Chronic Hyperammonemia Alters the Circadian Rhythms of Corticosteroid Hormone Levels and of Motor Activity in Rats Hanan Ahabrach, 1 Blanca Piedrafita, 2 Abdelmalik Ayad, 1 Nisrin El Mlili, 2 Mohammed Errami, 1 Vicente Felipo, 2 * and Marta Llansola 2 1 Departament de Biologie, Faculte des Sciences, Universite ´ Abdelmalek Essaadi, Te ´touan, Maroc 2 Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Valencia, Spain Patients with liver cirrhosis may present hepatic ence- phalopathy with a wide range of neurological disturban- ces and alterations in sleep quality and in the sleep- wake circadian rhythm. Hyperammonemia is a main contributor to the neurological alterations in hepatic encephalopathy. We have assessed, in an animal model of chronic hyperammonemia without liver failure, the effects of hyperammonemia per se on the circadian rhythms of motor activity, temperature, and plasma lev- els of adrenal corticosteroid hormones. Chronic hyper- ammonemia alters the circadian rhythms of locomotor activity and of cortisol and corticosterone levels in blood. Different types of motor activity are affected differentially. Hyperammonemia significantly alters the rhythm of spontaneous ambulatory activity, reducing strongly am- bulatory counts and slightly average velocity during the night (the active phase) but not during the day, resulting in altered circadian rhythms. In contrast, hyperammone- mia did not affect wheel running at all, indicating that it affects spontaneous but not voluntary activity. Vertical activity was affected only very slightly, indicating that hyperammonemia does not induce anxiety. Hyperammo- nemia abolished completely the circadian rhythm of cor- ticosteroid hormones in plasma, completely eliminating the peaks of cortisol and corticosterone present in con- trol rats at the start of the dark period. The data reported show that chronic hyperammonemia, similar to that pres- ent in patients with liver cirrhosis, alters the circadian rhythms of corticosteroid hormones and of motor activ- ity. This suggests that hyperammonemia would be a rele- vant contributor to the alterations in corticosteroid hor- mones and in circadian rhythms in patients with liver cirrhosis. V V C 2009 Wiley-Liss, Inc. Key words: hepatic encephalopathy; body temperature; plasma corticosterone; locomotor activity; wheel running; cosinor Hepatic encephalopathy (HE) is a complex neuro- psychiatric syndrome present in patients with liver dis- ease, which covers a wide range of neurological and neuropsychiatric disturbances. An early alteration in these patients is the impairment of the sleep-wake cycle, patients cannot sleep well during the night and show sleepiness in the morning (Co ´rdoba et al., 1998). The mechanisms by which liver failure leads to these altered circadian rhythm of sleep have not been clarified. Both melatonin and corticosteroid hormones are involved the regulation of the sleep-wake cycle (Buckley and Schatzberg, 2005; Pandi-Perumal et al., 2008). Light, through the suprachiasmatic nucleus, con- trols the circadian rhythms of the levels of melatonin and of hormonal corticosteroids. Circadian levels of melatonin are altered in cir- rhotic patients. Both the time of onset of melatonin secretion and the peak of plasma melatonin levels are delayed in cirrhotic patients, in agreement with the shift in the sleep-wake cycle (Steindl et al., 1995; Blei and Zee, 1998; Velissaris et al., 2009). Circadian rhythms of sleep are also modulated by corticosteroid hormones, whose secretion is regulated by the hypothalamus-pitui- tary-adrenal (HPA) gland axis (Buckley and Schatzberg, 2005). The suprachiasmatic nucleus modulates this axis and subsequently corticosteroid secretion from adrenal Contract grant sponsor: Ministerio de Ciencia e Innovacion; Contract grant number: SAF2005-06089; Contract grant number: SAF2008- 00062; Contract grant number: CSD2008-00005; Contract grant sponsor: Consellerı ´a de Educacion; Contract grant number: ACOMP06/005; Contract grant number: ACOMP-2009-025; Contract grant number: Prometeo/2009/027; Contract grant sponsor: Conselleria de Sanitat of Generalitat Valenciana; Contract grant number: AP005/06; Contract grant number: EVES 034/2007; Contract grant number: AP-024/08; Contract grant number: A-01/08. *Correspondence to: Vicente Felipo, Laboratory of Neurobiology, Cen- tro de Investigacion Principe Felipe, Avda Autopista del Saler 16, 46012 Valencia, Spain. E-mail: vfelipo@cipf.es Received 12 August 2009; Revised 25 September 2009; Accepted 30 September 2009 Published online 8 December 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.22311 Journal of Neuroscience Research 88:1605–1614 (2010) ' 2009 Wiley-Liss, Inc.