PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

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1) Structure and Function of Dopamine Receptors. To better understand and define the dopamine receptors mediating the effects of dopamine agonists in the basal ganglia, potency series have been determined for a series of selective and nonselective dopamine agonists at dopamine autoreceptors and postsynaptic receptors. The results support the idea that the dopamine autoreceptors, located on the substantia nigra pars compacta dopamine neurons, are of the classic D-2 subtype. However, at least some of the postsynaptic copamine receptors mediating nigra cell activity appear to be relatively insensitive not only to the selective D-1 agonist, but to the selective D-2 dopamine agonists as well. This suggests that these receptors are not classic D-2, or D-1, receptors. In addition, there appears to be an interaction between the receptors mediating the effects of the nonselective dopamine agonists and the D-1 receptors; the consequences of stimulating the former is attenuated by a D-1 receptor antagonist. 2) Substantia Nigra Pars Reticulata in Epilepsy. It has been suggested that enhancement of GABAergic transmission within the substantia nigra prevents the motor manifestations of kindled seizures. We have recorded single unit activity of substantia nigra neurons during electrical seizures in components of the EEG, indicating that the substantia nigra is directly transmitting seizure activity in the kindled rat. To explore further the importance of this area as a therapeutic target in epilepsy, we have evaluated the effects of a diverse group of anticonvulsant drugs on these cells. Consisstent inhibitory effects on tonic activity were produced only by drugs with proposed GSBAergic mechanisms. 3) Glutamate and Related Neurotransmitter in the Substantia Nigra. At least 2 and perhaps 3 excitatory amino acid receptor types have been demonstrated or both the substantia nigra dopamine and pars reticulata cells neuron. Moreover, n-methyl-D-asparate preferring receptors on the dopamine neurons mediate a previously undescribed firing pattern for these cells.