Research reportGABAA-receptor activation in the subthalamic nucleus compensates behavioral asymmetries in the hemiparkinsonian rat
Introduction
The subthalamic nucleus (STN) has a crucial role in the development of motor impairments and abnormal neural activity following degeneration of midbain dopamine (DA) neurons. Several manipulations of the STN (lesions, pharmacological or electrical stimulation) compensate for the deficits associated with parkinsonism. The neurochemical bases of such manipulations remain poorly understood. The present experiment aimed at characterizing the involvement of GABAergic and glutamatergic STN receptors in movement control in hemiparkinsonian rats.
The unilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) is a widely applied rodent model of experimental parkinsonism and is known to alter GABAergic [1], [2] and glutamatergic [3] neurotransmission within different nuclei of the basal ganglia (BG), including the STN. The DAergic degeneration of nigro-striatal projections has also been shown to alter the firing pattern [4] and oscillatory activity [5] of several nuclei of the BG. Excessive rhythmic burst-activity and an increase in local field potential oscillations in power and coherence in the beta range (∼15–30 Hz) of the STN have been discussed to contribute to the manifestation of motor impairments in animal models of PD [5], [6], [7] as well as in PD patients [8], [9], [10], [11], [12]. Several manipulations of the STN have been demonstrated to compensate behavioral deficits associated with DA-denervation, both, in PD patients and pre-clinical rodent models, including lesion procedures [13], [14], [15], electrical [16] and pharmacological [17], [18], as well as optogenetical modulations [19]. Lesions of the STN counteract experimental parkinsonism in monkeys [20]. Electrical high-frequency stimulation of the STN (STN-DBS) alleviates PD motor impairments in monkeys and rats [17], [21], [22], [23], [24]. GABAergic activation in the STN has antiparkinsonian effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys [25], [26] and in PD patients [18] and has beneficial effects on oscillatory activity in the DA-depleted BG [27]. Such manipulations of the STN lead to focal and remote changes in various neurotransmitter systems in diverse BG nuclei [28], [29], [30], [31], [32].
The STN holds a strategic position within the cortico-BG-thalamo-cortical loop and receives GABAergic inputs from the external part of the globus pallidus (GPe) and glutamatergic afferents from extensive cortical areas associated with motor control. It sends excitatory projections to the GPe, the internal segment of the globus pallidus (GPi) and to the substantia nigra pars reticulata (SNr), using glutamate as its major neurotransmitter. Given the unique role of GABA and glutamate in BG in- and output circuitry, these neurotransmitters have gained special attention in physiological and pathological BG functioning. Unilateral administration of the GABAA-receptor agonist muscimol into the STN evoked contraversive turning behavior (a widely applied behavioral measure in the assessment of unilateral nigro-striatal lesions) in rats with intact nigro-striatal projections [17] and in non-lesioned cats [33], although others have found no effects of subthalamic muscimol injection on turning behavior in non-parkinsonian rats [34]. There is also evidence for the participation of glutamatergic mechanisms in the control of motor behavior by the STN. The involvement of STN NMDA-receptors in turning behavior and other motor deficits incurred by nigro-striatal denervation has been shown with respect to prolonged intrasubthalamic NMDA antagonism. Prolonged (∼3 weeks) infusion of MK-801 into the STN immediately after administration of 6-OHDA prevented the development of motor impairments [35]. The acute unilateral injection of MK-801 into the STN led to contraversive dystonic postures when haloperidol was systemically administered afterwards [36]. Intranigral NMDA-antagonism evokes contralateral turning in intact [37] and 6-OHDA treated rats [38]. Furthermore, systemic administration of MK-801 was found to increase contraversive turning behavior evoked by systemically applied dopamine agonists in the unilaterally 6-OHDA lesioned rat [39].
In an attempt to characterize the involvement of subthalamic GABAergic and glutamatergic transmission on motor parameters in a unilateral rodent model of PD, we here administered the selective GABAA-agonist muscimol or the non-competitive NMDA-antagonist MK-801 focally into the STN. Given the role of GABA and glutamate in physiological and pathological movement control, we hypothesized that intrasubthalamic injections of muscimol and MK-801 would compensate for motoric deficits (including turning behavior and locomotion) in the hemiparkinsonian rat. We decided to determine the motoric effects of GABAA-agonism and NMDA-antagonism in the STN in rats experimentally rendered (hemi-)parkinsonian since, to our knowledge, this is the first study to behaviorally characterize the effects of focal pharmacological manipulations of the STN in rats bearing massive unilateral lesions of the nigrostriatal tract.
Turning behavior in the hemiparkinsonian rat is differentially modulated by different types of systemically applied dopamine agonists [40]. To characterize the distinct impact of GABAA-agonism and NMDA-antagonism on pre- vs. post-synaptic DAergic mechanisms, we also challenged animals with l-DOPA and d-amphetamine, respectively, in parallel with the intrasubthalamic administrations.
Section snippets
Experimental procedures
All experiments were performed in accordance with the European Communities Council Directive (86/609/EEC) and the effective German Law of animal protection of 1998 and have been approved by local authorities (Central Animal Facility of the University of Düsseldorf and the The North Rhine-Westphalia State Environment Agency). Efforts were made to minimize the number of animals used and to minimize suffering.
Neurochemistry
There was a significant reduction in content of DA in the lesioned striatum (t11 = 4.743, P = .001, mean 90.79%, ±3.00 SEM). There was also a significant decrease in DOPAC in the affected striatum (t11 = 5.295, P < .001) with a mean loss of 54.17% (±9.32 SEM). HVA content (mean 58.26%, ±16.16 SEM) did not differ significantly (t11 = .905, P = .05). See also Table 1 for an overview (the mean values presented display averages across individual animals).
Vehicle (control) group
There were differences between effects of sole STN
Discussion
The principal finding of the present experiment was that injections of a GABAA-receptor agonist into the STN ipsilateral to the side of the 6-OHDA lesion influenced turning behavior in a dose-dependent manner, while blocking NMDA-receptors had no effects on motor asymmetries. There was a distinct time-course effect displayed by the low-dose muscimol group in the asymmetry index showing a gradual shift from initial ipsiversive turning, over non-biased turning to contraversive turning. The
Conclusions
Taken together, the present findings indicate the participation of GABAergic STN receptors in the acute mediation of movement control in unilateral DA-depleted rats. The activation of GABAA-receptors in the STN alleviated motor impairments incurred by a unilateral 6-OHDA lesion. It seems that there is a therapeutic window with respect to stimulating GABAA-receptors in the STN and that an overshoot along this dimension evokes dyskinetic effects in 6-OHDA lesioned rats. Considering the behavioral
Conflict of interest
The authors declare no competing financial interests.
Acknowledgements
This project was supported by a grant provided by the Forschungskommision (FoKo) of the Medical Faculty, University of Düsseldorf and the Interdisciplinary Graduate School for Brain Research and Translational Neuroscience (iBrain) of the Neuroscience Network Düsseldorf (NND).
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