Prenatal nicotine exposure in mice induces sex-dependent anxiety-like behavior, cognitive deficits, hyperactivity, and changes in the expression of glutamate receptor associated-genes in the prefrontal cortex.

In rodents, prenatal nicotine exposure (PNE) has been associated with increased risk for development of cognitive and emotional disturbances, but the findings are somewhat conflicting. Lack of behavioral alterations following PNE could be due to the variety of methods available for nicotine delivery, exposure time and species used, with inbred strains being mostly employed. Such differences suggest the need to investigate the behavioral phenotype in each PNE model available if we are to find models with enhanced translational value. In this study, we assessed sex-dependent effects of PNE on ADHD-related behaviors and on the levels of mRNA coding for glutamate receptor subunits within the prefrontal cortex in the outbred NMRI mice exposed to nicotine via maternal drinking water during gestation. Cotinine levels were assessed in newborn pups. Behaviors related to anxiety, compulsivity, working memory, and locomotion were evaluated in both sexes of young adult offspring using the elevated zero maze, marble burying, spontaneous alternation behavior, and locomotor activity tests. Expression of mRNA coding for different glutamate receptors subunits within the prefrontal cortex (PFC) was measured using RT-qPCR. Cotinine levels in the serum of newborns confirmed fetal nicotine exposure. Both male and female offspring showed ADHD-like behaviors, such as deficit in the SAB test and hyperactivity. In addition, PNE male mice displayed anxiety- and compulsive-like behaviors, effects that were absent in female offspring. Finally, PNE reduced the mRNA expression of GluN1-, GluN2B-, and mGluR2-related genes within the PFC of male offspring, whereas it reduced the expression of mRNA coding for GluA2 subunit in female mice. PNE in NMRI mice induced sex-dependent behavioral changes, which parallels clinical findings following maternal cigarette smoke exposure. Alterations detected in PFC mRNA glutamate receptor proteins could contribute to the abnormal behavioral responses observed, but other signaling pathways or brain regions are likely involved in the behavioral susceptibility of PNE individuals.

Pharmacodynamics and metabonomics study of Tianma Gouteng Decoction for treatment of spontaneously hypertensive rats with liver-yang hyperactivity syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Essential hypertension is a prevalence chronic cardiovascular disease, which is treated by traditional Chinese medicine (TCM) in China. Metabolomics approach has achieved more attention in pharmacology studies of natural products. Tianma Gouteng Decoction (TGD) is effective for the therapeutic of hypertension in China. We aimed to investigate antihypertension effect of TGD on spontaneous hypertension rat (SHR) with live-Yang hyperactivity hypertension (Gan Yang Shang Kang, GYSK) and explore the mechanism by metabolomics method. MATERIALS AND METHODS: After establishing the GYSK-SHR model by giving aconite decoction, rats were randomly divided into four groups including model group, TGD qd group (66.88 mg/kg, once a day), TGD bid group (33.44 mg/kg, twice a day), TGD tid group (22.29 mg/kg, three times a day). Blood pressure (BP) and indexes of renin-angiotensin-aldosterone system (RAAS system) were measured. Metabolic profiling of rat plasma samples was performed by UPLC-Q-TOF/MS, which was analyzed with principal component analysis (PCA) and partial least-squares-discriminate analysis (PLS-DA) to explore the relationship between metabolic pathways and hypertension. RESULTS: To better explain the role of TGD on hypertension, we detected three different frequencies of TGD treatment with equal dosage. TGD reduced the BP in GYSH-SHR model and regulated the serum levels of NE, Ang II, ET, 5-HT, CRP, RENIN and ALD especially at TGD bid group. By UPLC-Q-TOF/MS analysis, we found 47 potential biomarkers in GYSK-SHR rats from the plasma metabolites, among which 15 biomarkers were regulated by TGD. Consisted with the antihypertension activity, TGD bid group showed the significantly moderating effect on the regulating biomarkers. CONCLUSIONS: TGD exhibited the antihypertensive activity at the frequency of administration twice a day, which had the association with RAAS system and mediated 15 biomarkers by regulating metabolisms of glycerol phospholipid, sphingomyelin, energy and amino acid.

Cannabinoid CB1 /CB2 receptor agonists attenuate hyperactivity and body weight loss in a rat model of activity-based anorexia.

BACKGROUND AND PURPOSE: Anorexia nervosa (AN) is a serious psychiatric condition characterized by excessive body weight loss and disturbed perceptions of body shape and size, often associated with excessive physical activity. There is currently no effective drug-related therapy of this disease and this leads to high relapse rate. Clinical data suggest that a promising therapy to treat and reduce reoccurrence of AN may be based on the use of drugs that target the endocannabinoid (EC) system, which appears dysregulated in AN patients. EXPERIMENTAL APPROACH: The activity-based anorexia (ABA) rodent model mimics the severe body weight loss and increased physical activity, as well as the neuroendocrine disturbances (i.e. hypoleptinaemia and hypercortisolaemia) in AN. This study investigated whether cannabinoid agonists can effectively modify anorexic-like behaviours and neuroendocrine changes in rats subjected to a repeated ABA regime that mimics the human condition in which patients repeatedly undergo a recovery and illness cycle. KEY RESULTS: Our data show that subchronic treatment with both the natural CB1 /CB2 receptor agonist Δ9 -tetrahydrocannabinol and the synthetic CB1 /CB2 receptor agonist CP-55,940 significantly reduced body weight loss and running wheel activity in ABA rats. These behavioural effects were accompanied by an increase in leptin signalling and a decrease in plasma levels of corticosterone. CONCLUSION AND IMPLICATIONS: Taken together, our results further demonstrate the involvement of the EC system in AN pathophysiology and that strategies which modulate EC signalling are useful to treat this disorder, specifically in patients where physical hyperactivity plays a central role in its progression and maintenance.

Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia.

Environmental factors have been associated with psychiatric disorders and recent epidemiological studies suggest an association between prenatal lead (Pb(2+)) exposure and schizophrenia (SZ). Pb(2+) is a potent antagonist of the N-methyl-D-aspartate receptor (NMDAR) and converging evidence indicates that NMDAR hypofunction has a key role in the pathophysiology of SZ. The glutamatergic hypothesis of SZ posits that NMDAR hypofunction results in the loss of parvalbumin (PV)-positive GABAergic interneurons (PVGI) in the brain. Loss of PVGI inhibitory control to pyramidal cells alters the excitatory drive to midbrain dopamine neurons increasing subcortical dopaminergic activity. We hypothesized that if Pb(2+) exposure in early life is an environmental risk factor for SZ, it should recapitulate the loss of PVGI and reproduce subcortical dopaminergic hyperactivity. We report that on postnatal day 50 (PN50), adolescence rats chronically exposed to Pb(2+) from gestation through adolescence exhibit loss of PVGI in SZ-relevant brain regions. PV and glutamic acid decarboxylase 67 kDa (GAD67) protein were significantly decreased in Pb(2+) exposed rats with no apparent change in calretinin or calbindin protein levels suggesting a selective effect on the PV phenotype of GABAergic interneurons. We also show that Pb(2+) animals exhibit a heightened locomotor response to cocaine and express significantly higher levels of dopamine metabolites and D2-dopamine receptors relative to controls indicative of subcortical dopaminergic hyperactivity. Our results show that developmental Pb(2+) exposure reproduces specific neuropathology and functional dopamine system changes present in SZ. We propose that exposure to environmental toxins that produce NMDAR hypofunction during critical periods of brain development may contribute significantly to the etiology of mental disorders.

Understanding the reward system functioning in anorexia nervosa: crucial role of physical activity.

Hyperactivity is a potential neurobiological marker and a core psychopathological trait in anorexia nervosa (AN). We investigated the processing of hyperactivity-related information in fifteen AN patients, 15 athletes and 15 non-athletes to examine if they represent disorder-related reward information using eye tracking. We assessed the extent of individually performed physical activity, mood, trait reward sensitivity and serum leptin levels. Results revealed a pronounced bias in overall attentional engagement toward stimuli associated with physical activity in patients and athletes as compared to non-athletes. In patients, relevant correlations were found: trait reward sensitivity and attentional orienting were strongly correlated and amount of physical activity correlated with attentional orienting and engagement. Compared to non-athletes, patients and athletes rated exercise stimuli as more pleasant. Findings suggest that exercise-related stimuli are perceived as rewarding by AN patients. Positive motivational valence of physical activity might contribute to disorder development and maintenance.

Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype.

Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via ß(2)-adrenoceptor (ß2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, α(2A)-AR and α(2C)-AR (α(2A) /α(2C)-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In α(2A) /α(2C)-ARKO versus wild-type (WT) mice, micro-computed tomographic (µCT) analysis showed increased, better connected, and more plate-shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate-resistant acid phosphatase (TRACP) and receptor activator of NF-κB (RANK), which are osteoclast-related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine-regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial ß(2)-AR mRNA expression also was similar in KO and WT littermates, whereas α(2A)-, α(2B)- and α(2C)-AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected α(2A)-, α(2B)-, α(2C)- and ß(2)-ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5-day-old mouse fetuses and 35-day-old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective α(2)-AR agonist clonidine and to the nonspecific α-AR antagonist phentolamine. These findings suggest that ß(2)-AR is not the single adrenoceptor involved in bone turnover regulation and show that α(2)-AR signaling also may mediate the SNS actions in the skeleton.

Involvement of high plasma corticosterone status and activation of brain regional serotonin metabolism in long-term erythrosine-induced rearing motor hyper activity in young adult male rats.

Long-term consumption of artificial food color(s) can induce behavioral hyperactivity in human and experimental animals, but no neurobiochemical mechanism is defined. This study investigates the role of brain regional serotonin metabolism including its turnover, MAO-A activity, and plasma corticosterone status in relation to behavioral disturbances due to an artificial food color, erythrosine. Long-term (15 or 30 consecutive days) erythrosine administration with higher dosage (10 or 100 mg/kg/day, p.o.) produced optimal hyperactive state in exploratory behavior (rearing motor activity) after 2 h of last erythrosine administration, in young adult male albino rats. Erythrosine-induced stimulation in brain regional (medulla-pons, hypothalamus, hippocampus, and corpus striatum) serotonin metabolism (measuring steady state levels of 5-HT and 5-HIAA, MAO-A activity), including its turnover (pargyline-induced 5-HT accumulation and 5-HIAA declination rate), as well as plasma corticosterone were also observed depending on dosage(s) and duration(s) of erythrosine administration under similar experimental conditions. The lower dosage of erythrosine (1 mg/kg/day, p.o.) under similar conditions did not affect either of the above. These findings suggests (a) the induction as well as optimal effect of long-term erythrosine (artificial food color) on behavioral hyperactivity in parallel with increase in 5-HT level in brain regions, (b) the activation of brain regional serotonin biosynthesis in accordance with plasma corticosterone status under such behavioral hyperactivity, and (c) a possible inhibitory influence of the enhanced glucocorticoids-serotonin interaction on erythrosine-induced rearing motor hyperactivity in young adult mammals.

Specific adipocytokines profiles in patients with hyperactive and/or binge/purge form of anorexia nervosa.

OBJECTIVE: The aim of our study was to determine whether eating behaviors and/or physical activity level may explain contradicting results in adipocytokines levels in anorexia nervosa (AN). SUBJECTS/METHODS: Fasting levels of circulating adipocytokines (adiponectin, resistin and leptin), insulin, glucose, C-reactive protein, cytokines (tumor necrosis factor-alpha and interleukin (IL)-1beta), body composition and resting energy expenditure were measured in 24 women AN patients and 14 women controls. These parameters were compared according to AN subtypes: 15 patients with restrictive (R-AN) form versus 9 patients with binge/purge (BP-AN) form; 15 patients with hyperactive (H-AN) form versus 9 patients with nonhyperactive (NH-AN) form. RESULTS: BP-AN patients had significantly higher serum adiponectin levels compared with R-AN patients (P<0.05), and H-AN patients had higher serum leptin and lower serum resistin levels compared with NH-AN patients (P<0.05 for both). CONCLUSIONS: Our study shows specific adipocytokines profiles depending on the subtype of AN: restrictive versus binge/purge and hyperactive versus Nonhyperactive forms. We suggest that these biological signatures could interfere with the outcome of the disease.

Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1.

NPSR1 is a G protein coupled receptor expressed in multiple brain regions involved in modulation of stress. Central administration of NPS, the putative endogenous ligand of NPSR1, can induce hyperlocomotion, anxiolytic effects and activation of the HPA axis. The role of NPSR1 in the brain remains unsettled. Here we used NPSR1 gene-targeted mice to define the functional role of NPSR1 under basal conditions on locomotion, anxiety- and/or depression-like behavior, corticosterone levels, acoustic startle with prepulse inhibition, learning and memory, and under NPS-induced locomotor activation, anxiolysis, and corticosterone release. Male, but not female, NPSR1-deficient mice exhibited enhanced depression-like behavior in a forced swim test, reduced acoustic startle response, and minor changes in the Morris water maze. Neither male nor female NPSR1-deficient mice showed alterations of baseline locomotion, anxiety-like behavior, or corticosterone release after exposure to a forced swim test or methamphetamine challenge in an open-field. After intracerebroventricular (ICV) administration of NPS, NPSR1-deficient mice failed to show normal NPS-induced increases in locomotion, anxiolysis, or corticosterone release compared with WT NPS-treated mice. These findings demonstrate that NPSR1 is essential in mediating NPS effects on behavior.

The role of leptin and cortisol in hyperactivity in patients with acute and weight-recovered anorexia nervosa.

INTRODUCTION: In food-restricted rats, leptin as well as corticotropin releasing factor attenuate semistarvation-induced hyperactivity (SIH). Results from studies in patients with anorexia nervosa (AN) showed an association between excessive physical activity (PA) and leptin. One recent report suggests a role for cortisol in PA. In this study, we assessed the relationships between PA and both, cortisol and leptin levels at the same time in patients with acute anorexia nervosa (acAN) in comparison to recovered patients (recAN). METHODS: Plasma leptin, plasma cortisol, body mass index (BMI), and expert-ratings of qualities of PA were assessed in 36 acAN patients, 27 recAN patients and 44 healthy control woman (HCW). Regression analyses were used to predict PA using BMI, leptin and cortisol levels as predictor variables. RESULTS: Leptin levels but not cortisol significantly contributed to the prediction of PA in acAN. In recAN PA was not elevated and not related to endocrine parameters but correlated positively with core eating disorder symptoms. CONCLUSIONS: Our work lends support to the proposed inverse association between peripheral leptin levels and excessive physical activity in AN. This relationship is specific to the state of semistarvation. The role of additional mediators remains to be clarified.

The impact of hyperactivity and leptin on recovery from anorexia nervosa.

In anorexia nervosa (AN), hyperactivity is observed in about 80% of patients and has been associated with low leptin levels in the acute stage of AN and in anorexia animal models. To further understand the importance of this correlation in AN, we investigated the relationship between hypoleptinaemia and hyperactivity in AN patients longitudinally and assessed their predictive value for recovery. Body weight, activity levels, and serum leptin levels were assessed in adolescents and adult AN patient groups at the start and during treatment, up to a year. In the adolescent group, initial leptin and activity levels were correlated. This negative correlation changes over time into a positive correlation with physiological recovery. Treatment outcome in both groups could be predicted by initial BMI and leptin levels but not by activity levels. No major relationship of activity with the course of recovery was detected, suggesting that in contrast to the acute stage of the disease, leptin and activity levels during the recovery process are dissociated.

Psychoneuroendocrine profile associated with hypertension or hyperactivity in spontaneously hypertensive rats.

The behavioral and neuroendocrine reactivity to a novel environment (open field) and the adrenocorticotropic hormone (ACTH)/corticosterone response to a corticotropin-releasing factor (CRF) challenge were measured in 2-mo-old rats from four inbred strains derived from the Wistar-Kyoto rat: spontaneously hypertensive rats (SHRs), hypertensive and behaviorally hyperactive to novelty; WKY, neither hypertensive nor hyperactive; WKHA, hyperactive but normotensive; and WKHT, only hypertensive. The ACTH response to CRF was much lower in SHRs than WKYs, this reduced reactivity being clearly associated with the hyperactivity trait, since it was present in the WKHA and absent in the WKHT strain. On the other hand, the ACTH/corticosterone response to a psychological stimulus (open field) could not clearly discriminate the four strains. The largest difference was found in the prolactin response. Post-open-field levels were much lower in the WKHA (27.11 +/- 4.69 ng/ml) than in the parent WKY strain (83.65 +/- 6.84 ng/ml), the hypertensive strains having intermediate levels (WKHT: 58.05 +/- 7.65 ng/ml; SHR: 64.13 +/- 7.19 ng/ml). Other differences were also found in the levels of aldosterone and renin activity. These results indicate that these strains are an excellent model to study neuroendocrine correlates of hypertension and hyperactivity, which are associated in the SHR strain and may be of interest for the study of the association between neuroendocrine and behavioral characteristics.

Hyperkinesia, plasma corticotropin releasing hormone and ACTH in senile dementia.

Senile dementia of the Alzheimer type (SDAT), in contrast to multi-infarct dementia (MID) was associated with delirium and marked increases in the number of walking steps taken during both the day and night. In SDAT patients, plasma ACTH levels in the afternoon and evening were higher but plasma corticotropin releasing hormone (CRH) levels in the evening were lower than in the MID patients. A positive correlation between ACTH levels and walking steps and a negative correlation between plasma levels of CRH and ACTH were found. These results suggest relevance of hyper-kinetic delirium to disruption of diurnal rhythm of the pituitary-adrenal axis, and a possible mechanism of the short feedback suppression of CRH release by increased circulating ACTH.

Neonatal hyperexcitability in relation to plasma ionized calcium, magnesium, phosphate and glucose.

Twenty-two full-term babies were examined with a quantitative neurological assessment on days 1, 2 and 5 in order to confirm the clinical impression of hyperexcitability observed at the routine examination on day 1. Ultrasound examination of the head was normal in all cases. Plasma ionized calcium, phosphate and glucose in the hyperexcitability group fell within the neonatal reference ranges, as described previously. However, serum magnesium was significantly lower on day 1, but spontaneously normalized on day 5. Routine check-ups at the well-baby-clinics did not reveal any major illnesses or developmental abnormalities.

Trace metal abnormalities in long-stay hyperactive mentally handicapped children and agitated senile dements.

Gross metal poisoning as a causative factor in mental handicap is now relatively rare although historically it was important. Currently attention is being focused on the importance of chronic metal poisoning, there being much debate on, for instance, the possible effects of low levels of lead on intelligence in childhood. This paper examines the levels of a number of metals, both toxic and essential, in two groups of agitated patients in a long-stay psychiatric hospital in the UK. The two groups examined comprise 'hyperactive' mentally handicapped children and senile dementia patients, all of whom showed moderate to severe agitation. Blood and hair tissue were used to assess the body status of a number of metals and the results were compared with controls matched as closely as possible and from a similar hospital environment. The most significant findings are the raised levels of aluminium in the agitated senile dementia patients and the low levels of zinc and raised levels of lead in the hyperactive children.

Neonatal jitteriness of unknown origin and circulating catecholamines.

Jitteriness is a common problem affecting neonates. Although the cause can sometimes be determined by history or conventional laboratory evaluations, nevertheless, in many instances the cause of the jitteriness is unknown. To determine if either intracranial hemorrhage (ICH) or elevated catecholamines are responsible for jitteriness in neonates, we studied 34 healthy term neonates with normal hematocrits, serum glucose, Ca, Mg, Na, K and P. Thirteen of the infants had jitteriness as their only clinical problem. There were no differences in Apgar scores, birthweight, or gestational age in the two groups. Norepinephrine levels were significantly elevated in the jittery group as compared to the control group: 1276 +/- 574 vs. 914 +/- 338, p less than 0.05. Epinephrine levels were not different in the two groups. Intracranial hemorrhage was not found in any of the patients. Jittery neonates have increased sympathetic activity. What influence the increased levels have on other metabolic and hormonal systems is yet to be determined.

Chelation therapy in children as treatment of sequelae in severe lead toxicity.

Certain children who experience a toxic lead episode requiring hospitalization in infancy or early childhood will manifest central nervous system dysfunctions, including hyperactivity, as sequelae of this experience. In this study, findings indicate that persistent, higher-than-normal lead levels, dating back to the time of the initial toxicity, may well be a mechanism underlying some of these sequelae. Consequently, some part of these sequelae may be preventable and/or treatable.

The relationship of hyperactivity to moderately elevated lead levels.

Controversy exists with respect to whether moderately elevated lead levels are toxic in certain children with various central nervous system dysfunctions. One way of addressing this controversy is to remove the lead; if the condition is ameliorated a presumption of toxicity becomes reasonable. Such a strategy is reported herein. Children with an operationally defined central nervous system dysfunction (hyperactivity) and moderately elevated lead levels were treated with a lead chelating agent in a random allocation double blind treatment regimen. The finding of statistically significant and obvious behavioral improvement reported by three separate evaluators (i.e., parent, teacher, and treating physician) of the child suggests that the presumption of a toxic relationship between moderately elevated lead levels and hyperactivity is supported.

Pharmacokinetics of methylphenidate in man, rat and monkey.

The pharmacokinetics and bioavailability of methylphenidate (MPH) and a metabolite, ritalinic acid (RA), were studied in normal adults, children with hyperactivity, monkeys and rats. Adult males received 0.15 or 0.3 mg/kg of MPH orally and MPH and RA were analyzed in plasma samples obtained at various times after treatment. Maximal MPH concentrations in plasma were found to occur 2.2 hr after administration of either dose (range: 1.0-4.0). The mean (+/-S.E.) maximal concentration in plasma for MPH was 3.5 +/- 0.4 ng/ml after 0.15 mg/kg and 7.8 +/- 0.8 ng/ml after 0.3 mg/kg. MPH clearances were high (10.1 liters/hr/kg) and variable (range: 3.6-23.2) for the 0.3 mg/kg dose. Pharmacokinetic parameters for children receiving 0.3 mg/kg were essentially the same as for adults. RA plasma levels were 50 to 100 times greater than MPH levels in normal adults. The clearance of RA is less than that of MPH. The absolute bioavailability of MPH was found to be 0.19 in the rat and 0.22 in the monkey, suggesting substantial presystemic elimination of MPH.