292 Brain Research, 490 (1989) 292-300 Elsevier BRE 14587 Prolactin, vasoactive intestinal peptide, and peptide histidine methionine elicit selective increases in REM sleep in rabbits Ferenc Obal Jr.*, Mark Opp, Alan B. Cady, Lars Johannsen and James M. Krueger Department of Physiology and Biophysics, University of Tennessee, Memphis, TN 38163 (U.S.A.) (Accepted 6 December 1988) Key words: Prolactin; Vasoactive intestinal peptide; Peptide histidine isoleucine/peptide histidine methionine; Rapid eye movement sleep; Brain temperature; Non-rapid eye movement sleep The purpose of these experiments was to determine whether (1) vasoactive intestinal peptide (VIP) produces effects on rabbit sleep similar to those reported for rats and cats; (2) peptide histidine methionine (PHM), a peptide closely related to VIP, mimics the sleep effects of VIP; and (3) pituitary prolactin (PRL), a pituitary hormone that has a sleep-related secretory pattern and for which VIP and PHM act as releasing factors, has similar effects on sleep. VIP or PHM (0.01, 0.1 and 1.0 nmol/kg) was intracerebroventricularly (i.c.v.) injected; PRL (ovine PRL, 45 and 200 IU/kg) was subcutaneously (s.c,) administered. Sleep-wake activity and brain temperature were recorded for 6 h. For controls, rabbits received artificial cerebrospinal fluid i.c.v, or PRL-vehicle s.c. VIP and PHM promoted rapid eye movement sleep (REMS), although these effects were not dose-dependent. In addition, the high dose of VIP and PHM transiently increased wakefulness. Increases in REMS occurred only during hours 2-6 after i.c.v. injection of VIP and peptide histidine leucine (PHI). After s.c. injection of PRL, REMS started to increase in postinjection hour 3. The effect of the high dose was significantly more pronounced than that of the small dose. Each substance enhanced the frequency of REMS episodes, and the high dose of PRL also increased the duration of REMS bouts. These results are consistent with the hypothesis that VIP is involved in physiological regulation of REMS, and that the VIP- and PHM-induced increases in REMS may be mediated via release of PRL. INTRODUCTION Vasoactive intestinal peptide (VIP) belongs to the secretin-glucagon peptide family that also includes gastric inhibitory peptide (GIP), growth hormone releasing factor (GRF), and peptide histidine iso- leucine (PHI) or peptide histidine methionine (PHM). (PHM differs in two amino acids from PHI and is regarded as the human PHI 13'41. Accordingly, except for specific references, PHI and PHM are discussed as the species variant of a single peptide marked as PHI/M.) GRF and VIP are somnogenic. GRF promotes rapid eye movement sleep (REMS) and non-REMS (NREMS) in both rats 1°'31'32 and rabbits 31. VIP increases NREMS and REMS in rats 22'33'35, but promotes only REMS in cats 8. Although various lines of evidence suggest that endogenous VIP is involved in sleep regulation 9, the mechanism of VIP somnogenic effects remains un- clear. Recent evidence suggests that VIP and PHI/M act as physiological hypothalamic releasing factors for pituitary prolactin (PRL) secretion. Hypothalamic neurons containing VIP 11 and PHI-like 28 immuno- reactivity project to the median eminence. VIP and PHI concentrations in pituitary portal blood are much higher than in systemic circulation 37'4°. Intra- cerebroventricular (i.c.v.) or systemic administration of VIP and PHI elicits PRL release, and VIP and PHI stimulate PRL secretion by pituitary lactotrophs in vitro (see ref. 17 for a review). PRL release induced by serotonin can be abolished by immuno- neutralization of endogenous VIP and PHI 15, and PRL secretion elicited by suckling or ether stress can * Permanent address: Department of Physiology, University Medical School, Szeged, Hungary. Correspondence: J.M. Krueger, Department of Physiology and Biophysics, University of Tennessee, 894 Union Avenue, Memphis, TN 38163, U.S.A. 0006-8993/89/$03.50 ~ 1989 Elsevier Science Publishers B.V. (Biomedical Division)