The proposed experiments investigate the effects of ethanol on the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). Alcohol abuse and withdrawal have pro profo found und effects on circadian rhythms and sleep. These two phenomena are likely interrelated, since disruptions in circadian functioning are a major cause of many sleep irregularities. Since sleep problems have been linked to both the development of alcoholism and the likelihood of relapse in recovering alcoholics, it is important to better understand the neural processes that contribute to these sleep problems. Known cellular targets of ethanol include glutamate N-methyl-D-aspartate (NMDA) receptor receptors. s. NMDA receptor activation in the SCN is necessary for the circadian clock to properly synchronize to the environment. Our preliminary data show that acute eth ethanol tre anol treatment blocks glutamate stimulation of the SCN circadian clock. We propose to follow up thes these preliminary experiments by pursuing the following specific aims:
AIM 1 : Does acute or chronic ethanol treatment affect photic phase shifts in vivo? Our preliminary data involve an in vitro preparation, and it is important to determine wheth whether ethanol has similar effects in vivo. Furthermore, given the many differences in acute vs. chronic ethanol exposure, we will also investigate how chronic ethanol treatment affects circadian rhythms in general, and photic phase shifting in particular.
AIM 2 : Does acute ethanol treatment in vitro block glutamate-induced phase shifts through direct or indirect actions on glutamatergic NM c NMDA receptors? These experiments will DA in investigate vestigate the mechanisms through which ethanol inhibits the phase-shifting effects of glutamate on the circadian clock. In this initial stage we AIM 3: Does acute ethanol treatment affect non-photic phase shifts in vitro? While many of ethanol's effects appear to center a around NM round NMDA receptors, other DA neuroturotransmitters, such as serotonin, are also affected by alcohol. Thus, we will investi investigate gate whether acute ethanol alters in vitro phase shifts induced by the neurotransmitter, serotonin. Future Directions: The results of these studies will provide the basis of a more extensive investigation into the effects of acute and chronic ethanol, and ethanol withdrawal, on the mammalian circadian clock. ? ? ?
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