Haloperidol-induced hypokinesia in rats is differentially affected by the light/dark phase, age, and melatonin.

It has been well established that the striatal dopaminergic system is compromised with aging, namely D2 receptor function. Also well documented is the age related decline of the neurohormone, melatonin, in both humans and nonhuman animals. What has not been well studied is the possible interaction between the D2 receptor system and the age related decline in melatonin with its unmistakable pattern of synthesis and release exclusively during the dark phase. We tested the effect of the D2 antagonist, haloperidol (1.0 mg/kg ip), in adolescent (2 mo old) and adult rats (10 mo old) in the light (ZT3) and dark phases (ZT 15) in rats kept in a 12 L/12D cycle and the effect of exogenous melatonin (15 mg/kg ip/day x 4 days for a total of 60 mg/kg) on D2 antagonism. Using the bar test, measuring the extrapyramidal side-effect of hypokinesia, we report haloperidol to work differentially depending on both age and phase. Adult rats experienced the effect of the D2 antagonist in both the light and dark phases, while younger rats did not show hypokinetic affects in the dark. By manipulated lighting, we were able to restore the effect of haloperidol in younger rats in the dark phase. We also found ameliorating effects of melatonin lessening time on the bar after treatment with haloperidol, however, this effect was only found in older rats. These data demonstrate the importance of the light/dark cycle and age in the susceptibility of extrapyramidal effects with use of drugs that target D2 receptor function.

Procrastination, Flow, and Academic Performance in Real Time Using the Experience Sampling Method.

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.

Differential effects of a short-term high-fat diet in an animal model of depression in rats treated with the 5-HT3 receptor antagonist, ondansetron, the 5-HT3 receptor agonist, 2-methyl-5-HT, and the SSRI, fluoxetine.

Investigation into the effects of a high-fat diet on depression in the context of 5-HT3 receptor function is important given 5-HT3 antagonism may represent a novel candidate for drug discovery. To more fully understand the relationship between the 5-HT3 receptor system, depression, and high-fat intake, our main interest was to study the short-term effects of a high-fat diet on the 5-HT3 receptor antagonist, ondansetron, and the 5-HT3 receptor agonist, 2-methyl-5-HT, as well as the SSRI, fluoxetine, in an animal model of depression. Male Sprague Dawley rats were fed either a standard diet (11% fat) or a high-fat diet (32.5% fat) for seven days then treated with either fluoxetine (10mg/kg, ip), ondansetron (1mg/kg, ip), 2-methyl-5-HT (3mg/kg, ip), fluoxetine+ondansetron or, 2-methyl-5-HT+ondansetron prior to the Forced Swim Test. In the standard diet group, treatment with the 5HT3 receptor agonist, 2-methyl-5-HT, served to significantly decrease time of immobility as compared to controls thus showing anti-depressive-like effects. Treatment with the 5-HT3 receptor antagonist, ondansetron, served to enhance the anti-depressive like effects of the SSRI, fluoxetine, as treatment with both the SSRI and 5-HT3 receptor antagonist dramatically decreased immobility. Importantly, in the high-fat diet groups, a week of high-fat intake served to: 1) counteract the anti-depressive-like effect of the SSRI, fluoxetine, 2) reverse the anti-depressive-like effect of the 5HT3 receptor agonist, 2-methyl-5-HT and 3) provide protection against the depressive-like effects induced by the Forced Swim Test as rats fed a high-fat diet displayed the lowest amounts of immobility. In the aggregate, these data suggest that both SSRIs and the 5HT3 receptor system are affected by short-term high-fat intake and that a short-term high-fat diet protects against depressive-like effects in an animal model of depression.

A randomized phase I study of methanesulfonyl fluoride, an irreversible cholinesterase inhibitor, for the treatment of Alzheimer's disease.

AIMS: To 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. METHODS: To 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. RESULTS: Twenty-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%). CONCLUSIONS: MSF 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.

Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORbeta knockout.

This study reports for the first time the effects of retinoid-related orphan receptors [RORbeta; receptor gene deletion RORbeta(C3H)(-/-)] 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 (+/+), heterozygous (+/-), and knockout (-/-) mice. The RORbeta(C3H)(-/-) mice displayed motor ("duck gait," hind paw clasping reflex) and olfactory deficits, and reduced anxiety and learned helplessness-related behaviors. Circadian rhythms of wheel-running activity in all genotypes showed entrainment to the light-dark (LD) cycle, and free running in constant dark, with RORbeta(C3H)(-/-) mice showing a significant increase in circadian period (tau). Melatonin administration (90 microg/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 RORbeta(C3H)(-/-) 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 (+/+) mice. Yet, the rate of reentrainment was significantly advanced by melatonin administration at the new dark onset in both (+/+) and (-/-) mice. We conclude that the RORbeta 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.

Prenatal exposure to the acetylcholinesterase inhibitor methanesulfonyl fluoride alters forebrain morphology and gene expression.

Methanesulfonyl fluoride (MSF) is a CNS-selective acetylcholinesterase (AChE) inhibitor, currently being developed and tested for the treatment of symptoms of Alzheimer's disease. We have previously confirmed that a single in utero exposure to MSF at clinically appropriate doses inhibits AChE activity in fetal rat brain by 20%, and when administered throughout gestation, MSF achieves a 40% level of inhibition. Here, we show that rats chronically exposed in utero to MSF display marked sex-specific differences in morphological development of the cerebral cortical layers compared with controls at 7 days of age. Forebrain size and cortical thickness were increased in females and decreased in males. An analysis of gene expression in neonate brain on the day of birth revealed sex-specific differential expression of over 25 genes, including choline acetyltransferase (ChAT), which were affected by prenatal MSF exposure. Many of these genes are associated with sexual differentiation and brain development, while others are involved in more generalized cellular and metabolic processes. The changes observed in cortical morphology and gene expression suggest a critical developmental role for AChE in the fetal nervous system, most likely through its effect on cholinergic neurotransmission.

Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates simple learning and memory deficits in ischemic rats.

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 +/- 10%) and significantly prolonged acquisition (398 +/- 62 s) and shortened retention (79 +/- 26 s) of the passive avoidance task. Interestingly, while the ischemic animals that received the MSF exhibited elevated body swing biased activity (87.7 +/- 8%), they performed significantly better in the passive avoidance task (255 +/- 36 s and 145 +/- 18 s in acquisition and retention) than the vehicle-treated animals. Moreover, whereas brains from both groups of animals revealed similar extent and degree of cerebral infarction, the MSF-treated 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.