Compensatory sleep responses (CSR) following extended prior waking constitute a central tenet of sleep physiology-- that sleep is """"""""homeostatically"""""""" regulated. NonREM sleep time, sleep episode duration, and EEG delta power normally increase proportional to prior wake duration. Waking from stimulants (methamphetamine and methylphenidate) also induce CSR. However, waking induced by pemoline or selective dopamine reuptake blockers (DARBs) produces no CSR, suggesting that dopamine-induced wakefulness can uncouple the sleep homeostatic mechanism. The cholinergic neurons in the nucleus basalis (NBM) and adjacent basal forebrain regions that diffusely project to the cerebral cortex have been extensively characterized in promotion of wakefulness. Because the NBM receives dopaminergic input directly from the ventral tegmental area (VTA), wakefulness produced by DARBs is likely to be mediated directly in this region. Given the hypothetical role of adenosine as an endogenous sleep factor, it is possible that adenosine levels in this region may interact with dopaminergic influences on the NBM. The research proposed investigates dopaminergic interaction with sleep homeostasis in terms of its generality, involvement of the basal forebrain, DA receptor subtypes involved, interaction with sleep deprivation, and interaction with adenosinergic mechanisms that also modulate sleep-wakefulness. Six interrelated specific aims will examine the role of DA in sleep homeostasis using computerized sleep recording, microinjection, and in vivo dialysis techniques in rats. The experiments will test the hypotheses that: 1.) Wakefulness induced by selective increase in DA neurotransmission is uncoupled from the sleep homeostatic process; 2.) Direct VTA dopaminergic projections to the NBM mediate DA waking without subsequent compensatory sleep; 3.) Specific DA receptor subtypes mediate the ability of DARBs to promote waking without subsequent compensatory hypersomnolence; 4.) DA-induced basal forebrain waking counteracts compensatory sleep drive following sleep deprivation; 5.) Elevated adenosine levels mediate hypersomnolence following sleep deprivation or waking induced by classic psychomotor stimulants (methamphetamine, methylphenidate); 6.) Adenosinergic agonists in the NBM can restore CSR after pemoline or DARB-induced wakefulness. Excessive sleepiness undermines the health and quality of life in millions of people including the elderly, sleep apnea sufferers, narcoleptics, and shift-workers. Sleep regulation is also highly disturbed in patients with abnormal DA production, such as in Parkinson's Disease. The proposed studies will advance our basic understanding of central mechanisms underlying compensatory sleep, with the hope that this basic knowledge will lead to better long-term treatments for excessive sleepiness.
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| Wisor, J P; Nishino, S; Sora, I et al. (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787-94 |
