Effects of Chronic Oral Administration of Midazolam on Memory and Circadian Rhythms in Rats.

Studies have shown the ability of benzodiazepine drugs to cause memory loss in animals and humans. Midazolam is a benzodiazepine commonly administered intravenously during surgical procedures because it reacts rapidly, causes anterograde amnesia, and has few side effects. It has also been used in palliative medicine where, among others, an oral route has been employed for chronic administration of the drug. The current study evaluated the effects of chronic orally administered midazolam on spatial working memory and procedural memory in control and experimental female rats over a three-week experimental period utilizing the Morris water maze. Sample and test run times to a submerged platform in the maze were recorded daily. In addition, activity wheels attached to each cage were employed to monitor daily circadian activity of the animals. Spatial working memory was not impaired in either group. However, procedural memory amnesia occurred in animals receiving the drug indicative of a consolidation or retrieval problem. Concerning circadian rhythms, a phase-shift was noted in experimental animals possibly indicating that time of day of drug administration is important. The findings of the present study could shed insight into altered reactions observed in humans who have received midazolam as a component of treatment in palliative medicine.

The effects of the prodrug Vyvanse on spatial working memory and adiposity in rats.

The present study investigated the influence of Vyvanse (lisdexamfetamine), a psychomotor stimulant, on spatial working memory, body weight, and adiposity in rats. Control and experimental rats were placed in individual cages equipped with a running wheel, and food and water were provided ad-libitum. The study was divided into three periods: 1) habituation, 2) experimental, and 3) withdrawal. Control rats received a placebo in periods 1, 2 and 3, while experimental rats received a placebo in periods 1 and 3. Experimental rats received a treatment of Vyvanse in place of the placebo during period 2. Spatial working memory was examined by utilizing the methodology of the Morris Water Maze. Rats were evaluated by performance in the maze each day during the experimental and withdrawal periods. Each assessment consisted of two trials. The first was a sample trial in which an escape platform was discovered by trial and error. The second was a test trial in which the platform location was recalled using working memory. Platform placement and start location of the rats were changed every session. It was hypothesized that Vyvanse would effectively enhance spatial working memory, and significantly decrease body weight and adiposity without side effects on activity level and anxiety in rats. Results supported the hypothesis. Compared to control rats, Vyvanse treated rats had significant improvement in working memory and significantly lowered body weight, as well as significantly decreased mesenteric, renal, and epididymal adiposity. No significant effects on activity level and task specific anxiety were noted in experimental animals. When compared to placebo treatment, Vyvanse treatment produced no significant influence on food and water intake. It was concluded that Vyvanse treatment in rats can enhance spatial working memory, and decrease adiposity without suppressing normal appetite.

Modafinil as a cognitive enhancer of spatial working memory in rats.

The present experiment examined the influence of modafinil on working memory in rats. Control and experimental rats were placed in cages equipped with a running wheel. The study was divided into three periods: 1) habituation, 2) experimental - in which modafinil was orally administered to experimental animals, and 3) withdrawal. Spatial working memory was tested utilizing the Morris Water Maze. Animals were given two trials in each session: 1) a sample trial in which they discovered the location of the platform and 2) a test trial in which they recalled the location of the platform. Platform placement and starting place location of the rats were changed every session. Performance of control animals during sample trials and test trials showed no difference in time to reach the platform; whereas, experimental animals demonstrated faster attainment of the goal during the test trial. In withdrawal, there was no difference in time between the two trials for experimental animals. Wheel running activity of the experimental group was lower than that of the control group during the experimental period. This study supports the hypothesis that modafinil has a positive effect on working memory in rats. It is suggested that benefits of modafinil can extend beyond its prescribed usage; however, these advantages of modafinil use should be addressed in discussions related to ethical concerns associated with neuroenhancers.

An animal model of stress-induced cardiomyopathy utilizing the social defeat paradigm.

Stress-induced cardiomyopathy (SIC) is a form of acute heart disease triggered by extreme psychological stress. In patients who develop SIC, the outward symptoms are almost indistinguishable from acute myocardial infarction (AMI). However, some important criteria differentiate patients with SIC from those with AMI. Patients with SIC: (1) experience some form of extreme psychological stress from minutes to hours before developing heart disease, (2) do not suffer from atherosclerosis or coronary artery obstruction, and 3) exhibit abnormal ballooning of the left ventricle. In the present study, the resident-intruder (RI) social defeat test was investigated as a potential rat model for stressed-induced cardiomyopathy. Adult Long-Evans rats were implanted with a biotelemetry transmitter for ECG recordings and habituated for two weeks. An intruder rat was placed in the cage of a resident rat behind a wire-mesh partition for 5 min. The partition was then removed for 5 min to allow direct contact between the intruder and resident rats. After this interval, the wire-mesh partition was replaced and the intruder rat remained behind the partition for an additional 50 min. Behavioral responses were noted and ECG recordings were collected during the entire 60-min testing period. Upon completion of the test, the intruder rat was removed from the cage of the resident rat and sacrificed. The heart was examined and blood was collected. Heart weight/body weight ratio, left ventricle/body weight ratio, heart length, plasma corticosterone levels, and plasma troponin I levels of intruder rats were significantly higher as compared to control rats. Intruder rats significantly increased their heart rate during the first 5 min of the RI test. It is concluded that the RI test to induce social defeat is a novel rodent paradigm for modeling stress-induced cardiomyopathy in the human.

Zolpidem-induced changes in activity, metabolism, and anxiety in rats.

Gamma aminobutyric acid (GABA)-A receptor modulators constitute the majority of clinically relevant sedative-hypnotics. Zolpidem (Ambien) is a nonbenzodiazepine GABA-A receptor modulator that binds with high affinity to GABA-A receptors expressing alpha-1 subunits. The present study examined the effects of a new approach to the oral administration of zolpidem on locomotor activity, body weight, food intake, relative food intake, feed efficiency, anxiety, and visceral adiposity in rats. Effects of withdrawal associated with cessation of the drug were also recorded. A daily chronically administered oral 10 mg/kg dose of zolpidem caused a decrease in locomotor activity, an increase in food intake and relative food intake, and a more positive feed efficiency during the drug-administration period. Anxiety and visceral adiposity also increased in animals receiving the drug. During withdrawal of zolpidem, there was a decrease in body weight, food intake, relative food intake, and anxiety, as well as a negative feed efficiency. These results suggest that zolpidem can modulate locomotor activity, metabolism, and anxiety-related behavior. A highly positive feed efficiency and increased visceral adiposity associated with zolpidem intake were unique findings of this study.

Constant light induces alterations in melatonin levels, food intake, feed efficiency, visceral adiposity, and circadian rhythms in rats.

Melatonin levels, metabolic parameters, circadian rhythm activity patterns, and behavior were observed in rats subjected to a 12-h/12-h light/dark cycle (LD) compared to animals exposed to continuous dark (DD) or continuous light (LL). LD and DD animals were similar in melatonin levels, food intake, relative food intake, feed efficiency, water intake, circadian activity levels, and behavior. LL animals had lower melatonin levels in the subjective dark compared to LD and DD animals. Food intake, relative food intake, and water intake values were lower and feed efficiency was more positive in LL animals compared to LD and DD animals. In addition, LL animals exhibited greater visceral adiposity than the other two groups. The circadian rhythmicity of activity became free-running in LL animals and there was a decrease in overall activity. Notable behavioral changes in LL animals were an increase in irritability and excitability. Results indicate that a decrease in melatonin levels and concomitant changes in metabolism, circadian rhythms, and behavior are consequences of exposure to constant light.

A laboratory animal model of human shift work.

The purpose of this study was to develop a laboratory animal model of human shift work. Two methods of monitoring circadian rhythms in rats were employed: an activity wheel cage, where number of wheel revolutions (WR) were counted, and an internal radio transmitter, which recorded gross motor activity (GMA) and body temperature (BT). Rats were implanted with biotelemetry transmitters that detected GMA and BT and were placed in activity wheel cages. A 12 hour/12 hour light/dark cycle was maintained. Subjects were subdivided into two groups: control and experimental. Following a habituation period of 15 days, in which animals had ad-libitum access to food and water and unlimited access to the running wheel, the experimental period ensued for 22 days. Control animals were food restricted and their activity wheels were locked during the light; experimental animals were food restricted and their activity wheels were locked during the dark. At the end of the experimental period, animals were returned to the habituation paradigm for 15 days. Recordings of WR, GMA and BT, as well as daily monitoring of body weight and food intake, indicated that experimental animals resembled humans employed in a shift work schedule. In the experiment, the light entrainable oscillator and the food entrainable oscillator were uncoupled in experimental animals, producing alterations in activity/rest cycles, consummatory behavior, and overt behavior. Since similar alterations occur in shift workers, it is proposed that the experimental paradigm presented in this manuscript is a useful model of shift work and provides a framework upon which future experiments may be conducted.

Telemetry provides new insights into entrainment of activity wheel circadian rhythms and the role of body temperature in the development of ulcers in the activity-stress paradigm.

Two methods of monitoring the circadian rhythm of activity in rodents: (1) an activity wheel cage, which detects the number of wheel revolutions, and (2) an internal radio transmitter, which records gross motor activity (GMA) of the animal, were compared in both normal circadian cycles and during the development of activity-stress ulcers. Rats were implanted with a biotelemetry transmitter that detected GMA and body temperature (BT) and placed in activity wheel cages. A 12 hour/12 hour light/dark cycle was maintained throughout the experiment. Subjects were subdivided into two groups: (1) unlimited access to activity wheel (AW) cages and (2) locked activity wheel (LW) cages. Following an ad-libitum habituation period, animals were allowed food access for 1 hour/day during the light. In the habituation period, the animals showed higher GMA and BT during the dark phase when housed in AW cages than in LW cages. Both GMA and number of wheel revolutions increased dramatically after the onset of food restriction for the AW animals. There was a deleterious drop in BT in AW animals as the food-restricted period continued and a significant correlation existed between severity of ulcerations and BT. The findings of this experiment demonstrate that the activity wheel imposes an alternation of the circadian cycle, which, in turn, influences rhythmicity through reentrainment. Additionally, in the activity-stress paradigm, a significant drop in BT correlates with severity of ulcerations. A disrupted circadian cycle, involving hypothermia, is proposed as the mechanism underlying the demise of animals in the activity-stress paradigm.