Dysfunctioning of the midbrain dopamine system has been suggest as an important etiologic factor in schizophrenia and related psychoses and a number of motor disorders. Although much progress has been made in recent years towards understanding the intrinsic cellular mechanisms that control dopamine neuronal activity and the release of dopamine in the brain, progress towards understanding the afferent control of dopamine neuron activity has been slower in coming. In particular, the inputs that modulate the firing rate and pattern of dopaminergic neurons in vivo remain unclear. That the firing patterns of dopaminergic neurons are controlled principally by afferent input is demonstrated by the fact that in vivo, these neurons exhibit firing patterns that range along a continuum from pacemaker-like firing through random firing to bursty firing, but in vitro, only the pacemaker pattern is observed. Based on neuroanatomical evidence, the most important afferents to substantia nigra neurons are likely to be GABAergic and glutamatergic. The densest and best-studied GABAergic inputs to dopaminergic neurons are thought to originate in the neostriatum and globus pallidus, while the most prominent excitatory inputs arise from the subthalamic and pedunculopontine nuclei, and the frontal cortex. However, it is not possible to elicit bursting activity in dopaminergic neurons by stimulation of any of these sites, and the most common response of dopaminergic neurons to simulation of the subthalamic or pedunculopontine nuclei or frontal cortex is inhibition. The experiments in this application for a competitive renewal are designed to t est various aspects of the general hypothesis that there exists an important GABAergic pathway to dopaminergic neurons originating from the local axon collaterals of non-dopaminergic substantia nigra pars reticulate projection neurons. A corollary of this hypothesis is the idea that many of the most excitatory important inputs to dopaminergic neurons that control the rate and pattern of spontaneous activity are """"""""filtered"""""""" through these pars reticulate neurons. These ideas will be tested with a variety of electrophysiological and neuroanatomical methods including in vivo and in vitro intracellular recording and intracellular labeling of substantia nigra dopaminergic and non-dopaminergic neurons in vivo extracellular recording from identified substantia nigra dopaminergic and non- dopaminergic neurons, sequential light and electron microscopy of double labeling of anterograde tracers or intracellular biocytin labeling and dopaminergic neurons, and intracellular labeling coupled with immunocytochemical identification of the postsynaptic targets.
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