Alterations in the functional state of mesotelencephalic dopamine (DA)-containing neurons have been implicated in the etiology of a variety of pathological and iatrogenic conditions including schizophrenia and tardive dyskinesia. Involvement of these neurons in disorders of clinical relevance has led to a number of basic studies directed at obtaining a better understanding of the factors involved in their regulation at the cellular level. One area of potential importance that has remained largely unexplored pertains to the role of neuronal discharge pattern as a means of modulating neuronal activity and thus expression of dopaminergic systems in brain. The research proposed in our application seeks to explore the ionic and cellular basis of the diverse group of activity patterns exhibited by mesencephalic DA-containing neurons in the rat. Our initial studies will focus on intrinsic mechanisms of pattern generation. Experiments will be performed to identify and characterize several voltage- and ligand-gated ion conductances, which by virtue of their ability to become activated during the interspike interval, are likely to be involved in regulating neuronal discharge pattern. Single electrode voltage clamp techniques will be used in conjunction with several highly selective pharmacological probes to specify the contribution made by individual current components to repetitive single spike and burst firing patterns. The second series of experiments will focus on extrinsic factors likely to contribute to generation of normal patterned activity. In the first group of experiments, extracellular single unit recording techniques will be used to explore the contribution. made by excitatory amino acid-containing afferents to the firing patterns typically observed among identified DA neurons in vivo. Excitatory projections originating in the cortex and pedunculopontine tegmentum will be the focus of these experiments. Finally, we will examine the role of other neuroactive substances contained in afferents to the principle mesencephalic DA cell groups as possible modulators of the individual conductance mechanisms characterized in the earlier phases of the project. By more clearly understanding the nature of the contributions made by intrinsic and extrinsic mechanisms to the patterned electrical activity of DA-containing neurons, we hope to gain further insights into an important physiological process which may be centrally involved in regulating the expression of these neurons in normal and pathological states.
