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.

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.

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.

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.

Plasma cyclic AMP level in psychiatric diseases of childhood.

Determinations were made of the plasma cyclic AM level to examine its relationship with hyperkinesis (Werry-Weiss-Peters Activity Scale, WWPAS) and other features of mental disorders in 80 children, of whom 21 had early infantile autism, 15 hyperkinetic mental retardation, 12 minimal brain dysfunction and 32 Down's syndrome. In autistic and hyperkinetic mentally retarded children, the plasma cyclic AMP levels were higher than in normal children and were positively correlated with the WWPAS score. In children with minimal brain dysfunction, the plasma cyclic AMP level was significantly lower than in normal children and was not correlated with the WWPAS score. In children with Down's syndrome, the plasma cyclic AMP level was somewhat higher than in normal children.

A reproducible gas chromatographic mass spectrometric assay for low levels of methylphenidate and ritalinic acid in blood and urine.

A rapid, sensitive method of analysis for methylphenidate and ritalinic acid in blood and urine has been developed using gas chromatography mass spectrometry and selected ion monitoring for separation and detection. The methylphenidate is isolated by solvent extraction into chloroform and the ritalinic acid is isolated by salting out into isopropyl alcohol, followed by methylation and subsequent solvent extraction. The method has been applied to the study of methylphenidate metabolism and excretion in adults and hyperactive children undergoing treatment with methylphenidate.