ABSTRACT
Recent epidemiological and clinical studies indicate that the control of sleep-wake states may be an important factor in the regulation of energy metabolism. Leptin is a peripherally synthesized hormone that has critical signaling properties in the brain for the control of long-term energy homeostasis. In this study, we examined the hypothesis that leptin signaling exerts a role in sleep-wake regulation and that leptin may represent an important mechanistic link in the coordination of sleep-wake states and metabolism. Sleep-wake patterns were recorded in a genetic mouse model of obesity and diabetes, the db/db mouse, which harbors a mutation in a particular isoform of the leptin receptor (long form, LRb). We found that db/db mice exhibit a variety of alterations in sleep regulation, including an increase in overall sleep time, a dramatic increase in sleep fragmentation, attenuated diurnal rhythmicity in rapid eye movement sleep and non-rapid eye movement EEG delta power (a measure of sleep homeostatic drive), and a decrease in the compensatory response to acute (i.e., 6 h) sleep deprivation. The db/db mice also generated low amounts of locomotor activity and a reduction in the diurnal rhythm of activity. These results indicate that impaired leptin signaling has deleterious effects on the regulation of sleep amount, sleep architecture, and temporal consolidation of these arousal states. In summary, leptin may represent an important molecular component in the integration of sleep, circadian rhythms, and energy metabolism.
Subject(s)
Behavior, Animal , Circadian Rhythm , Diabetes Mellitus/physiopathology , Leptin/metabolism , Obesity/physiopathology , Signal Transduction , Sleep , Wakefulness , Animals , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Models, Animal , Electroencephalography , Electromyography , Energy Metabolism , Male , Mice , Mice, Obese , Motor Activity , Mutation , Obesity/genetics , Obesity/metabolism , Phenotype , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , Recovery of Function , Sleep Deprivation/metabolism , Sleep Deprivation/physiopathologyABSTRACT
1 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine (JNJ-5207852) is a novel, non-imidazole histamine H3 receptor antagonist, with high affinity at the rat (pKi=8.9) and human (pKi=9.24) H3 receptor. JNJ-5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 microm. 2 JNJ-5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED50 of 0.13 mg kg(-1) in mice). In vitro autoradiography with 3H-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of 3H-R-alpha-methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3H-JNJ-5207852 was observed in brains of H3 receptor knockout mice. 3 In mice and rats, JNJ-5207852 (1-10 mg kg(-1) s.c.) increases time spent awake and decreases REM sleep and slow-wave sleep, but fails to have an effect on wakefulness or sleep in H3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wake-promoting effects of this H3 receptor antagonist are not associated with hypermotility. 4 A 4-week daily treatment of mice with JNJ-5207852 (10 mg kg(-1) i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H3 receptor. 5 JNJ-5207852 is extensively absorbed after oral administration and reaches high brain levels. 6 The data indicate that JNJ-5207852 is a novel, potent and selective H3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H3 receptor antagonists.
Subject(s)
Histamine Antagonists/pharmacology , Piperidines/pharmacology , Receptors, Histamine H3/drug effects , Wakefulness/drug effects , Administration, Oral , Animals , Autoradiography , Body Temperature/drug effects , Body Weight/drug effects , Cyclic AMP/metabolism , Electrodes , Electroencephalography/drug effects , Electromyography/drug effects , Histamine Antagonists/administration & dosage , Histamine Antagonists/pharmacokinetics , Humans , Injections, Intravenous , Male , Mice , Mice, Knockout , Mice, Obese , Motor Activity/drug effects , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Polysomnography , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/genetics , Sleep/drug effects , TransducersABSTRACT
Oleamide (OA) is an endogenous unsaturated fatty acid amide with demonstrated sleep promoting effects in rodents. The sleep enhancing actions of OA may be mediated through interactions with the GABAergic, serotonergic or cannabinergic receptor systems. In this study, we investigated the possible interaction of OA with the GABA(A )receptor by administering OA to mice with a targeted mutation of the GABAA receptor beta 3 subunit (Gabarb3-/-). Peripherally administered OA significantly decreased sleep latency and wake time, while it increased non-rapid eye movement and total sleep times in wild-type (Gabarb3+/+) mice. OA failed to have any sleep-wake effect in Gabarb3-/- mice. On 24 h baseline recordings, no differences between Gabarb3-/- and Gabarb3+/+ mice were observed, indicating that the lack of a pharmacological response to OA in the Gabarb3-/- animals was not secondary to disruptions in physiological. sleep. Therefore, one mechanism by which OA exerts its sleep effects may be through interactions with GABA(A) receptors containing the beta 3 subunit.
Subject(s)
Hypnotics and Sedatives/pharmacology , Oleic Acids/pharmacology , Receptors, GABA-A/genetics , Sleep Stages/drug effects , Sleep Stages/physiology , Animals , Brain Chemistry/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagenesis/physiology , Wakefulness/drug effects , Wakefulness/physiologyABSTRACT
Myelin mutants provide an opportunity to study neurophysiological and behavioral effects of demyelination. The taiep rats are myelin mutants with progressive demyelination of the central nervous system (CNS), resulting in five neurological symptoms: tremor, ataxia, immobility, epilepsy, and paralysis. The demyelination affects the brainstem, an important area in the control of sleep. This study compared eye movement density (EMD) in taiep vs. normal control rats during paradoxical sleep (PS). It was hypothesized that taiep rats would have significantly reduced EMD during PS in comparison to normal controls due to their demyelinating disease. In addition, demyelination of brainstem structures would suggest possible changes in sleep-wake structure. Hence, we compared sleep-wake stages in taiep vs. normal, control rats. The results confirmed significantly reduced EMD during PS in taiep rats compared to normal rats during the 12-h (light) recording period. In addition, analysis of EMD values across the 12-h light period revealed significant differences in EMD values as a function of time of day in the taeip rats only. Comparison of waking and sleep values across the 12-h light phase revealed an "immobility episode" in three taiep rats, which was not present in normal controls. In addition, PS percentage was significantly lower and low-voltage sleep was significantly higher in taiep rats. These results suggest that EMD, immobility episodes, and sleep architecture may be useful as measurable biological events in the study of demyelinating disease. The results were discussed in terms of possible mechanisms underlying these differences, as well as possible implications for future studies.
