In the mouse suprachiasmatic nucleus (SCN), melatonin activates MT1 and MT2 G-protein coupled receptors, which are involved primarily in inhibition of neuronal firing and phase shift of circadian rhythms. This study investigated the ability of melatonin to phase shift circadian rhythms in wild type (WT) and MT1 melatonin receptor knockout (KO) C57BL/6 mice. In WT mice, melatonin (90 microg/mouse, s.c.) administered at circadian time 10 (CT10; CT12 onset of activity) significantly phase advanced the onset of the circadian activity rhythm (0.60 +/- 0.09 hr, n = 41) when compared with vehicle treated controls (-0.02 +/- 0.07 hr, n = 28) (P < 0.001). In contrast, C57 MT1KO mice treated with melatonin did not phase shift circadian activity rhythms (-0.10 +/- 0.12 hr, n = 42) when compared with vehicle treated mice (-0.12 +/- 0.07 hr, n = 43). Similarly, in the C57 MT1KO mouse melatonin did not accelerate re-entrainment to a new dark onset after an abrupt advance of the dark cycle. In contrast, melatonin (3 and 10 pm) significantly phase advanced circadian rhythm of neuronal firing in SCN brain slices independent of genotype with an identical maximal shift at 10 pm (C57 WT: 3.61 +/- 0.38 hr, n = 3; C57 MT(1)KO: 3.45 +/- 0.11 hr, n = 4). Taken together, these results suggest that melatonin-mediated phase advances of circadian rhythms of neuronal firing in the SCN in vitro may involve activation of the MT2 receptor while in vivo activation of the MT1 and possibly the MT2 receptor may be necessary for the expression of melatonin-mediated phase shifts of overt circadian activity rhythms.

The results of the present study suggest that bright light treatment may be effective among institutionalized older adults, providing nonpharmacological intervention in the treatment of depression. Furthermore, the length of institutionalization may play an important role in determining the efficacy of bright light treatment for older adults in the nursing-home setting.

Masana MI, Sumaya IC, Becker-Andre M, Dubocovich ML. Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the ROR␤ knockout. Am J Physiol Regul Integr Comp Physiol 292: 2357-2367, 2007. First published February 15, 2007 doi:10.1152/ajpregu.00687.2006.-This study reports for the first time the effects of retinoid-related orphan receptors [ROR␤; receptor gene deletion ROR␤(C3H) Ϫ/Ϫ ] in C3H/ HeN mice on behavioral and circadian phenotypes. Pineal melatonin levels showed a robust diurnal rhythm with high levels at night in wild-type (ϩ/ϩ), heterozygous (ϩ/Ϫ), and knockout (Ϫ/Ϫ) mice. The ROR␤(C3H) Ϫ/Ϫ mice displayed motor ("duck gait," hind paw clasping reflex) and olfactory deficits, and reduced anxiety and learned helplessness-related behaviors. Circadian rhythms of wheelrunning activity in all genotypes showed entrainment to the light-dark (LD) cycle, and free running in constant dark, with ROR␤(C3H)mice showing a significant increase in circadian period (tau). Melatonin administration (90 g/mouse sc for 3 days) at circadian time (CT) 10 induced phase advances, while exposure to a light pulse (300 lux) at CT 14 induced phase delays of circadian activity rhythms of the same magnitude in all genotypes. In ROR␤(C3H) Ϫ/Ϫ mice a light pulse at CT 22 elicited a larger phase advance in activity rhythms and a slower rate of reentrainment after a 6-h advance in the LD cycle compared with (ϩ/ϩ) mice. Yet, the rate of reentrainment was significantly advanced by melatonin administration at the new dark onset in both (ϩ/ϩ) and (Ϫ/Ϫ) mice. We conclude that the ROR␤ nuclear receptor is not involved in either the rhythmic production of pineal melatonin or in mediating phase shifts of circadian rhythms by melatonin, but it may regulate clock responses to photic stimuli at certain time domains.retinoid-related orphan receptors ␤ gene; circadian activity rhythms; melatonin receptors; suprachiasmatic nucleus RETINOID-RELATED ORPHAN RECEPTORS (ROR) belong to a superfamily of nuclear hormone receptors comprising more than 40 transcription factors (7, 24). Members of this superfamily share a common modular structure consisting of a transactivation domain, a DNA-binding domain, and a ligand-binding domain (24). The family of ROR receptors is a subfamily of orphan receptors comprising ROR␣, ROR␤, and ROR␥ (21). ROR␤ is a nuclear receptor expressed in areas related to processing of sensory information, as well as circadian rhythmicity (27,33). Recently, structural data and structure-function analysis identified all-trans retinoic acid as a bona fide ligand for the ROR␤ nuclear receptor (37).Circadian oscillations of the mammalian biological clock within the suprachiasmatic nucleus (SCN) are driven by a main transcriptional/translational feedback loop of clock gene products. The negative arm of the loop involves the circadian oscillation of three period (Per) genes and two cryptochrome (Cry) genes, potent repressors of CLOCK/BAML1-induced transcription. The positive loop is...

Chronic systemic melatonin treatment attenuates abnormalities produced by occlusion of middle cerebral artery (MCA) in adult rats. Because the pineal gland secretes high levels of melatonin, we examined in the present study whether transplantation of pineal gland exerted similar protective effects in MCA-occluded adult rats. Animals underwent same-day MCA occlusion and either intrastriatal transplantation of pineal gland (harvested from 2-month-old rats) or vehicle infusion. Behavioral tests (from day of surgery to 3 days posttransplantation) revealed that transplanted stroke rats displayed significantly less motor asymmetrical behaviors than vehicle-infused stroke rats. Histological analysis at 3 days posttransplantation revealed that transplanted stroke rats had significantly smaller cerebral infarction than vehicle-infused rats. Additional experiments showed that pinealectomy affected transplantation outcome, in that transplantation of pineal gland only protected against stroke-induced deficits in stroke animals with intact pineal gland, but not in pinealectomized stroke rats. Interestingly, nonpinealectomized vehicle-infused stroke rats, as well as pinealectomized transplanted stroke rats, had significantly lower melatonin levels in the cerebrospinal fluid than nonpinealectomized transplanted stroke rats. We conclude that intracerebral transplantation of pineal gland, in the presence of host intact pineal gland, protected against stroke, possibly through secretion of melatonin.

We previously reported an antidepressant-like effect in C3H/HeN mice during the forced swimming test (FST) following treatment with the MT1/MT2 melatonin receptor ligand, luzindole. This study investigated the role melatonin receptors (MT1 and/or MT2) may play in the effect of luzindole in the FST using C3H/HeN mice with a genetic deletion of either MT1 (MT1KO) or MT2 (MT2KO) melatonin receptors. In the light phase (ZT 9-11), luzindole (30 mg/kg, i.p.) significantly decreased immobility during swimming in both wild type (WT) (135.6 +/- 25.3 s, n = 7) and MT(1)KO (132.6 +/- 13.3 s, n = 8) as compared with vehicle-treated mice (WT: 207.1 +/- 6.0 s, n = 7; MT1KO: 209.5 +/- 6.2 s, n = 8) (P < 0.001). In the dark phase (ZT 20-22), luzindole also decreased time of immobility in both WT (89.5 +/- 13.9 s, n = 8) and MT1KO (66.5 +/- 6.4 s, n = 8) mice as compared with the vehicle treated (WT: 193.8 +/- 3.5, n = 6; MT1KO: 176.6 +/- 6.2 s, n = 8) (P < 0.001). Genetic disruption of the MT1 gene did not alter the diurnal rhythm of serum melatonin in MT1KO mice (ZT 9-11: 1.3 +/- 0.6 pg/mL, n = 7; ZT 20-22: 10.3 +/- 1.1 pg/mL, n = 8) as compared with WT (ZT 9-11: 1.4 +/- 0.7 pg/mL; ZT 20-22: 10.6 pg/mL). Swimming did not alter the serum melatonin diurnal rhythm in WT and MT1KO mice. Decreases in immobility of WT and MT1KO mice by luzindole treatment were not affected by gender or age (3 months versus 8 months). In contrast, luzindole did not decrease immobility during the FST in MT2KO mice. We conclude that the antidepressant-like effect of luzindole may be mediated through blockade of MT2 rather than MT1 melatonin receptors.

AimsTo ascertain the tolerability profile of single and repeated oral doses of methanesulfonyl fluoride (MSF, SNX-001) in healthy aged subjects, and to determine the degree of erythrocyte acetylcholinesterase (AChE) inhibition induced by MSF after single and repeated oral doses.MethodsTo calculate properly the kinetics and the duration of AChE inhibition, the effects of MSF were also studied in rodents. These experiments suggested that MSF administered three times per week should provide safe and efficacious AChE inhibition. In a randomized placebo-controlled phase I study, 3.6 mg, 7.2 mg or 10.8 mg MSF were then orally administered to 27 consenting healthy volunteers (aged 50 to 72 years). After a single dose phase and a 1 week wash-out period, the subjects received the same doses three times per week for 2 weeks.ResultsTwenty-two out of the 27 subjects completed the study. Four patients withdrew due to adverse events (AEs) and one for non-compliance. Erythrocyte AChE was inhibited by a total of 33%, 46%, and 62% after 2 weeks of 3.6 mg, 7.2 mg and 10.8 mg MSF, respectively. No serious AEs occurred. The most frequent AEs were headache (27%), nausea (11%) and diarrhoea (8%).ConclusionsMSF proved to be well tolerated even with repeated oral dosing. It is estimated that MSF provided a degree of AChE inhibition that should effectively enhance memory. This molecule deserves to be tested for efficacy in a pilot randomized controlled study in patients with Alzheimer's disease.

Methanesulfonyl fluoride (MSF), a highly selective CNS inhibitor of acetylcholinesterase, has been recently demonstrated to promote improvement in cognitive performance in patients with senile dementia of Alzheimer type. Because a similar cognitive impairment may accompany stroke, we investigated in the present study whether treatment with MSF could produce beneficial effects in adult rats subjected to an experimental stroke model. Sprague-Dawley rats received transient 60 min intraluminal occlusion of the right middle cerebral artery (MCAo) and were given i.p. injections of either MSF (1 mg/kg at 24 and 48 h post-MCAo and 0.3 mg/kg thereafter every other day) or the vehicle, peanut oil, for 4 weeks. Behavioral tests and biochemical assays were performed at 28 days post-surgery. MSF treatment produced about 90% inhibition of acetylcholinesterase in the brain. Ischemic animals that received the vehicle displayed significant elevated body swing biased activity (84.8 F 10%) and significantly prolonged acquisition (398 F 62 s) and shortened retention (79 F 26 s) of the passive avoidance task. Interestingly, while the ischemic animals that received the MSF exhibited elevated body swing biased activity (87.7 F 8%), they performed significantly better in the passive avoidance task (255 F 36 s and 145 F 18 s in acquisition and retention) than the vehicletreated animals. Moreover, whereas brains from both groups of animals revealed similar extent and degree of cerebral infarction, the MSFtreated ischemic animals showed more intense immunoreactivity, as well as a significantly higher number (10-15% increase) of septal choline acetyltransferase-positive cells than the vehicle-treated ischemic animals. These results show that MSF, possibly by preserving a functional cholinergic system, attenuated stroke-induced deficits in a simple learning and memory task. Published by Elsevier B.V.Theme: Disorders of the nervous system Topic: Ischemia

The authors' aim was to first provide an alternative methodology in the assessment of procrastination and flow that would not reply on retrospective or prospective self-reports. Using real-time assessment of both procrastination and flow, the authors investigated how these factors impact academic performance by using the Experience Sampling Method. They assessed flow by measuring student self-reported skill versus challenge, and procrastination by measuring the days to completion of an assignment. Procrastination and flow were measured for six days before a writing assignment due date while students (n = 14) were enrolled in a research methods course. Regardless of status of flow, both the nonflow and flow groups showed high levels of procrastination. Students who experienced flow as they worked on their paper, in real time, earned significantly higher grades (M = 3.05 ± 0.30: an average grade of B) as compared with the nonflow group (M = 1.16 ± 0.33: an average grade of D; p = .007). Additionally, students experiencing flow were more accurate in predicting their grade (difference scores, flow M = 0.12 ± 0.33 vs. nonflow M = 1.39 ± 0.29; p = .015). Students in the nonflow group were nearly a grade and a half off in their prediction of their grade on the paper. To the authors' knowledge, the study is the first to provide experimental evidence showing differences in academic performance between students experiencing flow and nonflow students.