SLEEP REGULATION--INVOLVEMENT OF CHOLECYSTOKININ

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The broad objective of this proposal is to study the role of cholecystokinin (CCK) in the regulation of sleep-wake activity. Two distinct CCK pools are present in the body. CCK is a gastrointestinal peptide released from the small intestines, and also a neurotransmitter/neuromodulator in the nervous system. We hypothesize that peripheral CCK, present in the systemic circulation, contributes to the maintenance of normal sleep, and also mediates sleep responses to common daily activities which lead to sleep: eating and mating. Major evidence in support of this hypothesis includes: a) Systemic administration of CCK induces sleep in all species studied; results are from several independent laboratories, b) Systemic CCK, acting on peripheral structures, is capable of modulating complex higher nervous functions such as learning and hypothalamic hormone secretion, c) The two major stimuli for CCK production, eating and sexual activity, both induce characteristic sleep responses parallel to increased plasma CCK levels, and d) Released CCK, provides a feedback signal to feeding and sexual activity eliciting a typical behavioral syndrome, satiety. To test our hypothesis we propose to: l) test the effects of receptor specific CCK agonists and antagonists on spontaneous sleep; 2) correlate plasma CCK responses with sleep responses after eating and sexual activity; we will also test the effects of CCK receptor antagonists on those sleep responses accompanied with sexual- and feeding-satiety; and 3) we will determine the role of two possible peripheral mediators of sleep responses, the vagal nerve and vasoactive intestinal polypeptide, in CCK-induced sleep. The experiments will be carried out in rats chronically implanted with EEG electrodes, brain thermistors, and intracardial catheters. The proposed experiments will establish the role of CCK in physiological sleep. Almost everybody experiences sleep disturbance in his/her life time. However even today, when we are well into the decade of the brain, the treatments for disturbed sleep are exclusively on empirical bases. We have been able to manipulate vigilance for millennia, but we are still not able to restore physiological sleep. Unfortunately, we will not be able to do so until the physiological sleep signals/mechanisms are better understood.