NEUROPHYSIOLOGY OF A NOVEL DOPAMINERGIC SYSTEM

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LONG-TERM OBJECTIVE: To characterize the physiology and synaptic pharmacology of the dopaminergic projection to cholinergic neurons of the ventral pallidum/substantia innominata (VP/SI). The VP/SI is a basal forebrain structure which mediates complex behaviors such as cognition, reward, and goal-oriented responding. Acetylcholine-containing neurons of the VP/SI are thought to arbitrate these functions. Recent anatomical studies reveal that the VP/SI receives inputs from midbrain dopaminergic neurons. However, the physiology of this system has not been investigated. HYPOTHESIS: VP/SI cholinergic neurons are regulated by dopaminergic inputs, and this input is of sufficient importance that, when removed, the cholinergic neurons alter their activity and become supersensitive to the actions of dopaminergic agonists. SPECIFIC AIMS: I: To characterize the dopamine receptor subtype which mediates VP/SI neuronal responses to activation of dopaminergic fibers. Electrophysiologic responses by VP/SI cells to stimulation of midbrain dopamine inputs will be studied. It will be determined if these responses can be attenuated by microiontophoretic application of dopaminergic antagonists which are specific for the D1 or D2 receptor subtype. II: To determine if midbrain dopaminergic projections regulate acetylcholine-containing VP/SI neurons. Putative cholinergic neurons of the VP/SI will be electrophysiologically characterized. It will be determined if stimulation of dopaminergic neurons also alter the responses of these cells. III: To determine if destruction of midbrain dopamine-containing cells impairs normal function of VP/SI cholinergic neurons. Continuity of neuronal inputs is known to be vital for normal function of brain cells. Experiments will determine whether loss of the dopaminergic input diminishes the ability of VP/SI cholinergic neurons to communicate. Cholinergic function will be quantified before and after destruction of dopamine pathways by measuring 1) changes in acetylcholine turnover, and 2) shifts in the sensitivity curve generated electrophysiologically for the VP/SI cholinergic neuronal response to dopamine agonists. This work will pioneer physiological evaluations of this unexplored dopamine projection. Results will provide new insight towards understanding abnormal mental states where perceptive, cognitive and motor dysfunctions exist simultaneously.