Nicotine Exposure in a Phencyclidine-Induced Mice Model of Schizophrenia: Sex-Selective Medial Prefrontal Cortex Protein Markers of the Combined Insults in Adolescent Mice.

Tobacco misuse as a comorbidity of schizophrenia is frequently established during adolescence. However, comorbidity markers are still missing. Here, the method of label-free proteomics was used to identify deregulated proteins in the medial prefrontal cortex (prelimbic and infralimbic) of male and female mice modelled to schizophrenia with a history of nicotine exposure during adolescence. Phencyclidine (PCP), used to model schizophrenia (SCHZ), was combined with an established model of nicotine minipump infusions (NIC). The combined insults led to worse outcomes than each insult separately when considering the absolute number of deregulated proteins and that of exclusively deregulated ones. Partially shared Reactome pathways between sexes and between PCP, NIC and PCPNIC groups indicate functional overlaps. Distinctively, proteins differentially expressed exclusively in PCPNIC mice reveal unique effects associated with the comorbidity model. Interactome maps of these proteins identified sex-selective subnetworks, within which some proteins stood out: for females, peptidyl-prolyl cis-trans isomerase (Fkbp1a) and heat shock 70 kDa protein 1B (Hspa1b), both components of the oxidative stress subnetwork, and gamma-enolase (Eno2), a component of the energy metabolism subnetwork; and for males, amphiphysin (Amph), a component of the synaptic transmission subnetwork. These are proposed to be further investigated and validated as markers of the combined insult during adolescence.

Adolescent nicotine potentiates the inhibitory effect of raclopride, a D2R antagonist, on phencyclidine-sensitized psychotic-like behavior in mice.

The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early establishment of this comorbidity, we used phencyclidine-evoked locomotor sensitization, a proxy model of psychotic behavior, and nicotine minipump infusions in adolescent mice. Considering the involvement of dopamine D2 receptors in both schizophrenia and addiction, we further tested their role by exposing mice to raclopride. Adolescent mice that were either exposed to nicotine (24 mg/Kg/day) or not, received single daily raclopride (0.5 mg/kg, s.c.) or saline followed by phencyclidine injections (10 mg/Kg, s.c.) during open field testing for 6 consecutive days (Acquisition phase, ACQ). Phencyclidine and nicotine challenges (Sensitization Test, ST) were carried out after a 5-day withdrawal. Ambulation escalated in response to repeated phencyclidine exposure during ACQ and was increased after phencyclidine challenge, evidencing development and expression of locomotor sensitization. Raclopride prevented phencyclidine-evoked development of sensitization. However, raclopride pre-exposure during ACQ only shortened its expression in phencyclidine-challenged mice. Nicotine failed to interfere with phencyclidine stimulatory effects during ACQ but potentiated raclopride inhibition during the first ACQ days. During ST, nicotine history shortened the expression of phencyclidine-evoked sensitization. Nicotine challenge had no impact on locomotion, which is consistent with a lack of nicotine/phencyclidine cross-sensitization. In conclusion, our results show that nicotine does not worsen, and may even ameliorate phencyclidine-sensitized psychotic-like behavior in adolescent mice. The potentiation of raclopride-mediated inhibition further suggests that nicotine transiently improves the therapeutic efficacy of medication on psychotic symptoms through mechanisms that converge on D2 receptors.

Effect of tobacco smoke exposure during pregnancy and preschool age on growth from birth to adolescence: a cohort study.

BACKGROUND: There is strong evidence of an association between maternal smoking during pregnancy and restriction of intrauterine growth, but the effects of this exposure on postnatal linear growth are not well defined. Furthermore, few studies have investigated the role of tobacco smoke exposure also after pregnancy on linear growth until adolescence. In this study we investigated the effect of maternal smoking exposure during pregnancy and preschool age on linear growth from birth to adolescence. METHODS: We evaluated a cohort of children born between 1994 and 1999 in Cuiabá, Brazil, who attended primary health clinics for vaccination between the years 1999 and 2000 (at preschool age) and followed-up after approximately ten years. Individuals were located in public and private schools throughout the country using the national school census. Height/length was measured, and length at birth was collected at maternity departments. Stature in childhood and adolescence was assessed using the height-for-age index sex-specific expressed as z-score from curves published by the World Health Organization. Linear mixed effects models were used to estimate the association between exposure to maternal smoking, during pregnancy and preschool age, and height of children assessed at birth, preschool and school age, adjusted for age of the children. RESULTS: We evaluated 2405 children in 1999-2000, length at birth was obtained from 2394 (99.5%), and 1716 at follow-up (71.4% of baseline), 50.7% of the adolescents were male. The z-score of height-for-age was lower among adolescents exposed to maternal smoking both during pregnancy and childhood (p < 0.01). Adjusting for age, sex, maternal height, maternal schooling, socioeconomic position at preschool age, and breastfeeding, children exposed to maternal smoking both during pregnancy and preschool age showed persistent lower height-for-age since birth to adolescence (coefficient: -0.32, p < 0.001) compared to non-exposed. Paternal smoking at preschool age was not associated with growth after adjustment for confounders. CONCLUSION: Exposure to maternal smoking not only during pregnancy, but also at early childhood, showed long-term negative effect on height of children until adolescence.

Ontogenetic analysis of behavior in the tail suspension test: temporal differences in the emergence of within- and between-session habituation in Swiss mice.

Habituation is an important tool in the investigation of learning/memory throughout life. Despite that, few studies describe habituation from an ontogenetic perspective. Considering that, as soon as they are born, rodents can twist their bodies when lifted by their tails in an attempt to escape, this behavior should be well suited to study habituation behavior from birth to adulthood. Here, we implement a tail suspension test to study the ontogenetic development of habituation in Swiss mice. Our data indicate that a continuous within-session decrease in trunk movements can be observed from postnatal day (P) 10 onwards and that between-sessions habituation (from one day to another) can be observed from P16 onwards. Furthermore, we show that the adult pattern of within- and between-sessions reductions in activity is already present by the beginning of adolescence, at P28. Our results indicate that between-sessions habituation involves a more complex mechanism of memory and learning than within-session habituation, requiring a longer period of brain maturation before it can be displayed.

Changes in the proteome of Apis mellifera acutely exposed to sublethal dosage of glyphosate and imidacloprid.

Uncontrolled use of pesticides has caused a dramatic reduction in the number of pollinators, including bees. Studies on the effects of pesticides on bees have reported effects on both metabolic and neurological levels under chronic exposure. In this study, variations in the differential expression of head and thorax-abdomen proteins in Africanized A. mellifera bees treated acutely with sublethal doses of glyphosate and imidacloprid were studied using a proteomic approach. A total of 92 proteins were detected, 49 of which were differentially expressed compared to those in the control group (47 downregulated and 2 upregulated). Protein interaction networks with differential protein expression ratios suggested that acute exposure of A. mellifera to sublethal doses of glyphosate could cause head damage, which is mainly associated with behavior and metabolism. Simultaneously, imidacloprid can cause damage associated with metabolism as well as, neuronal damage, cellular stress, and impairment of the detoxification system. Regarding the thorax-abdomen fractions, glyphosate could lead to cytoskeleton reorganization and a reduction in defense mechanisms, whereas imidacloprid could affect the coordination and impairment of the oxidative stress response.

Nicotine affects cutaneous wound healing in stressed mice.

Stress is an important condition of modern life. Nicotine addiction can modulate the physiological response to stress. Cutaneous healing is a complex process resulting in scar formation, which can be delayed by stress. Therefore, the aim of this study was to investigate the effects of nicotine administration on cutaneous wound healing in chronically stressed mice. Male mice were submitted to rotational stress, whereas control animals were not subjected to stress. These stressed and control animals were treated with a transdermal nicotine patch that was changed every day. A full-thickness excisional lesion was also generated, and 14 days later, lesions had recovered. However, the Stress + Nicotine group presented a delay in wound contraction. These wounds showed a decrease in inflammatory cell infiltration and lower expression of transforming growth factor-ß (TGF-ß), whereas there was an increase in angiogenesis and tumor necrosis factor-α (TNF-α) expression. In vitro fibroblast migration was also impaired by the nicotine treatment of stressed-stimulated cells. In conclusion, nicotine administration potentiates the delay in wound closure observed in mice submitted to stress.

Combined exposure to tobacco smoke and ethanol in adolescent mice elicits memory and learning deficits both during exposure and withdrawal.

INTRODUCTION: Adolescents often associate tobacco smoking and consumption of alcoholic beverages. In spite of that, little is known about the neurobehavioral consequences of the dual exposure in the adolescent brain. In the present work, we assessed the effects of tobacco smoke and/or ethanol exposure during adolescence on memory/learning. METHODS: From postnatal day 30 to 45 (PN30-45), male and female Swiss mice were exposed to tobacco smoke (SMK-generated from research cigarettes type 3R4F, whole body exposure, 8hr/day) and/or ethanol (ETOH-25% solution, 2g/kg intraperitoneally injected every other day) as follows: (a) SMK+ETOH exposure; (b) SMK exposure; (c) ETOH exposure; (d) Control. Memory/learning was evaluated during exposure (PN44-45) and during short- (PN49-50) and long-standing withdrawal (PN74-75). At each timepoint, mice were trained and tested in a step-down passive avoidance task (0.3 mA, 3 s footshock). Two retention tests were carried out in each animal, one at 3hr after training to measure short-term memory and another at 24hr to measure long-term memory. RESULTS: During exposure, the short-term memory was impaired in all groups and the long-term memory was impaired in SMK and SMK+ETOH. During the short-standing withdrawal, a significant impairment was observed only in long-term memory of the male SMK+ETOH mice. At long-standing withdrawal, there were no significant differences between groups. CONCLUSIONS: Tobacco smoke and ethanol exposures during adolescence of mice negatively affect learning/memory performance. Deficits that were still present during SMK+ETOH short-standing withdrawal suggest that the combined exposure elicits a worsened memory/learning outcome and that males are more susceptible.

Neonatal phencyclidine as a model of sex-biased schizophrenia symptomatology in adolescent mice.

Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.

Maternal protein restriction during the lactation period disrupts the ontogenetic development of behavioral traits in male Wistar rat offspring.

Neonatal undernutrition in rats results in short- and long-term behavioral and hormonal alterations in the offspring. It is not clear, however, whether these effects are present since the original insult or if they develop at some specific age later in life. Here, we assessed the ontogenetic profile of behavioral parameters associated with anxiety, exploration and memory/learning of Wistar rat offspring that were subjected to protein malnutrition during lactation. Dams and respective litters were separated into two groups: (1) protein-restricted (PR), which received a hypoproteic chow (8% protein) from birth to weaning [postnatal day (PN) 21]; (2) control (C), which received normoproteic chow. Offspring's behaviors, corticosterone, catecholamines, T3 and T4 levels were assessed at PN21 (weaning), PN45 (adolescence), PN90 (young adulthood) or PN180 (adulthood). PR offspring showed an age-independent reduction in the levels of anxiety-like behaviors in the Elevated Plus Maze and better memory performance in the Radial Arm Water Maze. PR offspring showed peak exploratory activity in the Open Field earlier in life, at PN45, than C, which showed theirs at PN90. Corticosterone was reduced in PR offspring, particularly at young adulthood, while catecholamines were increased at weaning and adulthood. The current study shows that considerable age-dependent variations in the expression of the observed behaviors and hormonal levels exist from weaning to adulthood in rats, and that protein restriction during lactation has complex variable-dependent effects on the ontogenesis of the assessed parameters.

Lifetime caffeine and adolescent nicotine exposure in mice: effects on anxiety-like behavior and reward.

Caffeine consumption occurs throughout life, while nicotine use typically begins during adolescence, the period when caffeine-nicotine epidemiological association begins in earnest. Despite that, few studies in animal models parallel the pattern of coexposure that occurs in humans. Therefore, the neurobehavioral consequences of the association between these drugs remain unclear. Here, we exposed Swiss mice to lifetime caffeine. Caffeine solutions of 0.1 g/L (CAF0.1), 0.3 g/L (CAF0.3), or water (CTRL) were used as the sole liquid source, being offered to progenitors until weaning and, after that, directly to the offspring until the last day of adolescent behavioral evaluation. The open field test was used to evaluate acute effects of nicotine, of lifetime caffeine and of their interaction on locomotion and anxiety-like behavior, while the conditioned place preference test was used to assess the impact of caffeine on nicotine (0.5 mg/Kg, i.p.) reward. Frontal cerebral cortex dopamine content, dopamine turnover, and norepinephrine levels, as well as hippocampal serotonin 1A receptor expression were assessed. CAF0.3 mice exhibited an increase in anxiety-like behavior when compared to CAF0.1 and CTRL ones, but nicotine coexposure mitigated the anxiogenic-like caffeine-induced effect. Distinctively, caffeine had no effect on locomotion and failed to interfere with both nicotine-induced hyperactivity and place preference. There were no significant effects on dopaminergic and serotonergic markers. In conclusion, although caffeine did not affect nicotine reward, considering the strong association between anxiety disorders and tobacco consumption, caffeine-induced anxiety-like behavior advises limiting its consumption during development, including adolescence, as caffeine could be a risk factor to nicotine use.

Unilateral hemispherectomy at adulthood asymmetrically affects motor performance of male Swiss mice.

Evidence exists indicating that cerebral lateralization is a fundamental feature of all vertebrates. In humans, a series of studies demonstrated that the left hemisphere plays a major role in controlling movement. No such asymmetries have been identified in rodents, in spite of the fact that these animals have been frequently used in studies assessing motor behavior. In this regard, here, we used unilateral hemispherectomy to study the relative importance of each hemisphere in controlling movement. Adult Swiss mice were submitted to right unilateral hemispherectomy (RH), left unilateral hemispherectomy (LH) or sham surgery. Fifteen days after surgery, motor performance was assessed in the accelerating rotarod test and in the foot-fault test (in which performance depends on skilled limb use) and in the elevated body swing test (in which performance depends on trunk movements). The surgical removal of the right hemisphere caused a more pronounced impairment in performance than the removal of the left hemisphere both in the rotarod and in the foot-fault tests. In the rotarod, the RH group presented smaller latencies to fall than both LH and sham groups. In the foot-fault test, while both the sham and the LH groups showed no differences between left and right hind limbs, the RH group showed significantly worse performance with the left hind limb than with the right one. The elevated body swing test revealed a similar impairment in the two hemispherectomized groups. Our data suggest a major role of the right hemisphere in controlling skilled limb movements in mice.

A systematic review of the mental health risks and resilience among pollution-exposed adolescents.

Pollution is harmful to human physical health and wellbeing. What is less well established is the relationship between adolescent mental health - a growing public health concern - and pollution. In response, we systematically reviewed studies documenting associations between pollution and mental health in adolescents. We searched Africa Wide, Medline, PsycArticles, PsycInfo, PubMed, CINAHL, ERIC, SciELO, Scopus, and Web of Science Core Collection for studies published up to 10 April 2020 that investigated exposure to any pollutant and symptoms of anxiety; depression; disruptive, impulse-control, and conduct disorders; neurodevelopmental disorders; psychosis; or substance abuse in 10-24-year-olds (i.e., adolescents as per expanded and more inclusive definition of adolescence). This identified 2291 records and we assessed 128 papers for inclusion. We used a narrative synthesis to coalesce the studies' findings. This review is registered on PROSPERO, CRD42020176664. Seventeen studies from Asia, Europe, the Middle East, and North America were included. Air and water pollution exposure was associated with elevated symptoms of depression, generalised anxiety, psychosis, and/or disruptive, impulse control and conduct disorder. Exposure to lead and solvents was associated with neurodevelopmental impairments. Most studies neglected factors that could have supported the mental health resilience of adolescents exposed to pollution. Notwithstanding the limited quality of most reviewed studies, results suggest that pollution exposure is a risk to adolescent mental health. High-quality research is urgently required, including the factors and processes that protect the mental health of pollution-exposed adolescents. Studies with adolescents living in low- and lower middle-income countries and the southern hemisphere must be prioritized.

Does nicotine exposure during adolescence modify the course of schizophrenia-like symptoms? Behavioral analysis in a phencyclidine-induced mice model.

The first symptoms of schizophrenia (SCHZ) are usually observed during adolescence, a developmental period during which first exposure to psychoactive drugs also occurs. These epidemiological findings point to adolescence as critical for nicotine addiction and SCHZ comorbidity, however it is not clear whether exposure to nicotine during this period has a detrimental impact on the development of SCHZ symptoms since there is a lack of studies that investigate the interactions between these conditions during this period of development. To elucidate the impact of a short course of nicotine exposure across the spectrum of SCHZ-like symptoms, we used a phencyclidine-induced adolescent mice model of SCHZ (2.5mg/Kg, s.c., daily, postnatal day (PN) 38-PN52; 10mg/Kg on PN53), combined with an established model of nicotine minipump infusions (24mg/Kg/day, PN37-44). Behavioral assessment began 4 days after the end of nicotine exposure (PN48) using the following tests: open field to assess the hyperlocomotion phenotype; novel object recognition, a declarative memory task; three-chamber sociability, to verify social interaction and prepulse inhibition, a measure of sensorimotor gating. Phencyclidine exposure evoked deficits in all analyzed behaviors. Nicotine history reduced the magnitude of phencyclidine-evoked hyperlocomotion and impeded the development of locomotor sensitization. It also mitigated the deficient sociability elicited by phencyclidine. In contrast, memory and sensorimotor gating deficits evoked by phencyclidine were neither improved nor worsened by nicotine history. In conclusion, our results show for the first time that nicotine history, restricted to a short period during adolescence, does not worsen SCHZ-like symptoms evoked by a phencyclidine-induced mice model.

Effects of pollution on adolescent mental health: a systematic review protocol.

BACKGROUND: Whilst there is little uncertainty about the deleterious impact of pollution on human and planetary health, pollution's impact on adolescent mental health is less well understood. This is particularly true for young people in underdeveloped and developing world contexts, about whom research is generally lacking. Furthermore, although adolescent resilience continues to be a research priority, little attention has been paid to adolescent pathways of resilience in the face or aftermath of pollution exposure. The objective of this study will be to examine the associations between pollution and mental health in 10- to 24-year-olds (i.e. adolescents). METHODS: We designed and registered a study protocol for a systematic review of studies which link pollution and mental health in adolescents. We will include observational studies (e.g. cohort, case-control, time series analyses) that assess the associations between exposure to any form of pollution and the mental health of 10- to 24-year-olds. The primary outcome will be symptoms associated with neurodevelopmental disorders; disruptive, impulse-control, and conduct disorders; depressive disorders; anxiety disorders; substance disorders; and schizophrenia. No secondary outcomes will be considered. Literature searches will be conducted in multiple electronic databases (from inception onwards), including PubMed, MEDLINE, SCOPUS, Web of Science, CINAHL, PsycINFO, SciELO, ERIC, and Africa-Wide. Two investigators will independently screen all citations, full-text articles, and abstract data. The methodological quality (or bias) of included studies will be appraised using appropriate tools. We will provide a narrative synthesis of the evidence. DISCUSSION: This systematic review will evaluate the evidence on the associations between pollution and the mental health of 10- to 24-year-olds. Our findings will be of potential interest to multiple audiences (including adolescent patients/clients, their families, caregivers, healthcare professionals, scientists, and policy makers) and could be used to develop prevention and intervention strategies as well as focus future research. Results will be published in a peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020176664.

Forced swimming stress increases natatory activity of lead-exposed mice.

Recent evidence points to the relationship between lead toxicity and the function of the hypothalamic-pituitary-adrenal axis, which suggests that lead exposure could influence how an individual cope with stress. Here we test this hypothesis by investigating the behavioral effects of lead exposure in mice during the forced swimming test (FST), a parading in which animals are exposed to a stressful situation and environment. Swiss mice received either 180 ppm or 540 ppm of lead acetate (Pb) in their ad-lib water supply for 60-90 days, starting at postnatal day 30. Control (Ctrl) mice drank tap water. At the end of the exposure period, mice were submitted to a 5-min session of FST or to an open-field session of the same duration. Data from naïve animals showed that corticosterone levels were higher for animals tested in the FST compared to animals tested in the open-field. Blood-lead levels (BLL) in Pb-exposed mice ranged from 14.3 to 106.9 µg/dL. No differences were observed in spontaneous locomotion between Ctrl and Pb-exposed groups in the open-field. However, in the FST, Pb-treated mice displayed higher swimming activity than Ctrl ones and this effect was observed even for animals with BLL higher than 20 µg/dL. Furthermore, significant differences in brain glutathione levels, used as an indicator of led toxicity, were only observed for BLL higher than 40 µg/dL. Overall, these findings suggest that swimming activity in the FST is a good indicator of lead toxicity and confirm our prediction that lead toxicity influences behavioral responses associated to stress.

Sex- and age-dependent differences in nicotine susceptibility evoked by developmental exposure to tobacco smoke and/or ethanol in mice.

Either tobacco smoking or alcohol consumption during pregnancy sex-selectively increases susceptibility to drugs of abuse later in life. Considering that pregnant smoking women are frequently intermittent consumers of alcoholic beverages, here, we investigated whether a short-term ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to tobacco smoke aggravates susceptibility to nicotine in adolescent and adult mice. Swiss male and female mice were exposed to tobacco smoke (SMK; research cigarettes 3R4F, whole-body exposure, 8 h/daily) or ambient air during the gestational period and until the tenth postnatal day (PN). Ethanol (ETOH, 2 g/Kg, 25%, i.p.) or saline was injected in the pups every other day from PN2 to PN10. There were no significant differences in cotinine (nicotine metabolite) and ethanol serum levels among SMK, ETOH and SMK + ETOH groups. During adolescence (PN30) and adulthood (PN90), nicotine (NIC, 0.5 mg/Kg) susceptibility was evaluated in the conditioned place preference and open field tests. NIC impact was more evident in females: SMK, ETOH and SMK + ETOH adolescent females were equally more susceptible to nicotine-induced place preference than control animals. At adulthood, SMK and SMK + ETOH adult females exhibited a nicotine-evoked hyperlocomotor profile in the open field, with a stronger effect in the SMK + ETOH group. Our results indicate that ethanol exposure during the brain growth spurt, when combined to developmental exposure to tobacco smoke, increases nicotine susceptibility with stronger effects in adult females. This result represents a worsened outcome from the early developmental dual exposure and may predispose nicotine use/abuse later in life.

Exposure to tobacco smoke containing either high or low levels of nicotine during adolescence: differential effects on choline uptake in the cerebral cortex and hippocampus.

INTRODUCTION: There is a lack of experimental studies that investigate the effects of tobacco smoke exposure during adolescence. Here, we investigated the effects of tobacco smoke generated from cigarettes containing either high or low levels of nicotine on the cholinergic system. METHODS: From postnatal day (PN) 30 to 45, 18 C57BL/6 (inbred) and 16 Swiss (outbred) mice of both sexes were exposed to tobacco smoke (whole body exposure for 8 hr/day and 7 days/week) generated from one of two reference research cigarettes: type 3R4F (HighNIC group-nicotine = 0.73 mg/cigarette) or type 4A1 (LowNIC group-nicotine = 0.14 mg/cigarette). Control mice (CT) were exposed to air. On PN 45, cotinine (nicotine metabolite) serum levels and [(3)H]choline uptake in the cerebral cortex and hippocampus were assessed. RESULTS: Cotinine serum levels were eight times higher in HighNIC mice (C57BL/6:142.0 +/- 16.7 ng/ml and Swiss: 197.6 +/- 11.1 ng/ml) when compared with LowNIC ones (C57BL/6:17.4 +/- 7.4 ng/ml and Swiss: 24.6 +/- 2.2 ng/ml). Only HighNIC mice presented a significant increase in [(3)H]choline uptake in the hippocampus (C57BL/6: HighNIC > CT and HighNIC > LowNIC, p < .001 and Swiss: HighNIC > CT and HighNIC > LowNIC, p < .001), whereas in the cerebral cortex, both HighNIC and LowNIC mice presented increased [(3)H]choline uptake (C57BL/6: HighNIC > CT and LowNIC > CT, p < .05 and Swiss: HighNIC > CT and LowNIC > CT, p < .001). DISCUSSION: Our results indicate that tobacco smoke exposure during adolescence increases [(3)H]choline uptake. However, the effects are dependent on the type of cigarette and on the brain region.

Mood disorders hospitalizations, suicide attempts, and suicide mortality among agricultural workers and residents in an area with intensive use of pesticides in Brazil.

As suicide rates have increased in rural areas in Brazil, it was postulated that pesticide exposure may play a role in this phenomenon. Our study compared the suicide mortality rates observed among agricultural workers from a pesticide-intensive area in Brazil to the suicide mortality frequency noted in three reference populations. In addition, hospitalization rates attributed to suicide attempts and mood disorders including depression in residents of the same agricultural area were compared to two reference populations. Finally, data on pesticide sales per agricultural worker were obtained for each city of Rio de Janeiro State and suicide mortality risk was then calculated according to the quartiles of pesticide sales per agricultural workers, using the first quartile as reference. Agricultural workers were at greater risk for lethality due to suicide when compared to all three reference populations. In addition, residents of the same study area showed higher hospitalization rates by suicide attempts and mood disorders than observed in comparison populations. Results also showed that the risk of death by suicide was significantly higher among agricultural workers who lived in areas of Rio de Janeiro State displaying higher rates of pesticide expenditure per agricultural worker. These results suggest that pesticide exposure may indeed increase the risk of suicide frequency, especially among agricultural workers.

Profiling of behavioral effects evoked by ketamine and the role of 5HT2 and D2 receptors in ketamine-induced locomotor sensitization in mice.

Ketamine has addictive potential, a troublesome fact due to its promising use as a therapeutic drug. An important phenomenon associated with drug addiction is behavioral sensitization, usually characterized as augmented locomotion. However, other behaviors may also be susceptible to sensitization, and/or interfere with locomotor activity. Thus, this study drew a comprehensive behavioral 'profiling' in an animal model of repeated administration of ketamine. Adult Swiss mice received single daily ketamine injections (30 or 50 mg/Kg, i.p.), which were followed by open field testing for 7 days (acquisition period, ACQ). A ketamine challenge (sensitization test, ST) was carried out after a 5-day withdrawal. Locomotion, rearing, grooming, rotation and falling were assessed during ACQ and ST. All behaviors were affected from the first ACQ day onwards, with no indication of competition between locomotion and the other behaviors. Only locomotion in response to 30 mg/Kg of ketamine both escalated during ACQ and expressed increased levels at ST, evidencing development and expression of locomotor sensitization. Considering the involvement of serotonin 5HT(2) and dopamine D(2) receptors on addiction mechanisms, we further tested the involvement of these receptors in ketamine-induced sensitization. Ketanserin (5HT2 antagonist, 3 mg/Kg, s.c.) prevented ketamine-evoked development of locomotor sensitization. However, ketanserin pretreatment during ACQ failed to inhibit its expression during ST. Raclopride (D2 antagonist, 0.5 mg/Kg, s.c.) evoked less robust reductions in locomotion but prevented the development of ketamine-evoked sensitization. Pretreatment during ACQ further inhibited the expression of sensitization during ST. These results indicate that a partial overlap in serotonergic and dopaminergic mechanisms underlies ketamine-induced locomotor sensitization.

Mood-related behavioral and neurochemical alterations in mice exposed to low chlorpyrifos levels during the brain growth spurt.

Organophosphates are among the most used pesticides. Particularly, chlorpyrifos (CPF) is responsible for a number of deleterious effects on brain development, which may program behavioral changes later in life. Here, we investigated whether a regimen of early low level CPF exposure that did not result in a significant inhibition of acetylcholinesterase (AChE) had deleterious effects on mood-related behaviors, as well as on cholinergic and serotonergic biomarkers in the mice brain. From the 3rd to 9th postnatal day (PN), male and female Swiss mice were subcutaneously injected with CPF. Mice were submitted to a battery of behavioral tests from PN60 to PN63: open field, elevated plus maze and forced swimming tests. The cholinergic and serotonergic biomarkers were assessed at PN10 and PN63. Our data indicated that early CPF exposure increased anxiety-like behavior in females and altered decision-making behavior in both sexes. Most biochemical alterations were sex-dependent and restricted to females. At PN10, CPF female mice showed increased serotonin and choline transporter binding in cerebral cortex. Distinctively, in adult females, the effects indicated a hypoactive state: CPF exposure reduced 5-HT1a receptor binding in cerebral cortex, as well as serotonin transporter binding and choline acetyltransferase activity in brainstem. Our results indicate that CPF exposure during the brain growth spurt deregulates serotonergic and cholinergic biomarkers. The effects are consistent with impaired synaptic function, may be related to long-term mood disorders and point out to higher female susceptibility.