PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

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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 FY2000 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. There has been a growing interest in the importance of oscillatory firing patterns in the nervous system. However, most studies have only examined spike trains for oscillatory structure at frequencies greater than 1 Hz. In extracellular single unit recording studies, the Physiological Neuorpharmacology Section has found that many tonically-active neurons in 4 different basal ganglia nuclei have slow, recurrent multisecond oscillations in baseline firing rate in immobilized, awake rats. These studies have previously demonstrated that: 1) systemic administration of drugs that increase dopamine receptor stimulation such as apomorphine, amphetamine, and cocaine increases 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 FY 99, we have found the selective dopamine uptake blockers also significantly decrease oscillatory periods in basal ganglia firing rates, whereas the norepinephrine and serotonin uptake blockers have no significant effect. Current theories proposing that low doses of stimulants such as amphetamine and methylphenidate (Ritalin) reduce symptoms in attention deficit hyperactivity disorder patients by acting on dopamine autoreceptors to reduce catecholaminergic transmission have been contradicted by investigations of effects of these drugs on firing rates of basal ganglia neurons. The ability of these widely used therapies to dramatically alter periodicities of multisecond oscillations in basal ganglia activity support the view that catecholaminergic stimulants might affect motor and attentive processes by modulating temporal patterns of central activity. The relationship of these dopamine-modulated multisecond oscillations in basal ganglia activity to cerebrocortical activity and the possibility that thalamic neurons also express these slow oscillations has been assessed. The data show that multisecond oscillations in basal ganglia and thalamic neuronal firing rates have a correlate in variations in EEG theta power, an index of cortical activity associated with attention or arousal. Moreover, this correlation is strengthened by systemically-administered dopamine agonists, and agonist effects are enhanced after dopamine cell lesion in an animal model of Parkinson's disease. These investigations have also shown new parallels between the physiology of the rodent entopeduncular nucleus and its homolog in the primate, the internal segment of the globus pallidus. Impressive correlations between neurophysiological data from the rodent and primate models of Parkinson's disease and Parkinson's disease patients support the relevance of findings emerging from rodent studies with respect to basal ganglia function in humans and non-human primates.