BACKGROUND Heightened stress reactivity is associated with hippocampal atrophy, age-related cognitive deficits, and increased risk for Alzheimer's disease. This temperament predisposition may aggravate age-associated brain pathology or be reflective of it. This association may be mediated through repeated activation of the stress hormone axis over time. Dietary interventions, such as calorie restriction (CR), affect stress biology and may moderate the pathogenic relationship between stress reactivity and brain in limbic and prefrontal regions. METHODS Rhesus monkeys (Macaca mulatta) aged 19-31 years consumed either a standard diet (N=18) or were maintained on 30% CR relative to baseline intake (N=26) for 13-19 years. Behavior was rated in both normative and aversive contexts. Urinary cortisol was collected. Animals underwent magnetic resonance imaging and diffusion tensor imaging (DTI) to acquire volumetric and tissue microstructure data respectively. Voxel-wise statistics regressed a global stress reactivity factor, cortisol, and their interaction on brain indices across and between dietary groups. RESULTS CR significantly reduced stress reactivity during aversive contexts without affecting activity, orientation, or attention behavior. Stress reactivity was associated with less volume and tissue density in areas important for emotional regulation and the endocrine axis including prefrontal cortices, hippocampus, amygdala, and hypothalamus. CR reduced these relationships. A Cortisol by Stress Reactivity voxel-wise interaction indicated that only monkeys with high stress reactivity and high basal cortisol demonstrated lower brain volume and tissue density in prefrontal cortices, hippocampus, and amygdala. CONCLUSIONS High stress reactivity predicted lower volume and microstructural tissue density in regions involved in emotional processing and modulation. A CR diet reduced stress reactivity and regional associations with neural modalities. High levels of cortisol appear to mediate some of these relationships.

In the laboratory, food restriction has been shown to induce neuroadaptations in brain reward circuitry which are likely to be among those that facilitate survival during periods of food scarcity in the wild. However, the upregulation of mechanisms that promote foraging and reward-related learning may pose a hazard when food restriction is self-imposed in an ecology of abundant appetitive rewards. For example, episodes of loss of control during weight-loss dieting, use of drugs with addictive potential as diet aids, and alternating fasting with alcohol consumption in order to avoid weight gain, may induce synaptic plasticity that increases the risk of enduring maladaptive reward-directed behavior. In the present mini-review, representative basic research findings are outlined which indicate that food restriction alters the function of mesoaccumbens dopamine neurons, potentiates cellular and behavioral responses to D-1 and D-2 dopamine receptor stimulation, and increases stimulus-induced synaptic insertion of AMPA receptors in nucleus accumbens. Possible mechanistic underpinnings of increased drug reward magnitude, drug-seeking, and binge intake of sucrose in food-restricted animal subjects are discussed and possible implications for human weight-loss dieting are considered.

Background: The current study explored the underlying behavioral, endocrine, and immune markers of vulnerability to stress-induced depression, and the impact of rearing environments on adult functioning. Method: Adult Sprague-Dawley rats (n=195) were reared in either Maternal Separation (MS), Early Weaning and Isolation (EWI), or Non-Handled (NH) conditions. Anxiety behavior was assessed using the emergence test at mean postnatal day (PND) 60. Stress-induced depressive behavior was measured at mean PND 86 using an intermittent cold water swim stress and swim escape test (SET) paradigm. Immediately following the SET, and in a sample of naïve controls (N=31), trunk blood was collected to assay for serum corticosterone (CORT) and spleens were removed for determination of Concanavalin A (Con-A) stimulated T-cell proliferation. Results: Stress vulnerable rats (top tertile of SET swim time) were characterised by increased anxiety-like behavior, greater post-stress CORT concentrations, and a significantly higher Con-A induced T-cell proliferative response compared to stress resilient rats (bottom tertile of SET swim time). The EWI rearing condition was a contributing factor in predicting total swim escape time, however MS was not. MS offspring did have double the basal level of CORT than NH offspring, suggestive of a hyperfunctioning HPA axis. Conclusion: The swim stress animal model enabled observation of stress vulnerability and resilience; results point towards the existence of distinct behavioral, endocrine, and immunological profiles of the vulnerable and resilient animal, which may have important implications for mental health and stress research.

Calorie restriction (CR) has been demonstrated to alter cytokine levels; however, its potential to modify sickness behavior (fever, anorexia, cachexia) has not. The effect of CR on sickness behavior was examined in male C57BL/6J mice fed ad libitum or restricted 25%(CR25%) or restricted 50%(CR50%) in food intake for 28 days and injected with 50 μg/kg of LPS on day 29. Changes in body temperature, locomotor activity, body weight, and food intake were determined. A separate cohort of mice were fed ad libitum or CR50% for 28 days, and hypothalamic mRNA expression of inhibitory factor κB-α (IκB-α), cyclooxygenase-2 (COX-2), prostaglandin E(2)(PGE(2)), suppressor of cytokine signaling 3 (SOCS3), IL-10, neuropeptide Y (NPY), leptin, proopiomelanocortin (POMC), and corticotrophin-releasing hormone (CRH) were determined at 0, 2, and 4 h post-LPS. CR50% mice did not develop fevers, whereas the CR25% mice displayed a fever shorter in duration but with the same peak as the controls. Both CR25% and CR50% mice showed no sign of anorexia and reduced cachexia after LPS administration. Hypothalamic mRNA expression of NPY and CRH were both increased by severalfold in CR50% animals preinjection compared with controls. The CR50% mice did not demonstrate the expected rise in hypothalamic mRNA expression of COX-2, microsomal prostaglandin E synthase-1, POMC, or CRH 2 h post-LPS, and leptin expression was decreased at this time point. Increases in SOCS3, IL-10, and IκB-α expression in CR50% animals were enhanced compared with ad libitum-fed controls at 4 h post-LPS. CR results in a suppression of sickness behavior in a dose-dependent manner, which may be due to CR attenuating proinflammatory pathways and enhancing anti-inflammatory pathways.

Food restriction (FR) has a beneficial effect on aging process and exerts a significant effect on the responses of rodents to standard behavioral tasks. The aim of this study was to assess the cumulative influence of FR on the behavioral and biochemical parameters in Wistar rats. Six-month-old rats were subjected to restrictive feeding (50% of the daily food intake, every-other-day feeding regimen) for one month or for six months until ages of 7 and 12months, respectively. We examined the habituation of exploratory movement, amphetamine (AMPH)-induced motor activity, as well as changes in serum corticosterone (CORT) and glucose levels. The results obtained from FR animals were compared with ad libitum (AL)-fed age-matched control rats. Habituation of motor activity was only affected by six months of restrictive feeding. The sensitization of the motor response to AMPH that was observed in animals exposed to FR for one month was not observed in animals that were exposed to the same feeding regimen for six months. Serum CORT was increased and serum glucose was decreased in both FR groups. These results clearly show that despite the similarity of the biochemical changes that were induced by one and six months of FR, the nature of the changes in motor activities in these two groups of animals during habituation and after AMPH treatment was different. Our findings indicate that long-term FR has complex behavioral consequences that need to be carefully evaluated with respect to animal age, duration of FR and severity of the diet.

The anti-aging activities of persimmon oligomeric proanthocyanidins (POPs), reported to improve life span and behavioral characteristics associated with the aging process, were investigated using the senescence-accelerated mouse (SAM) P8, which is a good model for studies on aging-related behavioral changes as well as life span. We demonstrated that the administration of POPs extended the life span of SAMP8. In addition, POPs elevated Sirt1 expression, which is recognized as an essential factor for life span extension in the brain. On the other hand, the administration of POPs did not induce stereotypical behaviors such as rearing, jumping, and hanging from the lid of a cage, whereas food restriction increased these frequencies without a significant change in motor function. The present study suggests a promising role of POPs as anti-aging agents to extend life span, although further studies elucidating their anti-aging mechanisms acting are needed.

Developmental programming of neuroendocrine systems is profoundly influenced by environmental cues such as caloric availability. The focus of investigations in this area has been on the effects of under- and malnutrition while there is a paucity of research examining the effects of more mild levels of calorie restriction (CR). Rat dams and their offspring were subjected to one of five dietary regimens: control, CR50% for 3 days preconception, CR25% during gestation, CR25% during lactation, and CR25% during gestation, lactation, and post-weaning (lifelong). Adult male offspring were decapitated and trunk blood collected to assay for basal concentrations of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT), as well as plasma concentrations of adrenalin (A) and noradrenalin (NA). Basal serum ACTH was reduced by 35-43% in all dietary regimens except the lifelong group. Although a similar trend was observed in the concentrations of serum CORT, only the decrease in the lactation group attained statistical significance. A was reduced by 33-49% as a result of all dietary regimens and NA was reduced in the gestation and lifelong groups by 51% and 39%, respectively. The potential mechanisms underlying these neuroendocrine alterations are discussed.

Caloric restriction (CR) is an effective method for prevention of age-associated diseases as well as overweight and obesity; however, there is controversy regarding the effects of dieting regimens on behavior. In this study, we investigated two different dieting regimens: repeated fasting and refeeding (RFR) and daily feeding of half the amount of food consumed by RFR mice (CR). CR and RFR mice had an approximate 20% reduction in food intake compared with control mice. Open field, light-dark transition, elevated plus maze, and forced swimming tests indicated that CR, but not RFR, reduced anxiety- and depressive-like behaviors, with a reduction peak on day 8. Using a mouse whole genome microarray, we analyzed gene expression in the prefrontal cortex, amygdala, and hypothalamus. In addition to the CR-responsive genes commonly modified by RFR and CR, each regimen differentially changed the expression of distinct genes in each region. The most profound change was observed in the amygdalas of CR mice: 884 genes were specifically upregulated. Ingenuity pathway analysis revealed that these 884 genes significantly modified nine canonical pathways in the amygdala. alpha-Adrenergic and dopamine receptor signalings were the two top-scoring pathways. Quantitative RT-PCR confirmed the upregulation of six genes in these pathways. Western blotting confirmed that CR specifically increased dopamine- and cAMP-regulated phosphoprotein (Darpp-32), a key regulator of dopamine receptor signaling, in the amygdala. Our results suggest that CR may change behavior through altered gene expression.

The purpose of this study was to determine the effects of food restriction (FR) and paradoxical sleep deprivation (PSD), either alone or in combination, on sexual behaviours (mount, intromission and ejaculation) in adult male rats. Diet restriction began at weaning with 6g/day of food, and the amount of food was increased by 1g/week until it reached 15g/day amount (in adulthood). During adulthood, rats under FR and those fed ad libitum were either subjected to PSD for 96h or maintained in home-cage groups. The results indicated that both FR and ad libitum sleep-deprived groups showed a significant decrease in performance and motivation to initiate sexual behaviour, reflected by the increase in mount and intromission latencies and decreased copulatory rate. FR associated with PSD reversed the adverse effects of sleep deprivation on the number of ejaculations and inter-copulatory interval. Testosterone concentrations decreased after sleep deprivation, regardless of food availability; while progesterone was significantly higher in the FR-PSD group only. In light of the limited understanding of the link between secretion patterns and neural-hormonal control of food availability related to sexual behaviour, our data indicate that sleep loss affects sexual responses, and FR was able to restore some of the sexual parameters investigated.

Olfactory stimuli and calorie restriction (CR) have both been found to reduce anxiety-like behaviour and alter anxiety-related neurochemical mechanisms in rats. The aim of this study was to determine if exposure to olfactory cues from 25% CR male rats leads to anxiolytic-like behaviour in male rats fed ad libitum. Animals were divided into four groups: control (fed ad libitum and given new bedding every 5 days), control olfactory group (fed ad libitum and given the bedding from the control group every 5 days), CR (fed a 25% CR regime and given new bedding every 5 days), and CR olfaction (fed ad libitum and given the bedding from the CR group every 5 days). All animals were assessed on two measures of anxiety-like behaviour: the open field and the elevated plus maze. The CR group demonstrated anxiolytic-like behavioural responses in the open field test, characterised by more time spent in the aversive central zone and a higher frequency of central and middle zone entries compared to all other groups. Intriguingly, the CR olfaction group demonstrated anxiolytic-like behaviour in the elevated plus maze test, characterised by more time spent on the open arms, and a higher ratio of open compared to total arm entries relative to the control and control olfaction groups. After the completion of behavioural testing, serum corticosterone assays were conducted on trunk blood. However, only the CR group demonstrated an increase in corticosterone. Olfactory cues from conspecifics on a CR regime significantly reduced anxiety-like behaviour in rats fed ad libitum, similar to the reduction in anxiety-like behaviour following CR. This may have implications for the development of more efficacious novel treatments for anxiety disorders.

Developmental programming of neuroendocrine systems is profoundly influenced by environmental cues such as caloric availability. The focus of investigations in this area has been on the effects of under- and malnutrition while there is a paucity of research examining the effects of more mild levels of calorie restriction (CR). Rat dams and their offspring were subjected to one of five dietary regimens: control, CR50% for 3 days preconception, CR25% during gestation, CR25% during lactation, and CR25% during gestation, lactation, and post-weaning (lifelong). Adult male offspring were decapitated and trunk blood collected to assay for basal concentrations of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT), as well as plasma concentrations of adrenalin (A) and noradrenalin (NA). Basal serum ACTH was reduced by 35-43% in all dietary regimens except the lifelong group. Although a similar trend was observed in the concentrations of serum CORT, only the decrease in the lactation group attained statistical significance. A was reduced by 33-49% as a result of all dietary regimens and NA was reduced in the gestation and lifelong groups by 51% and 39%, respectively. The potential mechanisms underlying these neuroendocrine alterations are discussed.

Calorie restriction (CR) during sensitive perinatal periods has consistently been demonstrated to alter the development of a variety of physiological systems, which consequently affect behavior. This study compared the social behavior and sexual behavior of the adult male offspring of mothers administered a 25% CR at one of four times in the perinatal period: a brief period preconception, during gestation, during lactation, or a lifelong restriction (beginning at conception and continuing throughout life). Levels of serum testosterone were also determined in these animals. Social interaction increased in the gestation and lifelong CR groups. The lifelong group also exhibited more dominant type behaviors. CR during preconception and lactation resulted in offspring that displayed an enhanced and more efficient copulatory pattern compared to all other conditions. This was demonstrated by a reduced frequency of intromissions, shorter latency to ejaculation, and a greater frequency of ejaculations by the preconception and lactation group compared to some, if not all of the other CR groups and controls. Serum testosterone was significantly higher in the preconception group compared to controls. These findings indicate that CR during specific periods of development can differentially alter the social behavioral phenotype and hormone levels in adulthood.

Environmental stimuli such as caloric availability during the perinatal period exert a profound influence on the development of an organism. Studies in this domain have focused on the effects of under- and malnutrition while the effects of more mild levels of restriction have not been delineated. Rat dams and their offspring were subjected to one of five dietary regimens: control, CR50% for 3 days preconception, CR25% during gestation, CR25% during lactation, and CR25% during gestation, lactation, and post-weaning (lifelong). The pup retrieval test and maternal observations were conducted during lactation to quantify maternal care. In the pup retrieval test, dams that were concurrently experiencing CR (i.e., from the lactation and lifelong groups) displayed shorter latencies to retrieve all pups than the control and preconception groups and the lactation group constructed better nests than all groups. Adult offspring were tested in three tests of anxiety: the elevated plus maze, open field, and emergence test. No differences were observed in the elevated plus maze; however, in the open field preconception animals made fewer entries and spent more time in the central zone than controls. In addition, preconception offspring exhibited longer latencies to full body emergence, spent less time fully emerged, and spent more time engaged in risk assessment behaviours than all other groups. Offspring from the preconception group were also on average 11% heavier than control rats throughout life and displayed 37% higher serum leptin concentrations than controls. A potential role for leptin in the anxiogenic effect of preconception CR is discussed.

Despite an abundance of research on calorie restriction (CR) altering gonadal and appetite regulating hormones, the sexual behavioural consequences of CR remain to be examined systematically. This study compared the sexual behaviour, partner preference, serum testosterone and leptin levels of male adult Hooded Wistar rats administered a CR (continuous 25%, 50% CR or a temporary restriction) with ad libitum fed controls. The temporary restriction (Previous CR) failed to alter sexual behaviour, partner preference and levels of testosterone and leptin. The moderately 25% CR males did not demonstrate an impairment in sexual behaviour but did demonstrate a reduced level of attractiveness to females in one measure of partner preference. Sexual performance was affected by a substantial CR, as the CR 50% group exhibited a longer latency to the first intromission, indicating alteration in sexual arousal. Females also consistently demonstrated a clear preference for the control group compared to the CR 50% group. These findings indicate a possible reduction in the overall reproductive potential of the substantially CR animals. Testosterone levels were equally suppressed by both the 25% and 50% CR, while leptin levels were only reduced in the CR 50% group. Leptin, rather than testosterone, may have influenced the impairment in sexual behaviour only demonstrated by the substantially CR animals. Testosterone, may, however, play a role in modulating the preference of control over CR males, as attractiveness was totally reduced by a substantial CR, and partially reduced by a moderate restricted regimen.

The influence of calorie restriction (CR) on increasing life span, enhancing immunocompetence, and reducing the incidence of age-related diseases is well established. Evidence points to the involvement of neuroendocrine alterations in these beneficial effects. Accordingly, we hypothesized that CR will result in significant alterations to the hormones investigated. Little attention has been directed toward ascertaining the doses of CR required to obtain such alterations and, indeed, whether a dose-response exists. Adult rats were subjected to 1 of 5 dietary regimens: control, CR12.5%, CR25%, CR37.5%, or CR50%. Rats were decapitated 3 weeks following the onset of restriction; and trunk blood was collected and assayed for concentrations of serum adrenocorticotropic hormone, corticosterone, and testosterone, as well as plasma concentrations of noradrenalin and adrenalin. No effect was found as a result of dietary manipulation for serum concentrations of adrenocorticotropic hormone. However, all doses of CR resulted in increased serum corticosterone in a dose-response trend. A dose-response was also observed for serum testosterone, with higher doses of CR associated with lower testosterone. Concentrations of noradrenalin were not found to be altered by any CR dose, although a trend toward a down-regulation at CR50% was observed. Plasma adrenalin displayed a biphasic distribution with reductions observed at CR25% and CR50%, although the down-regulations only attained statistical significance relative to the CR37.5% and not the control group. As well as reporting the effect of CR on multiple hormones within individual animals, these results go some way in determining the optimal levels of CR needed to induce neuroendocrinologic alterations.

Olfactory stimuli and calorie restriction (CR) have both been found to reduce anxiety-like behaviour and alter anxiety-related neurochemical mechanisms in rats. The aim of this study was to determine if exposure to olfactory cues from 25% CR male rats leads to anxiolytic-like behaviour in male rats fed ad libitum. Animals were divided into four groups: control (fed ad libitum and given new bedding every 5 days), control olfactory group (fed ad libitum and given the bedding from the control group every 5 days), CR (fed a 25% CR regime and given new bedding every 5 days), and CR olfaction (fed ad libitum and given the bedding from the CR group every 5 days). All animals were assessed on two measures of anxiety-like behaviour: the open field and the elevated plus maze. The CR group demonstrated anxiolytic-like behavioural responses in the open field test, characterised by more time spent in the aversive central zone and a higher frequency of central and middle zone entries compared to all other groups. Intriguingly, the CR olfaction group demonstrated anxiolytic-like behaviour in the elevated plus maze test, characterised by more time spent on the open arms, and a higher ratio of open compared to total arm entries relative to the control and control olfaction groups. After the completion of behavioural testing, serum corticosterone assays were conducted on trunk blood. However, only the CR group demonstrated an increase in corticosterone. Olfactory cues from conspecifics on a CR regime significantly reduced anxiety-like behaviour in rats fed ad libitum, similar to the reduction in anxiety-like behaviour following CR. This may have implications for the development of more efficacious novel treatments for anxiety disorders.

The behavioral outcomes of a calorie restricted diet are often neglected in favour of a more physiological examination of the consequences of calorie restriction (CR). This is especially the case with social behavior. A few findings within the maternal CR literature suggest that adult male social behavior is altered by this regimen. Despite the paucity of findings within the maternal CR literature, a systematic investigation of the behavioral phenotype of males administered an adult-onset CR is completely lacking and was the focus of the current study. Adult male hooded Wistar rats were administered a three week CR, with one group receiving a 25% CR and another group receiving a 50% CR before male-to-male social behavior was examined and compared with ad libitium fed males. Various behavioral elements were modulated by CR, both the CR25% and 50% group initiated contact sooner and engaged in greater social activity compared to the ad libitum fed controls. The CR25% group also demonstrated less non-social (self-grooming) behavior and a greater frequency of walkovers compared to all groups, indicating a propensity towards dominance. The CR50% group demonstrated greater environmental assessment/exploration, as measured by the frequency of rearing. As with the maternal CR literature, an adult-onset chronic CR induces a more socially active behavioral phenotype and reduces interest in non-social behavior in the moderately CR group. Taken together, the social behavioral phenotype can be modulated by a CR initiated and maintained during adulthood.

Animal models of stress-induced depression have identified a bimodal reactivity to stress, namely 'resilience' and 'vulnerability.' Possible corresponding differences in endocrine and immunological responses between these groups have not been delineated. Male Sprague-Dawley rats were divided into three groups: stress (n=25), confined controls (n=7), and home cage controls (n=7). Stress rats were exposed to 80, 5-s inescapable cold water swim trials (15 degrees C). Twenty-four hours later, the stress rats were tested on an instrumental swim escape test (SET) but now they had access to an omnidirectional lever that terminated the stress. Immediately after the SET, trunk blood was collected to assay for serum corticosterone (CORT), and spleens were removed and natural killer cell activity (NKCA) and concanavalin A (CON-A) induced lymphocyte proliferation determined. Subjects in the stress treatment group were divided into distinct 'resilient' and 'vulnerable' categories by a median split for average escape latencies across the last 25 trials of the SET. Stress rats secreted more CORT than controls and vulnerable rats secreted greater levels than resilient rats. NKCA was greatest in control rats, and was decreased in the stress rats although the resilient and the vulnerable groups did not differ. Conversely, CON-A-induced lymphocyte proliferation was greatest in stress rats, vulnerable rats exhibiting more proliferation than resilient rats, but both were greater than both control groups. Stress animals were hypothermic throughout the swim stress procedures but exhibited a stress-induced fever following the initial swim trials. The observed differences may have important predictive and theoretical utility for vulnerable and resilient profiles.

Calorie restriction (CR) is well established in the research literature to have several beneficial effects on health and has also been found to induce anxiolytic effects in the rat. Heightened levels of stress and anxiety are often regarded as key precipitating factors of relapse to substance abuse and alcohol addiction. In this study, the potential implication of a 25% CR diet in altering drug-seeking and relapse like behaviour through its capacity to influence anxiolytic-like behavioural changes was investigated.Anxiety was assessed in all rats with the elevated plus maze (EPM) and open field test prior to being trained to operantly self-administer either 10% ethanol, or water. Differences were found between the groups in the percentage of open arm/total arm duration and open arm/total arm entries in the EPM,demonstrating the anxiolytic effects of CR25%. Both control and CR25% groups showed preference for alcohol vs. water, however, controls responded more for alcohol during the conditioning phase than the CR25% group. Controls exhibited an alcohol deprivation-effect (ADE) post abstinence, and a cue-induced reinstatement of alcohol-seeking post extinction however the CR25% did not. These results demonstrate that the anxiolytic effects of CR25% reduces operant responding for ethanol and inhibits relapse behaviour.Taken collectively, the results of this study suggest that in line with past research a CR25% dietary regime can induce anxiolytic effects in the alcohol preferring (iP) rat. Furthermore, it also reduces the intake of ethanol and inhibits the ADE and cue-induced relapse that is characteristic of addiction in this strain.

Calorie restriction (CR) has been demonstrated to alter cytokine levels; however, its potential to modify sickness behavior (fever, anorexia, cachexia) has not. The effect of CR on sickness behavior was examined in male C57BL/6J mice fed ad libitum or restricted 25%(CR25%) or restricted 50%(CR50%) in food intake for 28 days and injected with 50 μg/kg of LPS on day 29. Changes in body temperature, locomotor activity, body weight, and food intake were determined. A separate cohort of mice were fed ad libitum or CR50% for 28 days, and hypothalamic mRNA expression of inhibitory factor κB-α (IκB-α), cyclooxygenase-2 (COX-2), prostaglandin E(2)(PGE(2)), suppressor of cytokine signaling 3 (SOCS3), IL-10, neuropeptide Y (NPY), leptin, proopiomelanocortin (POMC), and corticotrophin-releasing hormone (CRH) were determined at 0, 2, and 4 h post-LPS. CR50% mice did not develop fevers, whereas the CR25% mice displayed a fever shorter in duration but with the same peak as the controls. Both CR25% and CR50% mice showed no sign of anorexia and reduced cachexia after LPS administration. Hypothalamic mRNA expression of NPY and CRH were both increased by severalfold in CR50% animals preinjection compared with controls. The CR50% mice did not demonstrate the expected rise in hypothalamic mRNA expression of COX-2, microsomal prostaglandin E synthase-1, POMC, or CRH 2 h post-LPS, and leptin expression was decreased at this time point. Increases in SOCS3, IL-10, and IκB-α expression in CR50% animals were enhanced compared with ad libitum-fed controls at 4 h post-LPS. CR results in a suppression of sickness behavior in a dose-dependent manner, which may be due to CR attenuating proinflammatory pathways and enhancing anti-inflammatory pathways.

Our prime objective was to establish an optimal model animal for studying avoidance learning and memory in rodents. The two-way rat inbred strains of Hatano high-(HAA) and low-avoidance (LAA) animals were originally selected and bred in accordance with their high or low performance respectively in the shuttle-box active avoidance task. Previous studies demonstrated that they have clear strain differences in endocrine stress response, which is related to acquisition of aversive learning and emotional reactivity. To evaluate the effect of selection by the shuttle-box task on avoidance performance and emotional reactivity, male Hatano rats underwent passive avoidance, open field and elevated plus maze tests. The present results show that the avoidance performance in the passive task was significantly greater in HAA rats than in LAA rats. Furthermore, HAA rats showed high anxiety-like behaviors compared with LAA rats in open field and elevated plus maze tests. Taken together, this study demonstrated that 1) selection and breeding of Hatano HAA and LAA strain rats by shuttle-box task had been properly carried out with the criterion of high and low avoidance performance respectively and that 2) HAA rats were predisposed to high anxiety compared with LAA rats. These results indicated that Hatano HAA and LAA rats can be useful models for studying avoidance learning and memory.

In the current study the modulatory role of mobile phone radio-frequency electromagnetic radiation (RF-EMR) on emotionality and locomotion was evaluated in adolescent rats. Male albino Wistar rats (6-8 weeks old) were randomly assigned into the following groups having 12 animals in each group. Group I (Control): they remained in the home cage throughout the experimental period. Group II (Sham exposed): they were exposed to mobile phone in switch-off mode for 28 days, and Group III (RF-EMR exposed): they were exposed to RF-EMR (900 MHz) from an active GSM (Global system for mobile communications) mobile phone with a peak power density of 146.60 μW/cm(2) for 28 days. On 29th day, the animals were tested for emotionality and locomotion. Elevated plus maze (EPM) test revealed that, percentage of entries into the open arm, percentage of time spent on the open arm and distance travelled on the open arm were significantly reduced in the RF-EMR exposed rats. Rearing frequency and grooming frequency were also decreased in the RF-EMR exposed rats. Defecation boli count during the EPM test was more with the RF-EMR group. No statistically significant difference was found in total distance travelled, total arm entries, percentage of closed arm entries and parallelism index in the RF-EMR exposed rats compared to controls. Results indicate that mobile phone radiation could affect the emotionality of rats without affecting the general locomotion.

The purpose of this study was to determine whether compound zhi zhu xiang (CZZX) exerts anxiolytic-like effects in rats. The animals were orally administered CZZX (0.75, 1.5, and 3 g/kg daily) for 10 days and tested in the elevated plus maze (EPM), Vogel conflict test (VCT), and open field. Repeated treatment with CZZX (3 g/kg/day, p.o.) significantly increased the percentage of both entries into and time spent on the open arms of the EPM compared with saline controls. In the VCT, repeated treatment with CZZX (1.5 and 3 g/kg/day, p.o.) significantly increased the number of punished licks. The drug did not change the total entries into the open arms of the EPM or interfere with water consumption or nociceptive threshold, discarding potential confounding factors in the two tests. In the open field, locomotion was not reduced, discarding the possible sedative effect of CZZX. In the binding assay, the binding of [(3)H] Ro 15-1788 (flumazenil) to the benzodiazepine binding site in washed crude synaptosomal membranes from rat cerebral cortex was affected by CZZX. These data indicate an anxiolytic-like profile of action for CZZX without sedative side effects, and this activity may be mediated by benzodiazepine binding site modulation at γ-aminobutyric acid-A receptors.

The neuropeptide Y (NPY) has been suggested to act as a major regulator of emotional processes and body weight. The full spectrum of biological effects of this peptide is mediated by at least four classes of receptors known as the Y(1), Y(2), Y(4), and Y(5) subtypes. However, the respective contribution of each of these receptor subtypes, especially the Y(5) subtype, in emotional processes is still mostly unknown. In the present study, we investigated the effect of long term administration of a selective Y(5) agonist [cPP(1-7), NPY(19-23), Ala(31), Aib(32), Gln(34)]hPP on emotional processes and body weight using two rat models of emotional dysfunctions, the corticosterone (CORT)-induced anxiety model as well as the olfactory bulbectomized (OBX) model of depression and anxiety in Wistar and Sprague-Dawley rats, respectively. The sub-chronic administration of the Y(5) agonist reversed the high levels of locomotion, rearing and grooming in the open field test and the impaired social activity induced by OBX, while increased the percentage of entries and time in the open arm of the elevated plus maze in CORT-treated rats. Furthermore, this Y(5) agonist increased body weight in both strains of control rats. These data further demonstrate that Y(5) receptors are not only involved in the control of body weight but also mediate emotional processing under challenged conditions. Thus, the pharmacotherapeutic administration of a Y(5) agonist could be considered as a potentially novel strategy to alleviate some forms of anxiety and depression in humans.

It has been recognized that the stress-related peptides are involved in anxiety states. Angiotensin II receptor blockade by systemic administration of the AT(1) receptor antagonists has been proposed as a new treatment possibility for anxiety disorders. For better understanding of the related mechanisms, in this study we evaluated effects of bilateral intraamygdaloid injections of 2 (LOS 2) and 4 (LOS 4) μg of losartan (LOS), a selective AT(1) receptor antagonist, on the behavior of the not stressed and acutely stressed rats in an elevated "plus" maze. Under non-stress conditions, LOS 4 increased time spent in the open arms (p < 0.01), number of extreme open arm arrivals (p < 0.05), time per entry (p < 0.01), and the number of total arm entries (p < 0.05) showing thus considerable anxiolytic activity. The open arm extreme arrivals were increased by LOS 4 in both not stressed (p < 0.05) and stressed (p < 0.05) rats. When no stressed and stressed LOS 4 animals were compared, time per entry and the number of closed arm entries (p < 0.05, both) were decreased in the latter group. Moreover, the LOS 4 stressed rats had significantly increased open/closed arm quotient (p < 0.05) as compared to the both control and LOS 4 non-stress group (p < 0.05, both). These findings suggest that the AT(1) receptor blockade in amygdala is important for the anxiolytic action of LOS (and probably other AT(1) receptor blockers) under both non-stress and stress conditions.

AIMS Our study focuses on the design and synthesis of a new piperazinic derivate, 4-(1-phenyl-1h-Pyrazol-4-Ylmethyl)-Piperazine-1-Carboxylic Acid Ethyl ester (LQFM008), and evaluation of its anxiolytic-like profile in Swiss mice. MAIN METHODS LQFM008 was evaluated in a screening test of the central nervous system including the rota-rod, sodium pentobarbital-induced sleep, open field, elevated plus maze and light-dark box tests. KEY FINDINGS LQFM008 induced convulsions at the dose of 1.1 mmol/kg (i.p., s.c. or p.o.). LQFM008 up to 400 μmol/kg had no effect in the rota rod test. In the open field test, LQFM008 increased the number of crossings and the time spent at the central area as well as the sleeping time in sodium pentobarbital-induced sleep. In the elevated plus maze and light-dark box tests, this compound showed an anxiolytic-like activity. This anxiolytic-like activity was antagonized by NAN-190 (5-HT(1A) antagonist) but not by flumazenil (benzodiazepine antagonist). SIGNIFICANCE The compound LQFM008 showed anxiolytic-like activity which may involve serotonergic pathway.

N-methyl-d-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. In our study, we evaluated the effects of neonatal NMDA receptor blockade on exploratory locomotion and anxiety-like behaviors of adult BALB/c and C57BL/6 mice. In this study, NMDA receptor hypofunction was induced 7-10 days after birth using MK-801 in BALB/c and C57BL/6 mice (0.25mg/kg twice a day for 4 days via intraperitoneal injection). The open-field (OF) and elevated plus maze (EPM) tests were used to evaluate exploratory locomotion and anxiety-like behaviors. In the OF, BALB/c mice spent less time in the center of the field (p<0.05) and had less vertical locomotor activity (p<0.01) compared to C57BL/6 mice. In BALB/c mice, MK-801 caused a decrease in vertical and horizontal locomotor activity in the OF test, compared to the control group (p<0.05). In C57BL/6 mice, MK-801 treatment increased horizontal locomotor activity and decreased time spent in the center in the OF test (p<0.05). In the EPM, the number of open-arm entries, the percentage of open-arm time (p<0.01) and total arm entries (p<0.05) were lower in BALB/c mice compared to C57BL/6 mice. In BALB/c mice, MK-801 caused an increase in the percentage of open-arm time compared to the control group (p<0.05). In C57BL/6 mice, MK-801 caused a decrease in the percentage of open-arm time compared to the control group (p<0.05). MK-801 decreased exploratory and anxiety-like behaviors in BALB/c mice. In contrast, MK-801 increased exploratory and anxiety-like behaviors in C57BL/6 mice. In conclusion, hereditary factors may play an important role in neonatal NMDA receptor blockade-induced responses.

Calorie restriction (CR) is well established in the research literature to have several beneficial effects on health and has also been found to induce anxiolytic effects in the rat. Heightened levels of stress and anxiety are often regarded as key precipitating factors of relapse to substance abuse and alcohol addiction. In this study, the potential implication of a 25% CR diet in altering drug-seeking and relapse like behaviour through its capacity to influence anxiolytic-like behavioural changes was investigated.Anxiety was assessed in all rats with the elevated plus maze (EPM) and open field test prior to being trained to operantly self-administer either 10% ethanol, or water. Differences were found between the groups in the percentage of open arm/total arm duration and open arm/total arm entries in the EPM,demonstrating the anxiolytic effects of CR25%. Both control and CR25% groups showed preference for alcohol vs. water, however, controls responded more for alcohol during the conditioning phase than the CR25% group. Controls exhibited an alcohol deprivation-effect (ADE) post abstinence, and a cue-induced reinstatement of alcohol-seeking post extinction however the CR25% did not. These results demonstrate that the anxiolytic effects of CR25% reduces operant responding for ethanol and inhibits relapse behaviour.Taken collectively, the results of this study suggest that in line with past research a CR25% dietary regime can induce anxiolytic effects in the alcohol preferring (iP) rat. Furthermore, it also reduces the intake of ethanol and inhibits the ADE and cue-induced relapse that is characteristic of addiction in this strain.

Regulator of calmodulin (CaM) signaling (RCS), when phosphorylated by protein kinase A (PKA) on Ser55, binds to CaM and inhibits CaM-dependent signaling. RCS expression is high in the dorsal striatum, nucleus accumbens and amygdala, suggesting that the protein is involved in limbic-striatal function. To test this hypothesis, we examined RCS knockout (KO) mice in behavioral models dependent on these brain areas. Mice were tested for food-reinforced instrumental conditioning and responding under a progressive ratio (PR) schedule of reinforcement and in models of anxiety (elevated plus maze and open field). While RCS KO mice showed normal acquisition of a food-motivated instrumental response, they exhibited a lower breakpoint value when tested on responding under a PR schedule of reinforcement. RCS KO mice also displayed decreased exploration in both the open arms of an elevated plus maze and in the center region of an open field, suggesting an enhanced anxiety response. Biochemical studies revealed a reduction in the levels of dopamine and cAMP-regulated phosphoprotein (DARPP-32) in the striatum of RCS KO mice. DARPP-32 is important in reward-mediated behavior, suggestive of a possible role for DARPP-32 in mediating some of the effects of RCS. Together these results implicate a novel PKA-regulated phosphoprotein, RCS, in the etiology of motivational deficits and anxiety.

For many patients, chronic pain is often accompanied, and sometimes amplified, by co-morbidities such as anxiety and depression. Although it represents important challenges, the establishment of appropriate preclinical behavioral models contributes to drug development for treating chronic inflammatory pain and associated psychopathologies. In this study, we investigated whether rats experiencing persistent inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) developed anxiety-like behaviors, and whether clinically used analgesic and anxiolytic drugs were able to reverse CFA-induced anxiety-related phenotypes. These behaviors were evaluated over 28 days in both CFA- and saline-treated groups with a variety of behavioral tests. CFA-induced mechanical allodynia resulted in increased anxiety-like behaviors as evidenced by:(1) a significant decrease in percentage of time spent and number of entries in open arms of the elevated-plus maze (EPM),(2) a decrease in number of central squares visited in the open field (OF), and (3) a reduction in active social interactions in the social interaction test (SI). The number of entries in closed arms in the EPM and the distance traveled in the OF used as indicators of locomotor performance did not differ between treatments. Our results also reveal that in CFA-treated rats, acute administration of morphine (3mg/kg, s.c.) abolished tactile allodynia and anxiety-like behaviors, whereas acute administration of diazepam (1mg/kg, s.c) solely reversed anxiety-like behaviors. Therefore, pharmacological treatment of anxiety-like behaviors induced by chronic inflammatory pain can be objectively evaluated using multiple behavioral tests. Such a model could help identify/validate alternative potential targets that influence pain and cognitive dimensions of anxiety.