Mechanism of Dopaminergic Arousal

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DESCRIPTION (provided by applicant): A variety of drugs of abuse, including especially cocaine and amphetamine that inhibit dopamine reuptake, cause a wakeful hypervigilant state, however the location of the dopamlnergic neurons that play this role remains unclear. The ventral tegmental area (VTA) dopaminergic neurons that project to the prefrontal cortex and ventral striatum do not change in firing rate during behavioral wakefulness. In additon, lesion of the VTA does not decrease wakefulness. We hypothesize that the dopaminergic cells in the ventral periaqueductal gray matter (vPAG) are the long-sought group. In aim 1, we will determine whether vPAG dopaminergic neurons are wake-active by labeing Fos and tyrosine hydroxylase following spontaneous wakefulness or sleep. In aim 2 and 4, we will apply anterograde and retrograde tracers to define the afferent and efferent connections of the vPAG DA neurons with the sleep-wake control system. In aim 3, we will examine the effects of dopamine and dopamine receptor agonists on the vPAG dopaminergic projected neurons via patch-clamping technique on in vitro slice. In aim 5, we will selectively lesion the wake-active dopaminergic neurons by 6-hydroxydopamine and examine baseline sleep-wake behavior and arousal state mediated by dopamine reuptake inhibitor. Our preliminary results suggest that the dopaminergic cells in the vPAG are wake-active, and they project to basal f6rebraih,!,tlialamus, and prefrontal cortex, and reciprocally communicate with laterodorsal tegmental cholinergic cells, perifornical orexin/hypocretin cells, and locus coeruleus as well as the ventrolateral preoptic nucleus Lesion of vPAG dopaminergic cells causes 20% increase in total sleep. The vPAG dopaminergie cells;rriay provide the long sought dopamine waking influence, and they may also play importanfrqles in arousal mechanisms of psychostimulants that inhibit dopamine reuptake and in sleep disorders of'Parkinson's disease that has extensive loss of mesopontine dopaminergic neurons.