons and also increased the dopamine level in striatum on both normal and 6-OHDA parkinsonian rats. The present electrophysiological, behavioral and immunohistochemical studies may provide a rational for further investigations into the potential of pallidal GABAergic and neurotensinergic neurotransmission in the treatment of Parkinson's disease. |
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