Theobromine improves hyperactivity, inattention, and working memory via modulation of dopaminergic neural function in the frontal cortex of spontaneously hypertensive rats.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents via the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar-Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1-5 (DRD1-5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD.

Perilla frutescens seed oil combined with Anredera cordifolia leaf powder attenuates age-related cognitive decline by reducing serum triglyceride and glucose levels in healthy elderly Japanese individuals: a possible supplement for brain health.

We have shown that Anredera cordifolia extract improves learning and memory in a senescence-accelerated mouse model, and that α-linolenic acid (ALA)-rich Perilla frutescens seed oil (PO) improves brain function in healthy Japanese adults and elderly individuals. Herein, we present a 12-month, randomised, double-blind, parallel-armed intervention trial examining the effects of PO supplementation alone or in combination with A. cordifolia leaf powder on brain function in healthy elderly Japanese individuals. Participants were randomly divided into two groups: the PO group received 1.47 mL PO (0.88 g ALA) daily via soft gelatine capsules, and the POAC group received 1.47 mL PO and 1.12 g A. cordifolia leaf powder (1.46 mg vitexin and 1.12 mg adenosine) daily. After 12 months of intervention, the POAC group showed generally higher cognitive index scores than the PO group. The beneficial effects of combined supplementation on cognitive function were associated with increased ALA and eicosapentaenoic acid levels in red blood cell plasma membranes, increased serum biological antioxidant potential, and decreased serum triglyceride, glucose, and N-(epsilon)-carboxymethyl-lysine (CML), an advanced glycation end-product and biochemical marker of oxidative stress levels. The effects of combined supplementation on cognitive function also showed a significant negative correlation with serum CML levels after 12 months of intervention. Our findings suggest that combined long-term supplementation with PO and A. cordifolia more effectively ameliorates age-related cognitive decline than PO alone. These findings may serve as a basis for the development of new supplements for brain health. Clinical Trial Registry, UMIN000040863.

Perilla seed oil in combination with nobiletin-rich ponkan powder enhances cognitive function in healthy elderly Japanese individuals: a possible supplement for brain health in the elderly.

Perilla (Perilla frutescens) seed oil (PO), rich in α-linolenic acid (ALA), can improve cognitive function in healthy elderly Japanese people. Here, supplements containing either PO alone or PO with nobiletin-rich air-dried immature ponkan powder were examined for their effects on cognitive function in 49 healthy elderly Japanese individuals. Patients were enrolled in a 12-month randomized, double-blind, parallel-armed study. Randomized participants in the PO group received soft gelatin capsules containing 1.47 mL (0.88 g of ALA) of PO daily, and those in the PO + ponkan powder (POPP) group received soft gelatin capsules containing both 1.47 mL of PO and 1.12 g ponkan powder (2.91 mg of nobiletin) daily. At the end of intervention, the POPP group showed significantly higher cognitive index scores than the PO group. The pro-cognitive effects of POPP treatment were accompanied by increases in ALA and docosahexaenoic acid levels in red blood cell plasma membranes, serum brain-derived neurotropic factor (BDNF) levels, and biological antioxidant potential. We demonstrate that 12-month intervention with POPP enhances serum BDNF and antioxidant potential, and may improve age-related cognitive impairment in healthy elderly people by increasing red blood cell ω-3 fatty acid levels. Clinical Trial Registry, UMIN000040863.

Role of linkage between cerebral activity and baroreflex control of heart rate via central vasopressin V1a receptors in food-deprived mice.

We previously reported that cerebral activation at the onset of voluntary locomotion suppressed baroreflex control of heart rate (HR) and increased arterial pressure via vasopressin V1a receptors in the brain. Here, we examined whether these responses were associated with food seeking, a motivated behavior, using free-moving wild type (WT, n = 10), V1a receptor knockout (KO, n = 9), and wild-type mice locally infused with a V1a receptor antagonist into the nucleus tractus solitarii (BLK, n = 10). For three consecutive days, mice were fed ad libitum (Fed), food deprived (FD), and refed (RF) under a dark/light cycle (1900/0700). Food was removed on day 2 and restored on day 3 at 1800. Throughout the protocol, cerebral activity was determined from the power density ratio of θ- to δ-wave band (θ/δ) by electroencephalogram every 4 s. Baroreflex was evaluated by the cross-correlation function [R(t)] between changes in HR and arterial pressure every 4 s. The cerebro-baroreflex linkage was then evaluated by the cross-correlation function between θ/δ and R(t). Behavior was recorded with CCD camera. We found that cerebro-baroreflex linkage, enhanced in WT at night after FD (P = 0.006), returned to Fed level after RF (P = 0.68). Similarly, food-seeking behavior increased after FD to a level twofold higher than during Fed (P < 0.001) and returned to Fed level after RF (P = 0.54). However, none of these changes occurred in KO or BLK (P > 0.11). Thus, the suppression of baroreflex control of HR linked with cerebral activation via central V1a receptors might play an important role at the onset of motivated behaviors, such as food seeking induced by FD.NEW & NOTEWORTHY Motivated behaviors, characterized by goal-directed and persistent movements, are indispensable for living. However, how cerebro-cardiovascular adjustment occurs during such behaviors remains unknown. By focusing on food-seeking behavior in a food-deprived condition using free-moving mice, we found that this condition enhanced the linkage between cerebral activation and suppression of baroreflex control of heart rate through central vasopressin V1a receptors, making it easier to start motivated behaviors by enhancing pressor response.

Anredera cordifolia extract enhances learning and memory in senescence-accelerated mouse-prone 8 (SAMP8) mice.

Learning and memory impairment may result from age-related decline in synaptic plasticity-related proteins in the hippocampus. Therefore, exploration of functional foods capable of ameliorating memory and cognition decline is an interesting endeavor in neuroscience research. We report the effects of Anredera cordifolia (AC) extract on learning and memory deficits in a senescence-accelerated mouse-prone 8 (SAMP8) mouse model, which demonstrate age-related memory deficits and related pathological changes in the brain. After 8 weeks of oral administration of AC extract, the mice were trained in the Novel Object Recognition (NOR) task, and after 7 more weeks, in the Morris Water Maze (MWM) task. Following the completion of behavioral testing, the blood biochemistry parameters, the hippocampal levels of brain-derived neurotropic factor (BDNF), PSD95, and NR2A, and the p-cAMP-response element binding (p-CREB)/CREB ratio were measured. The AC-treated group spent more time exploring the novel objects in the NOR task, and showed faster acquisition and better retention in the MWM task than the negative control (CN) group. In addition, AC enhanced the levels of the aforementioned neuronal plasticity-related proteins, and did not affect the blood biochemistry parameters. Therefore, our data suggest that the AC extract may improve learning and memory without causing any noticeable side effects in the body.

Ginger facilitates cell migration and heat tolerance in mouse fibroblast cells.

The components of ginger root (Zingiber officinale Roscoe) are widely used for various medicinal purposes. Several bioactive compounds have been identified in ginger, including 6­, 8­ and 10­gingerols, and 6­shogaol, which are agonists of the thermo­sensors transient receptor potential (TRP) cation channel subfamily V member 1 and TRP ankyrin 1. Our previous study demonstrated that ginger powder may affect human metabolism in vivo. However, the effects of the bioactive compounds of ginger on cells have not been completely elucidated. The present study investigated whether ginger powder extracts could modify cell functions in mouse fibroblast cells. The active components of ginger powder extracts were characterized using high­performance liquid chromatography. The activation of protein kinases, actin assembly, cell migration, expression levels of heat shock proteins (HSPs) and cell viability after heat shock were analyzed in NIH3T3 mouse fibroblast cells. Subsequently, 6­, 8­, 10­ and 12­gingerols, as well as 6­, 8­ and 10­shogaols, were detected in ginger powder extracts. The levels of phosphorylated Akt, mTOR, ERK and p38 MAPK increased after a 10­min stimulation with ginger powder extracts. In addition, HSP expression levels, lamellipodia formation occurring at cell edges, cell migration and tolerance against heat shock were facilitated following ginger powder extract stimulation. These results suggest that ginger modified cell functions, including actin assembly and heat tolerance, in vitro.

Countdown before voluntary exercise induces muscle vasodilation with baroreflex-mediated decrease in muscle sympathetic nerve activity in humans.

We examined whether a countdown (CD) before voluntary cycling exercise induced prospective vascular adjustment for the exercise and, if so, whether and how muscle sympathetic nerve activity (MSNA) was involved in the responses. Young men performed voluntary cycling in a semirecumbent position (n = 14) while middle cerebral artery blood flow velocity (VMCA; Doppler ultrasonography), heart rate (HR), arterial pressure (AP; finger photoplethysmography), oxygen consumption rate (V̇o2), oxygen saturation in the thigh muscle (StO2; near-infrared spectrometry), cardiac output (CO; Modelflow method), and total peripheral resistance (TPR) were measured (experiment 1). Another group underwent the same exercise protocol but used only the right leg (n = 10) while MSNA (microneurography) was measured in the peroneal nerve of the left leg (experiment 2). All subjects performed eight trials with a ≥5-min rest between trials. In four trials randomly selected from the eight trials, exercise onset was signaled by a 30-s CD, whereas in the remaining four trials, exercise was started without CD. We found that CD first increased VMCA, HR, CO, and mean AP, and then decreased TPR and increased StO2 and V̇o2 (experiment 1; all P < 0.021). Furthermore, the CD-induced increase in mean AP decreased total MSNA and burst frequency (experiment 2; both P < 0.048) through the baroreflex, with decreased TPR and increased StO2 (experiment 2; both P < 0.001). The vasodilation and increased V̇o2 continued after the start of exercise. Thus CD before starting exercise induced the muscle vasodilatory response with a concomitant reduction in MSNA through the baroreflex to accelerate aerobic energy production after the start of exercise.NEW & NOTEWORTHY Prospective cardiovascular adjustment occurs before starting voluntary exercise, increasing heart rate and arterial pressure followed by muscle vasodilation; however, the precise mechanisms and significance for this vasodilation remain unknown. We found that during the countdown before starting exercise cerebral blood flow velocity increased, followed by increases in heart rate and arterial pressure, which suppressed MSNA through baroreflex, resulting in thigh muscle vasodilation to increase oxygen consumption rate, which might make it easier to start exercise.

Salivary Immunoglobulin A Secretion and Polymeric Ig Receptor Expression in the Submandibular Glands Are Enhanced in Heat-Acclimated Rats.

Salivary immunoglobulin A (IgA) plays a critical role in mucosal immunity. Chronic exposure to moderate heat induces heat acclimation, which modifies salivary functions. However, the changes in salivary IgA secretion in heat-acclimated rats are unclear. In this study, we investigated salivary IgA secretion and the expression of polymeric Ig receptor (pIgR), a key mediator of mucosal IgA secretion, in the submandibular glands (SMGs) of heat-acclimated rats. Following maintenance at an ambient temperature (Ta) of 24 ± 0.1 °C for 10 days, male Wistar rats were subjected to Ta of 32 ± 0.2 °C for 5 days (HE group) for heat acclimation or maintained at Ta of 24 ± 0.1°C (CN group). The rats were then anesthetized, pilocarpine (0.5 mg/kg) was intraperitoneally injected, and saliva was collected. Afterward, the SMGs and plasma were sampled. The salivary IgA concentration and IgA flow rate were significantly higher in the HE group than in the CN group. Similarly, SMG pIgR expression was significantly higher in HE rats. The levels of plasma cytokines, including interleukin (IL)-5, IL-6, and interferon-γ, were significantly greater in HE rats than in CN rats. Heat acclimation may enhance oral immunity through salivary IgA secretion and pIgR upregulation in the SMGs.

Sub-Chronic Consumption of Dark Chocolate Enhances Cognitive Function and Releases Nerve Growth Factors: A Parallel-Group Randomized Trial.

Previous research has shown that habitual chocolate intake is related to cognitive performance and that frequent chocolate consumption is significantly associated with improved memory. However, little is known about the effects of the subchronic consumption of dark chocolate (DC) on cognitive function and neurotrophins. Eighteen healthy young subjects (both sexes; 20-31 years old) were randomly divided into two groups: a DC intake group (n = 10) and a cacao-free white chocolate (WC) intake group (n = 8). The subjects then consumed chocolate daily for 30 days. Blood samples were taken to measure plasma levels of theobromine (a methylxanthine most often present in DC), nerve growth factor (NGF), and brain-derived neurotrophic factor, and to analyze hemodynamic parameters. Cognitive function was assessed using a modified Stroop color word test and digital cancellation test. Prefrontal cerebral blood flow was measured during the tests. DC consumption increased the NGF and theobromine levels in plasma, enhancing cognitive function performance in both tests. Interestingly, the DC-mediated enhancement of cognitive function was observed three weeks after the end of chocolate intake. WC consumption did not affect NGF and theobromine levels or cognitive performance. These results suggest that DC consumption has beneficial effects on human health by enhancing cognitive function.

Long-Term Ultra-High Hydrostatic Pressurized Brown Rice Intake Prevents Bone Mineral Density Decline in Elderly Japanese Individuals.

Bone embrittlement with aging, namely osteoporosis, is characterized by low bone mass and deterioration of bone tissue, and can lead to increased risk of fracture. The development of functional foods that can prevent geriatric diseases is in progress. Our focus was on brown rice because of its properties. An interventional study using of ultra-high hydrostatic pressurized brown rice (UHHPBR) for human has not yet been conducted. In this study, we investigated whether long-term dietary intake of UHHPBR prevents aging-related decline of bone mineral density in elderly Japanese individuals. Elderly participants (n=40; mean 73.1 y) in Iinan-cho, Shimane, Japan, were randomly divided into two groups. The UHHPBR-intake group (n=20) consumed 100 g of UHHPBR and 100 g of white rice (WR) per day for 12 mo, while the WR-intake group (n=20) consumed 200 g of WR per day. Pre- and 12-mo post-intervention, bone mineral density was evaluated by quantitative ultrasound. After 12 mo of intervention, the UHHPBR group's bone mineral density was significantly higher than the WR group's bone mineral density. Moreover, chronic intake of UHHPBR had no adverse side effects on participants. Long-term oral UHHPBR intake may have beneficial effects on bone mineral density decline and may attenuate osteoporosis in the elderly.

Theobromine Improves Working Memory by Activating the CaMKII/CREB/BDNF Pathway in Rats.

Theobromine (TB) is a primary methylxanthine found in cacao beans. cAMP-response element-binding protein (CREB) is a transcription factor, which is involved in different brain processes that bring about cellular changes in response to discrete sets of instructions, including the induction of brain-derived neurotropic factor (BDNF). Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been strongly implicated in the memory formation of different species as a key regulator of gene expression. Here we investigated whether TB acts on the CaMKII/CREB/BDNF pathway in a way that might improve the cognitive and learning function in rats. Male Wistar rats (5 weeks old) were divided into two groups. For 73 days, the control rats (CN rats) were fed a normal diet, while the TB-fed rats (TB rats) received the same food, but with a 0.05% TB supplement. To assess the effects of TB on cognitive and learning ability in rats: The radial arm maze task, novel object recognition test, and Y-maze test were used. Then, the brain was removed and the medial prefrontal cortex (mPFC) was isolated for Western Blot, real-time PCR and enzyme-linked immunosorbent assay. Phosphorylated CaMKII (p-CaMKII), phosphorylated CREB (p-CREB), and BDNF level in the mPFC were measured. In all the behavior tests, working memory seemed to be improved by TB ingestion. In addition, p-CaMKII and p-CREB levels were significantly elevated in the mPFC of TB rats in comparison to those of CN rats. We also found that cortical BDNF protein and mRNA levels in TB rats were significantly greater than those in CN rats. These results suggest that orally supplemented TB upregulates the CaMKII/CREB/BDNF pathway in the mPFC, which may then improve working memory in rats.

Chronic administration of theobromine inhibits mTOR signal in rats.

Theobromine is a caffeine derivative and the primary methylxanthine in Theobroma cacao. We have shown previously that theobromine inhibits the Akt-mammalian target of rapamycin (mTOR) signal in vitro. In this study, we investigated whether orally administered theobromine could inhibit mTOR activity in rats. mTOR is phosphorylated by Akt. Thus, the level of phosphorylated mTOR was used as an index of mTOR activity. Male Wistar rats were divided into two groups. The control group (CN) was fed a normal diet, while the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 40 days. We measured body-weights and tissue weights, food and water intake, blood count, concentrations of theobromine in the plasma, liver and brain, and the levels of phosphorylated mTOR in the liver and brain. Orally administered theobromine did not affect the body-weights and tissue weights, food and water intake, and blood count as determined by comparison with levels in rats that were fed standard chow. Theobromine was detected in the plasma, liver and brain obtained from TB rats, but was not detected in tissues obtained from CN rats. The phosphorylated mTOR levels in the liver and brain were significantly lower in TB rats than in CN rats. The results suggest that oral theobromine inhibits mTOR signalling in vivo.

Daily voluntary exercise enhances pilocarpine-induced saliva secretion and aquaporin 1 expression in rat submandibular glands.

Saliva-a water-based fluid containing electrolytes, immunoglobulins, and enzymes-has many functions, including the protection and hydration of mucosal structures within the oral cavity and the initiation of digestion. Aquaporins (AQPs) are proteins that act as water channels through membranes. We have previously reported upregulation of the expression levels of AQP 1 and 5 in the submandibular glands (SMGs) in heat-acclimated rats. In this study, we investigated pilocarpine-induced saliva secretion and AQP expression in rats after voluntary exercise. Male, 10-week-old Wistar rats were initially maintained at an ambient temperature of 24 °C for 10 days and were then kept for 40 days in cages either with a running wheel (exercise rats, n = 6) or with a locked wheel [control rats (CN), n = 6]. After the training period, the rats were anesthetized and pilocarpine, an M3 muscarinic receptor agonist, was intraperitoneally injected (0.5 mg·kg-1) to stimulate saliva secretion. Saliva was collected, and the SMGs were sampled and subjected to western blot, RT-PCR, and immunohistochemical analyses. Pilocarpine induced a greater amount of saliva in the exercised rats than in the CN. Expression levels of AQP1 mRNA and protein were significantly higher in SMGs of exercised rats than in those of the CN, but the expression of AQP5 was not affected by voluntary exercise. Voluntary exercise increased the expression of vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31), a marker for endothelial cells, in the SMGs. Voluntary exercise promoted pilocarpine-induced saliva secretion, probably via an increase in the expression level of AQP1 due to VEGF-induced CD31-positive angiogenesis in the SMG.

Effects of hypervolemia by protein and glucose supplementation during aerobic training on thermal and arterial pressure regulations in hypertensive older men.

In Japan, the incidence of heat illness in older people has rapidly increased during midsummer in the last decade, and we suggested that whey-protein+carbohydrate supplementation during aerobic training would increased plasma volume (PV) to enhance thermoregulatory adaptation in older men (J Appl Physiol 107: 725-733, 2009); however, >60% of people age 65 and older suffer from hypertension, and the symptoms may be worsened by hypervolemia. To examine this, we randomly divided 21 older men (∼69 yr) with ∼160 mmHg for systolic and ∼90 mmHg for diastolic blood pressure at rest into two groups: Glc (n = 11) consuming glucose alone (25 g) and Pro-Glc (n = 10) consuming whey protein (10 g) + glucose (15 g), immediately after cycling exercise at 60-75% of peak aerobic capacity (V̇o2 peak) for 60 min/day, 3 days/wk, for 8 wk. Before and after training, we measured PV (dye dilution), baroreflex sensitivity (BRS) of heart rate (Valsalva maneuver), and carotid arterial compliance (CAC) from carotid arterial diameter (ultrasound imaging) responses to pulsatile arterial pressure change (photoplethysmography) at rest. Additionally, we measured esophageal temperature (Tes) and forearm skin blood flow (plethysmography) during exercise at 60% pretraining V̇o2 peak for 20 min in a warm environment. We found that the forearm skin vascular conductance response to increased Tes was enhanced in Pro-Glc with increased PV, but this was not found in Glc; however, despite the increased PV, arterial blood pressures rather decreased with increased CAC and BRS in Pro-Glc. Thus, the prescription was applicable to older men with hypertension to prevent heat illness during exercise.

Impact of 5-aminolevulinic acid with iron supplementation on exercise efficiency and home-based walking training achievement in older women.

A reduction in exercise efficiency with aging limits daily living activities. We examined whether 5-aminolevulinic acid (ALA) with sodium ferrous citrate (SFC) increased exercise efficiency and voluntary achievement of interval walking training (IWT) in older women. Ten women [65 ± 3(SD) yr] who had performed IWT for >12 mo and were currently performing IWT participated in this study. The study was conducted in a placebo-controlled, double-blind crossover design. All subjects underwent two trials for 7 days each in which they performed IWT with ALA+SFC (100 and 115 mg/day, respectively) or placebo supplement intake (CNT), intermittently with a 2-wk washout period. Before and after each trial, subjects underwent a graded cycling test at 27.0 °C atmospheric temperature and 50% relative humidity, and oxygen consumption rate, carbon dioxide production rate, and lactate concentration in plasma were measured. Furthermore, for the first 6 days of each trial, exercise intensity for IWT was measured by accelerometry. We found that, in the ALA+SFC trial, oxygen consumption rate and carbon dioxide production rate during graded cycling decreased by 12% (P < 0.001) and 11% (P = 0.001) at every workload, respectively, accompanied by a 16% reduction in lactate concentration in plasma (P < 0.001), although all remained unchanged in the CNT trial (P > 0.2). All of the reductions were significantly greater in the ALA+SFC than the CNT trial (P < 0.05). Furthermore, the training days, impulse, and time at fast walking were 42% (P = 0.028), 102% (P = 0.027), and 69% (P = 0.039) higher during the ALA+SFC than the CNT intake period, respectively. Thus ALA+SFC supplementation augmented exercise efficiency and thereby improved IWT achievement in older women.

The factors affecting adherence to a long-term interval walking training program in middle-aged and older people.

No long-term exercise training regimen with high adherence and effectiveness in middle-aged and older people is broadly available in the field. We assessed the adherence to, and effects of, our long-term training program comprising an interval walking training (IWT) and an information technology network system and the factors affecting adherence. Middle-aged and older men and women [n = 696, aged 65 ± 7(SD) yr] underwent IWT. The subjects were instructed to repeat five or more sets of fast and slow walking for 3 min each at ≥70 and 40% peak aerobic capacity for walking (V̇O2peak), respectively, per day ≥4 days/wk for 22 mo. Adherence was assessed as training days accomplished relative to the target of 4 days/wk over 22 mo. The effects on the V̇O2peak and lifestyle-related disease score were evaluated every 6 mo. The independent factors affecting adherence were assessed by multiple-regression analysis after adjustment for baseline physical characteristics and other possible covariates, including vasopressin V1a receptor polymorphisms. The adherence over 22 mo averaged 70% and was highly correlated with a 13% reduction in the lifestyle-related disease score (R(2) = 0.94, P = 0.006) and with a 12% increase in V̇O2peak (R(2) = 0.94, P = 0.006). The major determinant of higher adherence was lower baseline body mass index (BMI) (P < 0.0001) and male sex (P < 0.0001). For men, in addition to BMI, nonsmokers (P = 0.031) and V1a receptor polymorphisms (P = 0.033) were independent determinants of higher adherence. Thus the long-term IWT program is an effective regimen. Moreover, baseline BMI and sex for all subjects, and smoking and V1a receptor polymorphisms for men, were associated with adherence.

Voluntary locomotion linked with cerebral activation is mediated by vasopressin V1a receptors in free-moving mice.

We previously reported that cerebral activation suppressed baroreflex control of heart rate (HR) at the onset of voluntary locomotion. In the present study, we examined whether vasopressin V1a receptors in the brain were involved in these responses by using free-moving V1a receptor knockout (KO, n = 8), wild-type mice locally infused with a V1a receptor antagonist into the nucleus tractus solitarii (BLK, n = 8) and control mice (CNT, n = 8). Baroreflex sensitivity (HR/MAP) was determined from HR response (HR) to a spontaneous change in mean arterial pressure (MAP) every 4 s during the total resting period, which was ∼8.7 h, of the 12 h measuring period in the three groups. HR/MAP was determined during the periods when the cross-correlation function (R(t)) between HR and MAP was significant (P < 0.05). Cerebral activity was determined from the power density ratio of to δ wave band (/δ) on the electroencephalogram every 4 s. Spontaneous changes in /δ were significantly correlated with R(t) during 62 ± 3% of the total resting period in CNT (P < 0.05), but only 38 ± 4% in KO and 47 ± 2% in BLK (vs. CNT, both P < 0.001). When R(t) and HR/MAP were divided into six bins according to the level of /δ, both were positively correlated with /δ in CNT (both P < 0.001), while neither was correlated in KO or BLK (all P > 0.05). Moreover, the probability that mice started to move after an increase in /δ was 24 ± 4% in KO and 24 ± 6% in BLK, markedly lower than 61 ± 5% in CNT (both P < 0.001), with no suppression of the baroreflex control of HR. Thus, central V1a receptors might play an important role in suppressing baroreflex control of HR during cerebral activation at the onset of voluntary locomotion.