The anorexigenic peptide cocaine-and-amphetamine-regulated transcript modulates rem-sleep in rats M. Méndez-Díaz a , E. Domínguez Martín a , M. Pérez Morales a , A.E. Ruiz-Contreras b , L. Navarro a , O. Prospéro-García a, * a Grupo de Neurociencias, Depto de Fisiología, Fac. de Medicina, Universidad Nacional Autónoma de México. Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico b Grupo de Neurociencias, Lab. de Neurogenómica Cognitiva, Fac. de Psicología, Universidad Nacional Autónoma de México. Apdo. Postal 70-250, Mexico, D.F. 04510, Mexico article info Article history: Received 21 May 2009 Accepted 5 August 2009 Available online 31 August 2009 Keywords: CART Food intake REM sleep abstract It is known that the sleep-waking cycle is modulated by several molecules that may also regulate food intake, among them several neuropeptides. The cocaine-and-amphetamine-regulated transcript has been studied in relation to food ingestion, but it seems to have several other functions that may include sleep regulation. In this context, we studied the effect of the intracerebroventricular administration of the cocaine-and-amphetamine-regulated transcript (0.15, 0.3, 0.6, 0.9 nmol) on the sleep-waking cycle (12-h recordings), as well as its effect on food intake in rats. Additionally, we analyzed the neuronal activ- ity as measured by c-Fos expression induced by the cocaine-and-amphetamine-regulated transcript in neurons of nuclei involved in the regulation of sleep and feeding behavior. Our main finding is that 0.3 nmol of the cocaine-and-amphetamine-regulated transcript increases rapid-eye-movement sleep. In addition, our results further support that this neuropeptide triggers sati- ety; c-Fos expression suggested that the cocaine-and-amphetamine-regulated transcript activates spe- cific hypothalamic nuclei without affecting other brain structures known to be involved in sleep regulation. These data further support the notion that a few neuropeptides are involved in the regulation of both the sleep-waking and the hunger-satiety cycles. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction The cocaine-and-amphetamine-regulated transcript (CART) is predominantly expressed in neurons of the hypothalamus and lim- bic circuits in general (Hubert and Kuhar, 2008). Its mRNA is up- regulated by cocaine and amphetamine administration in rats (Douglass et al., 1995; Hubert and Kuhar, 2008). CART has been implicated in a variety of physiological processes; however, one of its effects most firmly supported is the induction of hyporexia (Kristensen et al., 1998). Intracerebroventricular (i.c.v.) and intra nucleus accumbens administration of CART reduces both food in- take and body weight in rats (Yang et al., 2005). This experimental evidence has been supported by observations made in humans. For example, an Italian family affected by obesity exhibited low serum concentration of CART. This condition seems to be a consequence of a mutation in the CARTPT, a gene that encodes the preprotein of CART (del Giudice et al., 2001). This gene is located in chromo- some 5q13.2 (Entrez Gene database). Although CART binding has been observed in AtT20 and PC12 cells and has been found recently in primary cell cultures of the nucleus accumbens (Jones and Kuhar, 2008), there is no evidence of CART’s receptors distribution in the central nervous system. Interestingly, several peptides found in the brain are also found in the intestine. Hence, they are called brain-gut peptides and seem to be involved in the regulation of feeding and other functions, such as sleep. For example, somatostatin, corticotropin-like inter- mediate lobe peptide (CLIP or ACTH 18–39), and melanin-concen- trating hormone (MCH) increase food ingestion and sleep (Danguir, 1986; Wetzel et al., 1994, 1997; Berenak et al., 1997; Steiger and Holsboer, 1997; Scalera and Tarozzi, 1998; Al-Barazanji et al., 2001; Verret et al., 2003; Morens et al., 2005; Steiger, 2007). Neuropeptide Y (NPY) increases food ingestion and waking (Israel et al., 2005; Szentirmai and Krueger, 2006). Cholecistokinin-8 (CCK-8) has satiety-inducing properties (Kapas et al., 1988, 1991) and increases sleep (Kapas et al., 1988, 1991). Probably CART is no exception, because it is also expressed in both, brain and intes- tine (Ekblad, 2006), and because it regulates feeding; hence, we hypothesized that CART regulates sleep as well. Additionally, the hypothalamus regulates the feeding-satiety cy- cle (Bernardis, 1985; Bellinger et al., 1986; Bernardis and Bellinger, 1993) and, since the beginning of the past century, it is known that it also participates in the modulation of the sleep-waking cycle. Knowing that both c-fos expression and electrophysiological 0143-4179/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.npep.2009.08.004 * Corresponding author. Tel.: +52 55 623 2509; fax: +52 55 623 2241. E-mail address: opg@unam.mx (O. Prospéro-García). Neuropeptides 43 (2009) 499–505 Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep