Research ReportCannabinoids and hamster circadian activity rhythms
Introduction
Photic information from the retina entrains the mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN) to the environmental light:dark cycle (Johnson et al., 1988). The SCN in turn functions as the body's master pacemaker as it synchronizes the timing of peripheral circadian pacemakers distributed in tissues and organs through direct and indirect mechanisms (Guo et al., 2005, Liu et al., 2007). In addition to afferent input from the retina, the SCN is also modulated by two other primary components of the circadian system, the intergeniculate leaflet of the thalamus (IGL) and the dorsal and median raphe nuclei of the midbrain (Meyer-Bernstein and Morin, 1996). The IGL is responsible for shifts in circadian timing in the absence of light (non-photic) and raphe input to the SCN inhibits the afferent signals from the retina (Mrosovsky, 1996, Morin, 1999). The ability of photic information from the retina to entrain the timing of the circadian pacemaker is known to be modulated by a variety of transmitter systems (for reviews see Sprouse, 2004, Morin and Allen, 2006), but any effects of the endocannabinoid system have not been reported.
There are a few reports that suggest endocannabinoid signaling may affect, or be affected by, circadian rhythms. The circadian rhythm of brain temperature became inverted following cessation of chronic Δ9-tetrahydrocannabinol administration in rats (Perron et al., 2001). Also, cannabinoid receptor 1 (CB1) gene expression in the rat pons is modulated by sleep (Martinez-Vargas et al., 2003), and the CB1 antagonist SR 1417161 has arousing properties in rats (Santucci et al., 1996); therefore both studies suggest that endocannabinoid signaling is involved in the circadian sleep/wake cycle. In addition, levels of the endocannabinoid anandamide and 2-arachidonoyl-glycerol also display diurnal variations in the rat brain (Valenti et al., 2004). CB1 receptors have been suggested to be required for normal glucocorticoid feedback of the hypothalamic-pituitary-axis in mice (Cota et al., 2007), and glucocorticoid rhythms are known to be controlled by the SCN (Moore and Eichler, 1972). Further, corticotropin-releasing-factor receptor 1 antagonists are known to inhibit light-induced phase shifts of hamster circadian activity rhythms (Gannon and Millan, 2006b). Therefore, endocannabinoids likely interact indirectly with circadian rhythms through the HPA axis. Finally, CB1 receptors have been identified in both the mouse SCN (Wittmann et al., 2007) and raphe nuclei (Haring et al., 2007).
There are two types of receptors for endocannabinoids, CB1 and CB2, with the former thought to be the major subtype located within the mammalian brain (Mackie, 2005). Therefore, in this study we sought to determine if the CB1 agonist CP55940 (Wiley et al., 1995) and CB1 antagonists AM 251 (Gatley et al., 1997), and LY320135 (Felder et al., 1998) had any effect on light-induced phase advances of hamster circadian wheel running activity. In addition, we sought to determine if CB1 receptors were located in the SCN, IGL or raphe nuclei of the hamster using standard antibody-mediated immunohistochemical techniques.
Section snippets
CB1 agonists and phase advances in activity rhythms
Hamster circadian activity rhythms were phase advanced by 1.6 ± 0.1 h following vehicle injections and a 10-minute light pulse at CT 19 (Fig. 1). The CB1 agonist CP55940 (Thomas et al., 1998) inhibited the effects of light with a maximal effect seen following a dose of 0.5 mg/kg CP55940 (shift = 0.2 ± 0.1 h, approximately 90% inhibition; Fig. 1). One-way ANOVA showed this to be a highly significant inhibitory dose–response F(3,32) = 43.34, P < 0.001 and post-hoc Student–Newman–Keuls analysis confirmed
Discussion
This report demonstrates that the CB1 receptor agonist CP55940 inhibits light-induced phase advances of hamster circadian wheel running activity rhythms (Fig. 1), and that CP55940 is quite potent with significant inhibition occurring at doses of 0.125 mg/kg CP55940 (Fig. 3). Specificity of CP55940 for the CB1 receptor in hamsters is confirmed by antagonism of the effect with two separate CB1 antagonists, LY320135 and AM 251 (Fig. 2, Fig. 3). The CB1 receptor was further shown to be expressed
Experimental procedures
Young male Syrian hamsters (Mesocricetus auratus) were purchased at one month of age from Charles River Laboratories (Kingston, NY, USA) and group housed in a 14 h:10 h light:dark cycle for several weeks until use. Food and water was provided ad libitum. The care and use of hamsters was approved by the Institutional Animal Care and Use Committee at Valdosta State University.
Acknowledgments
This study was supported by NSF IOB 0549980 (RLG). E. Castillo is an undergraduate student in the Department of Biology.
References (45)
- et al.
Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters
Pharmacol. Biochem. Behav.
(2001) - et al.
Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain
Neuroscience
(2006) - et al.
Cannabinoids augment the release of neuropeptide Y in the rat hypothalamus
Neuropharm.
(2005) - et al.
The selective tachykinin neurokinin1 (NK1) receptor antagonist, GR205,171, stereospecifically inhibits light-induced phase advances of hamster circadian activity rhythms
Eur. J. Pharmacol.
(2005) - et al.
Serotonin1A autoreceptor activation by S 15535 enhances circadian activity rhythms in hamsters: evaluation of potential interactions with serotonin2A and serotonin2C receptors
Neuroscience
(2006) - et al.
The corticotropin-releasing factor (CRF1) receptor antagonists CP154,526 and DMP695 inhibit light-induced phase advances of hamster circadian activity rhythms
Brain Res.
(2006) - et al.
Identification of the cannabinoid receptor type 1 in serotonergic cells of raphe nuclei in mice
Neuroscience
(2007) - et al.
Neuropeptide Y immunoreactivity in the hamster geniculo-suprachiasmatic tract
Brain Res. Bull.
(1985) - et al.
Retinohypothalamic projections in the hamster and rat demonstrated using cholera toxin
Brain Res.
(1988) The neurobiology and control of anxious states
Prog. Neurobiol.
(2003)
Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study
Peptides
Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat
Brain Res.
The circadian visual system, 2005
Brain Res. Rev.
Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia
Neuroscience
Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats
Neuropharmacology
Neuropeptide Y in the mammalian circadian system: effects on light-induced circadian responses
Peptides
Distribution of δ opioid receptor immunoreactivity in the hamster suprachiasmatic nucleus and intergeniculate leaflet
Brain Res.
Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function
Endocrinology
The neuropsychology of cannabis and other substance use in schizophrenia: review of the literature and critical evaluation of methodological issues
Aust. N.Z. J. Psychiatry
Immunohistochemical localization of neural cannabinoid receptor in rat brain
J. Neurosci. Res.
LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation
J. Pharmacol. Exp. Ther.
Role of endogenous cannabinoids in synaptic signaling
Physiol. Rev.
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