PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

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1)Previous studies from this laboratory have demonstrated periodic multisecond (2-60 s) oscillations in firing rate in the basal ganglia in vivo, which are modulated by a number of directly-acting dopamine receptor agonists. In FY 99 we have found that the stimulants d- amphetamine, cocaine and methylphenidate also increase the speed of multisecond oscillations in globus pallidus unit activity in awake, immobilized rats. The similarity of effects of stimulants and direct dopamine agonists (and the reversals by haloperidol) suggests that stimulant modulation of multisecond periodicities in the globus pallidus is mediated mainly via dopamine release. Changes in multisecond patterning of central activity may relate to the motor and cognitive effects of d-amphetamine, cocaine and methylphenidate.2)Current models of basal ganglia function make predictions about how DA affects the activity of the basal ganglia output nuclei, the EPN and the substantia nigra reticulata. However, few studies have examined the effects of DA agonists on EPN firing activity in rodents. We found unexpected effects of iv apomorphine on EPN activity in intact rats: apomorphine increased firing rates of most EPN neurons, and increased the strength and oscillatory frequency of multisecond periodicities which were present in most spike trains. Both D1 and D2 receptors appear to be involved in control of oscillatory strength. The data also show that nigrostriatal lesion causes supersensitivity of the D1 receptors that influence firing rate as well as slow oscillations in the EPN. DA-mediated behavioral activation is not necessarily related to net reductions in EPN firing rate, as predicted by many models.3)As coordination of neuronal activity is thought to relate to function in motor circuitry, experiments were performed to assess the coincidence of these multisecond oscillations in neuronal pairs within the basal ganglia. Results show that this multisecond oscillatory activity is synchronized to a substantial extent, in the sense that pairs of neurons recorded simultaneously in different areas of the basal ganglia and in opposite hemispheres were found to be oscillating with identical frequencies. enhanced coincidence, increased regularity and change in oscillatory period were induced by dopamine agonists. Coincident observations were also observed in the globus pallidus of awake freely moving rats. These observations suggest that the basal ganglia nuclei are connected by distributed networks which regulate firing rate on multisecond time scales. Synchronized periodic oscillations in firing rate may serve to coordinate activity between the basal ganglia and cortical structures. Effects of dopamine agonists could reflect dopamine-mediated changes in the functional connectivity of related circuits. - substantia nigra subthalamic nucleus neurophysiology D1 D2 striatum globus pallidus dopamine basal ganglia Parkinson's disease