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. Investigations into the role of dopamine in basal ganglia function in FY2002 have focused on the role of dopamine in regulating firing rate and firing patterns in different basal ganglia nuclei in intact rats and in a rodent model of Parkinson's disease. Currently of interest is the hypothesis that alterations in dopamine receptor stimulation regulate movement (and potentially other dopamine-modulated functions, such as attention and plasticity) through mechanisms regulating synchronization of activity within the basal ganglia, and between basal ganglia and other nuclei, on a variety of time scales. Previous studies in the Physiological Neuorpharmacology Section have focused on investigation of a novel ultraslow oscillation in the activity of tonically-active neurons throughout the basal ganglia of immobilized, awake rats. These studies have previously demonstrated that: 1) 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, 2) general anesthetics virtually eliminate them, and 3) pairs of basal ganglia neurons demonstrate a greater number of correlated multisecond oscillatory activity after dopamine agonist stimulation. In addition, bursts of theta rhythm (4-7 Hz) activity in the hippocampus and delta activity in the motor cortex correlate with these multisecond firing rate oscillations in the basal ganglia. In Fiscal Yeal 2002, paired recordings of single neurons combined with simultaneous recordings of local field potential have shown that increased dopamine receptor stimulation also dramatically affects the phase relationship of these ultraslow oscillations within basal ganglia, between basal ganglia in different hemispheres and between cortex, basal ganglia and hippocampus. When the globus pallidus is used as the reference, phase relationships with most other brain regions became strongly synchronized with increased dopamine receptor stimulation. However, the subthalamic nucleus shows a different response, maintaining a mixed phase/antiphase relationship with the globus pallidus after both increases and decreases in dopamine receptor stimulation. This observation supports the emerging role of the subthalamic nucleus as an independent source of input to the basal ganglia, as opposed to being simply a "pass-through" nucleus conveying information from globus pallidus to output nuclei, as has been postulated in popular basal ganglia models. This view was supported by observation that phase relationships between the globus pallidus and substantia nigra pars reticulata were disrupted by lesion of the subthalamic nucleus. The site of action of dopamine in altering activity in various central nervous system structures on a ultraslow time scale has been investigated and shown to be those dopamine receptors, predominately in the striatum, which are denervated with dopamine cell lesion. The role of the ultraslow oscillations in organized faster frequencies of oscillatory activity within and between these brain regions is a current focus. Work was initiated this year on studies of effects of alterations in dopamine receptor stimulation on synchronization and coherence of activity in frequencies shown to be relevant to movement and tremor. Effects of dopamine receptor stimulation on synchronization of activity within the basal ganglia and between basal ganglia and other regions in awake behaving rodent preparations is being investigated in two preparations using spectral and wavelet analyses techniques. Chronically implanted electrodes are being used to examine neuronal activity in the basal ganglia of awake behaving rats in conjunction with drug treatments to affect dopamine receptor function. Single unit and local field potential activity is also being recorded from rats trained to hang in slings to determine effects of alterations in dopamine receptor simulation on synchronization of neuronal activity in basal ganglia and other systems. This preparation allows the use of higher resistance electrodes whose location can be adjusted during the recordings. Recordings to date show these animals also demonstrate variable changes in firing rate on ultraslow time scales with correlations between basal ganglia and hippocampal activity in the absence of dopamine receptor manipulation. Relationships between movement, and periods of increased synchronization of activity, as indicated by increased amplitude in local field potential, are being examined. In addition effects of a series of anesthetics on alterations in slow oscillations (delta range, 0.3 - 4.0 Hz) are being studied to determine the potential for dopamine to affect these parameters in anesthetized preparations. Activity in this time scale has been studied extensively in anesthetized animals in thalamocortical circuits, but not in the basal ganglia. These studies should give insight into basal ganglia-thalamocortical relationships. Marked differences between anesthetics have been observed, with urethane being the agent most amenable to study of drug effects on these parameters. Future studies will examine the effects of nigrostriatal-lesion, a rodent model of parkinsonism, on these parameters and further investigate the potential importance of changes in firing pattern, as opposed to rate per se, in movement disorders.