Pharmacology And Physiology Of The Substantia Nigra And

Neurological Disorders And Stroke

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Abstract

The dopamine system is critical to appropriate information processing in the basal ganglia. Dysfunction of this neuronal system has been implicated in the etiology of many neurological diseases, including Parkinson's disease, tardive dyskinesia, Huntington's chorea and attention deficit hyperactivity disorder. Dopamine receptor stimulation has been shown to act through second messenger systems to alter the activity of a variety of voltage and receptor modulated ion channels. The net effect of these changes in ion channel function could provide dopaminergic innervation of the striatum and other basal ganglia nuclei with the ability to gate input/output relationships in the basal ganglia. To obtain evidence for the functional significance of such an effect, the Neurophysiological Pharmacology Section, in FY2003, has focused on the role of dopamine in regulating relationships between local field potential (LFP) and firing rate and pattern in different basal ganglia nuclei in intact rats and in a rodent model of Parkinson?s disease. Currently of interest is the hypothesis that dysfunctional effects of abnormally high or low levels of dopamine receptor stimulation on movement is associated with alterations in relationships between net input "as assessed by local field potential" and spiking activity in basal ganglia neurons. To this end, we have investigated effects of dopamine on relationships between single unit activity and LFP in the basal ganglia using 4 different approaches. characters left The current dat1) Section researchers have extensively documented the presence of ultraslow oscillation (2? 60 sec periods) in the basal ganglia of immobilized, awake rats. Drugs which alter dopamine receptor stimulation have the ability to modulate the properties of these ultraslow oscillations in the activity of tonically?active neurons throughout the basal ganglia. We have previously shown that systemic administration of drugs that increase dopamine receptor stimulation such as apomorphine, amphetamine, cocaine and selective dopamine uptake blockers increase the frequency of these oscillations and pairs of basal ganglia neurons demonstrate a greater number of correlated multisecond oscillatory activity after dopamine agonist stimulation. In FY03, analysis of data from paired recordings of single neurons combined with simultaneous recordings of local field potential has shown that increased dopamine receptor stimulation also dramatically affects the relationships of these ultraslow oscillations within basal ganglia, between basal ganglia in different hemispheres and between cortex, basal ganglia and hippocampus. Multisecond oscillations in the globus pallidus become strongly synchronized with other brain regions with increased dopamine receptor stimulation. 2) Spike train-LFP relationships were further utilized to investigate the ability of dopamine to modulate patterned and synchronized neuronal activity at faster time scales within and between two basal ganglia nuclei, the subthalamic nucleus (STN) and globus pallidus (GP). Effects of unilateral dopamine cell lesion and dopamine agonist and antagonist administration were examined in locally anesthetized, gallamine-immobilized, artificially-respired rats in paired STN-GP recordings of LFP and single unit activity. Coherence between STN and GP LFPs was highest in the 3-6 and 8-18 Hz ranges in both intact and lesioned groups. Notably, power in GP-triggered GP LFP waveform averages was significantly lower than in STN-triggered GP LFP averages in intact rats in the 3-6 Hz range. Dopamine agonist administration had a consistent tendency to reduce spike-triggered waveform power in all pairings, most significantly in the GP-triggered GP LFP averages after 6-OHDA lesion. Significant increases in power in STN-triggered STN and STN-triggered GP LFP waveform averages were induced by dopamine antagonists in intact rats. These results indicate that dopamine receptor stimulation modulates relationships between single unit activity and LFP in GP and STN, and reveals that under some conditions GP LFP is more correlated with neuronal activity in the STN than with activity in the GP. 3) Relationships between LFP and single unit firing patterns in paired substantia nigra pars reticlulata (SNpr) recordings ipsilateral and contralateral to unilateral 6-OHDA-induced DA cell lesion were studied in urethane-anesthetized rats. On the side of the dopamine cell lesion, SNpr, spike trains typically showed a much more bursty pattern than was observed on the intact side. Spectral analysis showed the the bursts occurred with significant rythmicity in 50% of spike trains recorded on the side of the lesion, with periods in slow and delta range (0.3?4 Hz). The timing of the bursts in the spiking activity of the SNpr neurons on the side of the lesion coincided with oscillations in SNpr LFPs recorded through the same electrode. What was surprising about this was the finding that while the firing pattern of the SNpr neurons on the intact side of the brain was relatively unbursty and very different from that on the lesioned side?the local field potential on the unlesioned side was very similar to that on the lesioned side. Thus, these results indicate that loss of dopamine modulates relationships between synaptic input and neuronal output in the SNpr of anesthetized rats where slow and delta range oscillations dominate the LFP. 4) To further investigate neurophysiological correlates of behaviorally significant reductions in DA receptor stimulation, the effects of cataleptic doses of the DA D2 antagonist eticlopride on relationships between single unit activity and LFP in the GP were studied in head-restrained and in freely moving rats. In GP, LFP showed patterns of power variation that were correlated with behavior. Epochs with increases in delta-alpha range (1-14 Hz) LFP power were related to significantly reduced incidence of limb movements, relative to epochs with LFP power decreases. Eticlopride administration was associated with a significant reduction in motor activity and with a significant increase both in LFP power, relative to baseline in theta-beta (4-30 Hz) ranges, and in total time of increased LFP power. Moreover, spike-triggered LFP waveform averages showed a significant increase in correlation between GP spiking activity and GP LFP power in beta and gamma ranges (14-30 and 30-50 Hz) after eticlopride. As LFP power reflects net synchronization of synaptic input in a given frequency range, the data support the view that the cataleptic effect of D2 receptor blockade is associated with enhanced synchronization of synaptic input and neuronal output in a population of GP neurons in specific frequency bands. In summary, lesion and drug-induced alterations in dopamine receptor stimulation were shown to induce functionally significant changes in input/output relationships in a variety of basal ganglia nuclei, assessed by alterations in relationships between synaptic input, as reflected by LFP, and output, as reflected by spiking activity. Overall, these results support a significant role for dopamine in gating input/output relationships in the basal ganglia.