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 FY2001 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, 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 FY 2001, spectral and wavelet analyses of transcortical EEG signals and field potential recordings in the hippocampus taken during extracellular single unit recording sessions in the basal ganglia in awake rats indicated that bursts of theta rhythm (4-7 Hz) activity in the hippocampus correlated with multisecond firing rate oscillations in the basal ganglia. After systemic stimulant injection (apomorphine, cocaine, methylphenidate or GBR12909), the incidence of correlation is increased and phase relationships between correlated slow oscillations in basal ganglia firing rates and hippocampal theta power are altered: phases became strongly synchronized. Stimulant injection also significantly increases the power of multisecond oscillations in hippocampal theta rhythm. The data indicate that dopamine strengthens the functional connectivity between the hippocampus and the basal ganglia. Given the involvement of hippocampal theta cells in memory and learning and the ability of theta-frequency hippocampal stimulation to reinstate cocaine self-administration, the data suggest that dopaminergic modulation of multisecond patterning of hippocampal theta might underlie stimulant-induced changes in learning, and strengthen the association of self-administration context with self-administered drug. In addition, understanding mechanisms through which dopamine modulates the network properties of the basal ganglia and its functional connectivity with other brain regions should provide new insight into how loss of dopamine, and intermittent long term l-dopa therapy affects basal ganglia function in Parkinson's disease. Progress has also been made in FY2001 in investigation of the changes in basal ganglia output in the rat model of Parkinson's disease. Altered activity of the internal segment of the globus pallidus is thought to mediate parkinsonian symptoms. While current models of basal ganglia function predict that loss of dopamine should lead to reduced firing rates in this nucleus, clinical response to pallidotomy and deep brain stimulation in this area suggest that changes in firing pattern, rather than firing rate, may be more relevant in mediating the dysfunctional activity in this nucleus. We have characterized changes in neuronal activity in the entopeduncular nucleus (the rodent analogue of the internal globus pallidus) after unilateral nigrostriatal dopaminergic lesion, and after systemic treatment with selective D1 and D2 dopamine agonists. Nigrostriatal lesion alters baseline activity of entopeduncular neurons in several ways: interspike interval distributions have significantly decreased modes and significantly increased variance, skewness and kurtosis; regular-spiking neurons are much less common; and the incidence of 4-18 Hz oscillations is increased. Nigrostriatal lesion also affects response to systemically administered D1 and D2 agonists. In intact rats, firing rates were increased by D2 receptor activation, with little effect of D1 receptor activation, in contrast to predictions of basal ganglia models. After lesion, D1 receptor activation reduces firing rates, while D2 receptor activation is without consistent effect. However, the combination of quinpirole with a low, ineffective dose of SKF 38393 consistently reduces firing rates, suggesting synergistic D1/D2 receptor effects. D2 receptor activation also reverses some lesion-induced firing pattern abnormalities. There are a number of electrophysiological parallels between this common rodent model and primate parkinsonian models, including interspike interval changes, emergence of 4-18 Hz oscillatory activity (which likely relates to post-lesion tremor found in humans and non-human primates), strong inhibition by D1/D2 receptor stimulation, and the presence of multisecond oscillatory activity. The data support the relevance of the nigrostriatal-lesion rodent model of parkinsonism, and call further attention to the potential importance of changes in firing pattern, as opposed to rate per se, in movement disorders.
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