' absract) One poorly understood neuromodulator of state is the mesostriatal dopamine (DA) system, which not only promotes motivation/reward and movement, but also arousal (viz., wakefulness). Conversely, DA blockade and interruption of mesostriatal pathways slows movement and promotes sleepiness. The details of mesostriatal DA's effects upon wake/sleep rhythms, and sleep architecture, and the cellular and subcellular substrates involved remain poorly defined. Circadian and homeostatic wake/sleep factors affect mesostriatal circuit plasticity, but their functional import is also undefined. Mice with genetic deletions of the dopamine transporter (DAT-/-), their heterozygotes (DAT+/-), wild type littermates, the pure C57BL/6 and S129/sv strains from which the transgenics derive, and the DBA/2 inbred strain with known under expression of mesostriatal D2 receptors afford a means to probe DA's role in state control, and to account for genetic variation in wake/sleep phenotypes.
Aim #1 proposes to characterize 24-hour motor activity patterns in relation to sleep/wake architecture in these mice. Motor hyperactivity in DAT -/- and DAT +/- during the subjective night yields to hypoactivity during subjective day suggesting a sleep/wake reversal in the face of chronically elevated synaptic DA (preliminary data). The mechanisms underlying a homeostatic sleep drive powerful enough to overcome chronic DA elevations - if indeed sleep attends the observed hypoactivity - may reside in other proteins involved in mesostriatal DA transmission.
Aim #2 therefore proposes to measure traditional DA markers, and molecularly defined D1 receptor, DAT and vesicular monoamine transporter (vMAT2) expression across 24-hours in limbic and motor striatal circuits to enhance interpretation of Aim #1 findings.
Aim #3 investigates the effects of prolonged wakefulness induced by physical means, bupropion (a DAT blocker), and caffeine (an adenosine receptor blocker), on the mesostriatal DA system in these same mice. The investigators postulate that these transgenic and inbred mice will exhibit unique circadian rhythms of proteins mediating DA neurotransmission and unique responses of these proteins to prolonged wakefulness that may be treatment modality specific, much the same way that depressives differ in their response to REM-sleep deprivation, and narcoleptics differ from depressives in their REM-sleep responses to DAT blockade. Taken together, the findings will advance an understanding of how state might modulate the course and treatment of insomnia, depression, and neuropsychiatric diseases whose pathophysiologies are rooted in DA sensitive basal ganglia circuits.
