A single high dose of methamphetamine increases cocaine self-administration by depletion of striatal dopamine in rats

Psychostimulant addicts often take high doses of drugs, and high doses of psychostimulants such as methamphetamine (METH) are neurotoxic to striatal dopamine (DA) terminals. Yet, the effects of high doses of METH on drug-seeking and drug-taking behavior have not been examined. In the present study, we found that single high doses of METH in rats (10–20 mg/kg) dose-dependently increased cocaine self-administration under fixed-ratio 2 (FR2) reinforcement conditions, while higher doses (40 mg/kg×1 or 10 mg/kg/2 h×4) caused high mortality among rats maintained on daily cocaine self-administration. The increased cocaine self-administration appeared to be a compensatory response to reduced cocaine reward after METH, because the same doses of METH caused a dose-dependent reduction both in “break-point” levels for cocaine self-administration under progressive-ratio reinforcement and in nucleus accumbens DA response to acute cocaine. Further, METH (10–20 mg/kg) produced large DA release (4000%–6000% over baseline), followed by a significant reduction in striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) contents, but without significant changes in striatal DA transporter levels. These findings suggest that the present high doses of METH caused striatal DA depletion or hypofunction without severe damage in DA terminals, which may contribute to the increased cocaine-taking behavior observed in the present study. Provided that the present doses of METH may mimic METH overdose incidents in humans, the present findings suggest that METH-induced DA depletion or neurotoxicity may lead to an increase in subsequent drug-taking and drug-seeking behavior.     

Alterations in behavior in adult offspring mice following maternal inflammation during pregnancy

Maternal intrauterine inflammation during pregnancy poses a major threat of neurodevelopmental brain damage in offspring and may cause poor cognitive and perceptual outcomes. In mice, we have previously shown that maternal inflammation induced by lipopolysaccharide (LPS) at gestation day 17th increased the levels of the pro-inflammatory cytokine IL-6 in the fetal brain. In this study, we used the same system and examined the effect of short, systemic maternal inflammation on anxiety and social behavior of the offspring. Adult offspring from the maternal inflammation group showed increased anxiety, as indicated by the elevated plus maze. Social interaction among offspring from the test groups was examined when two unfamiliar mice from different litters were introduced into a new home-cage. Offspring from the maternal inflammation group showed reduced activity, indicating increased fear. In addition, offspring from the maternal inflammation group were less aggressive towards their cagemates and they spent a significantly longer time trimming the whiskers of their cagemates during the first 30 min of their interaction, compared to offspring from the control group. Our data suggest that short systemic maternal inflammation have long-lasting consequences on the adult mouse stress and social behavior.     

Maternal cigarette-smoking during pregnancy disrupts rhythms in fetal heart rate

OBJECTIVE: To examine the effects of maternal cigarette smoking during pregnancy on the developing infant's autonomic regulation before the possible effects of parturition and neonatal withdrawal could alter outcome measures. METHODS: Heart rate variability (HRV) was assessed for 10 min during late gestation for 21 cigarette-exposed (CE) and 22 nonexposed (NE) fetuses. RESULTS: HRV was significantly lower in fetuses whose mothers smoked cigarettes during pregnancy. Spectrum analysis of that variability showed temporally organized rhythms at a frequency similar to rhythms previously found in fetal cyclic motility (approximately .3 cycles per min). Lower powered rhythms--associated with poorer development--at the first, second, and dominant rhythms, as well as lower overall power of the power spectrum, were found for CE fetuses. Pearson correlations showed significant negative correlations between the amount of maternal cigarette smoking during the first trimester of pregnancy and measures of fetal HRV and power of spectral peaks. CONCLUSIONS: Results show that CE fetuses have lower HRV and disrupted temporal organization of autonomic regulation before effects of parturition, postnatal adaptation, and possible nicotine withdrawal contributes to differences in infant neurobehavioral function.     

Patterns of neural activity associated with differential acute locomotor stimulation to cocaine and methamphetamine in adolescent versus adult male C57BL/6J mice

Adolescence is a time period when major changes occur in the brain with long-term consequences for behavior. One ramification is altered responses to drugs of abuse, but the specific brain mechanisms and implications for mental health are poorly understood. Here, we used a mouse model in which adolescents display dramatically reduced sensitivity to the acute locomotor stimulating effects of cocaine and methamphetamine. The goal was to identify key brain regions or circuits involved in the differential behavior. Male adolescent (postnatal day (PN), 30–35) and young adult (PN, 69–74) C57BL/6J mice were administered an i.p. injection of cocaine (0, 15, 30 mg/kg) or methamphetamine (0, 2, 4 mg/kg) and euthanized 90 min later. Locomotor activity was monitored continuously in the home cage by video tracking. Immunohistochemical detection of Fos protein was used to quantify neuronal activation in 16 different brain regions. As expected, adolescents were less sensitive to the locomotor stimulating effects of cocaine and methamphetamine as indicated by a rightward shift in the dose response relationship. After a saline injection, adolescents showed similar levels of Fos as adults in all regions except the dorsal caudate (CPuD) and lateral caudate (CPuL) where levels were lower in adolescents. Cocaine and methamphetamine dose dependently increased Fos in all brain regions sampled in both adolescents and adults, but Fos levels were similar in both age groups for a majority of regions and doses. Locomotor activity was correlated with Fos in several brain areas within adolescent and adult groups, and adolescents had a significantly greater induction of Fos for a given amount of locomotor activity in key brain regions including the caudate where they showed reduced Fos under baseline conditions. Future research will identify the molecular and cellular events that are responsible for the differential psychostimulant-induced patterns of brain activation and behavior observed in adolescent versus adult mice.     

Moderate prenatal ethanol exposure in the rat promotes kidney cell apoptosis,nephron deficits,and sex-specific kidney dysfunction in adult offspring

Alcohol during pregnancy can impair fetal development and result in offspring with neurodevelopmental deficits. Less is known about how low to moderate alcohol exposure can affect other organs, such as the kidney. Here, the effects of moderate ethanol exposure throughout pregnancy on kidney development were examined using a rat model. Rats were fed a liquid diet containing 6% ethanol (vol/vol) or control (0% ethanol) throughout pregnancy. Kidneys were collected at embryonic day (E) 20 or postnatal day (PN) 30 and total glomerular (nephron) number determined using unbiased stereology. Kidney function was examined in offspring at 8 and 19 months. At E20, fetuses exposed to ethanol had fewer nephrons with increased apoptosis. Alcohol exposure caused kidney dysregulation of pro- (Bax) and anti- (Bcl-2) apoptotic factors, and reduced expression of the cell proliferation marker, Ki67. Prenatal alcohol decreased expression of Gdnf and Tgfb1, important regulators of branching morphogenesis, in male fetuses. At PN30, kidney volume and nephron number were lower in offspring exposed to prenatal alcohol. Urine flow and osmolality were normal in offspring exposed to alcohol however sodium excretion tended to be lower in females prenatally exposed to alcohol. Findings suggest exposure to moderate levels of alcohol during pregnancy results in impaired kidney development and leads to a permanent nephron deficit. Although the impact on adult kidney function was relatively minor, these data highlight that even at moderate levels, alcohol consumption during pregnancy can have deleterious long-term outcomes and should be avoided.     

Maternal allergy acts synergistically with cigarette smoke exposure during pregnancy to induce hepatic fibrosis in adult male offspring

Maternal environmental exposures during pregnancy are known to affect disease onset in adult offspring. For example, maternal asthma exacerbations during pregnancy can worsen adult asthma in the offspring. Cigarette smoking during pregnancy is associated with future onset of cardiovascular disease, obesity and diabetes. However, little is known about the effect of maternal environmental exposures on offspring susceptibility to liver disease. This pilot study examined the long-term effect of maternal allergen challenge and/or cigarette smoking during pregnancy on hepatic inflammation and fibrosis in adult mouse offspring. Ovalbumin (OVA) or phosphate-buffered saline (PBS)-sensitized/challenged CD-1 dams were exposed to mainstream cigarette smoke (MCS) or filtered air from gestational day 4 until parturition. Eight weeks postnatally, offspring were sacrificed for comparison of hepatic histology and mRNA expression. Adult male offspring of OVA-sensitized/challenged dams exposed to MCS (OSM) displayed significantly increased liver fibrosis (9.2% collagen content vs. <4% for all other treatment groups). These mice also had 1.8-fold greater collagen 1A1 mRNA levels. From the results here, we concluded that maternal allergen challenge in combination with cigarette smoke exposure during pregnancy may be an important risk factor for liver disease in adult male offspring.     

Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: implications for schizophrenia

Prenatal exposures to a variety of infections have been associated with an increased incidence of schizophrenia. We have reported that a single injection of the synthetic cytokine releaser PolyI:C to pregnant mice produced offspring that exhibited multiple schizophrenia-related behavioral deficits in adulthood. Here, we characterized the effect of maternal inflammation during fetal brain development on adult limbic morphology and expression of GABAA-receptors. The PolyI:C treatment did not induce morphological abnormalities but resulted in a significant increase in GABAA receptor subunit alpha2 immunoreactivity (IR) in the ventral dentate gyrus and basolateral amygdala in adult treated compared to control subjects. Correlative analyses between the a2 subunit IR in the ventral dentate gyrus and the performance in the prepulse inhibition paradigm revealed a significant correlation in controls that was however absent in the pathological condition. These results suggest that prenatal immune activation-induced disturbances of early brain development result in profound alterations in the limbic expression of GABAA receptors that may underlie the schizophrenia-related behavioral deficits in the adult mice.     

Maternal allergen immunization during pregnancy in a mouse model reduces adult allergy-related antibody responses in the offspring

BACKGROUND: The immune status and allergen exposure of the mother may influence the immune response in the offspring after birth. This relationship may be important both for allergen avoidance strategies and, alternatively, for allergy prophylaxis by allergen exposure of the mother. OBJECTIVE: The aim of the present study was to investigate the effect of allergen immunization of the mother during pregnancy and postpartum, in relation to the allergy-related immune response (IgE) and the non-allergy-related (IgG2a) response in the offspring. METHODS: Pregnant NIH/OlaHsd females were immunized three times during pregnancy and one time postpartum with ovalbumin and the adjuvant Al(OH)3, and the offspring's ovalbumin-specific IgE, IgG1 and IgG2a responses were measured after challenge with the same allergen as young adults. Ovalbumin-specific IgE, IgG1 and IgG2a responses were also analysed in offspring of NIH/OlaHsd females immunized once at different times during pregnancy: about 3 days into pregnancy, mid-pregnancy (10 days into pregnancy) and about 4 days before giving birth (17 days into pregnancy). RESULTS: Allergen immunization of mother during pregnancy and postpartum significantly reduced the IgE response in the progenies, whereas the IgG2a response to the same allergen was increased. Allergen immunization of the mother 3 days into pregnancy resulted in a significantly lower IgE response in offspring compared with the response in offspring of non-immunized mothers and in offspring of mothers immunized 17 days into pregnancy. CONCLUSIONS: Maternal allergen immunization might favour selection for an allergen-specific Th1-dependent antibody response in the offspring. Our results indicate that IgE suppression is stronger after maternal allergen exposure during early pregnancy than after exposure in late pregnancy.     

孕期非那雄胺暴露致子代雄性小鼠生殖器官发育异常

目的:探讨孕期非那雄胺暴露对子代雄性小鼠生殖器官发育的影响。方法:CD-1小鼠在受孕后0～17 d给予非那雄胺处理,通过宏观观察、解剖分析与组织形态学染色观察子代雄性小鼠生殖器官的发育情况;通过免疫荧光染色分析子代雄性小鼠精子发生情况。结果:宏观观察结果显示,孕期非那雄胺暴露可导致子代雄性小鼠外生殖器官畸形,表现为阴囊未完全融合及阴茎畸形;此外,还观察到小鼠肛门与生殖器的距离显著缩短(P<0.01)。解剖分析结果显示,孕期非那雄胺暴露可导致子代雄性小鼠睾丸不同程度的不完全下降及长度显著缩短(P<0.01)。组织形态学结果显示,各阶段阴茎长度均显著缩短(P<0.01);睾丸生精小管密度和生精小管管腔成熟精子数均显著降低(P<0.01),生精小管管腔和睾丸间质间隙均显著增大(P<0.01)。免疫荧光染色结果显示,睾丸中支持细胞、睾丸间质细胞和精原细胞的密度均显著降低(P<0.01);生精小管细胞的caspase-3荧光强度显著增加(P<0.01),Ki67与沙漠刺猬因子(desert hedgehog,Dhh)荧光强度均显著降低(P<0.01...     

Prenatal ethanol exposure attenuates GABAergic inhibition in basolateral amygdala leading to neuronal hyperexcitability and anxiety-like behavior of adult rat offspring

Prenatal exposure to a relatively high-dose ethanol (EtOH) caused anxiety-like behavior of adult male rat offspring. Previous studies have demonstrated that GABA system in the basolateral amygdala complex (BLA) is involved in the pathogensis of anxiety-related disorders. The role of GABAergic system in the BLA was investigated in anxiety-like behavior evoked by prenatal EtOH exposure. The infusion of midazolam (MDZ), a positive modulator of GABA_A receptor, into the BLA prevented anxiety-like behavior in EtOH-offspring without affecting the corresponding behavior of control offspring. The data suggest that anxiety-like behavior could be causally related to increased neuronal excitability attributable to depressed GABAergic inhibition in the BLA. To test this hypothesis, evoked potential was studied using brain slices from EtOH-offspring. Potential evoked in the BLA by single stimuli applied to external capsule showed multispike responses, indicative of GABAergic disinhibition. These multiple responses were no longer evident after the perfusion with MDZ. In the slices from EtOH-offspring, paired-pulse inhibition (GABA_A-dependent) was suppressed. Also, in EtOH-offspring, long-term potentiation (LTP) was induced by a single train of high frequency stimulation, which did not induce LTP in control rats. Moreover, MDZ pretreatment prevented the facilitating effect of EtOH on LTP induction. The data provide the functional evidence that prenatal EtOH exposure attenuates GABAergic inhibition in the BLA resulting in neuronal hyperexcitability and anxiety-like behavior of adult rat offspring.     

Prenatal endotoxin exposure alters behavioural pain responses to lipopolysaccharide in adult offspring

Evidence suggests that exposure to bacterial endotoxin in early life can alter the production of pro-inflammatory cytokines in later life. This phenomenon may have significant consequences for pain and pain related behaviours as pro-inflammatory cytokines heighten pain sensitivity. This association has yet to be examined. As such, the aim of the present study was to characterize pain behaviours in adult rat offspring following prenatal endotoxin (PE) exposure. Pregnant F344 rats received endotoxin (200 µg/kg, s.c.) or saline on gestational days 16, 18 and 20. Pain thresholds were assessed in the adult PE offspring (n = 23) and control offspring (n = 24) prior to and 4 h following administration of lipopolysaccharide (LPS; 100 µg/kg, s.c.). Three assays of pain were employed — the hot plate, tail immersion and von Frey tests. Results demonstrated sex-specific effects of prenatal endotoxin on the offspring, with PE males displaying unaltered pain thresholds on the von Frey test post-LPS administration (p < 0.01), while male control offspring (n = 24) displayed the expected hyperalgesia. Male PE offspring also displayed increased pain thresholds on the tail immersion test (p < 0.01), while no change in pain sensitivity was observed in control males following LPS exposure. No difference in response was observed between the female PE and control offspring on the von Frey test, however PE female offspring displayed increased thresholds on the tail immersion test compared to baseline — an effect not observed in the control female offspring. Pain sensitivity on the hot plate test was unaffected by prenatal exposure to endotoxin. These data suggest that prenatal exposure to products associated with bacterial infection have the capacity to alter pain responses, which are evident in the adult offspring.     

Open-field behavior in rats exposed prenatally to a low intensity-low frequency, rotating magnetic field

Two experiments were conducted to study the behavioral effects of prenatal exposure to a low intensity, ultra-low-frequency magnetic field. In Experiment I, 117 albino rats that had been exposed continuously during their prenatal development to a 3 to 30 gauss, 0.5 Hz rotating magnetic field (RMF), and 83 control rats that had been exposed renatally to control conditions, were tested in an open field at 21 to 25 days of age. RMF-exposed animals traversed significantly fewer squares than their controls in the open field (p < .001), but defecated significantly more in that situation (p < .001). RMF-exposed males also traversed significantly fewer squares than the RMF-exposed females (p < .05). Three RMF-exposed litters that were nursed by control mothers did not differ significantly in open-field activity from the pups in the 4 RMF-exposed litters from which they were taken at birth. In Experiment 2, in which the experimenters did not know whether the subject was a RMF-exposed rat or a control rat, 19 RMF-exposed rats again traversed significantly fewer squares than the 20 control rats (p < .01).     

The association between maternal cocaine use during pregnancy and physiological regulation in 4- to 8-week-old infants: an examination of possible mediators and moderators

OBJECTIVE: To examine the association between maternal cocaine use during pregnancy and physiological measures of regulation, which included heart rate (HR) and respiratory sinus arrhythmia (RSA). METHODS: Potential mediators and moderators of this association were explored. Participants were 141 mother-infant dyads (77 cocaine exposed and 64 nonexposed) recruited at birth. Average infant HR and RSA was assessed at 4-8 weeks of age during a 15 minute period of sleep. RESULTS: Results indicated a dose-dependent effect of prenatal exposure to cocaine on RSA. There was no evidence that fetal growth or other prenatal exposure to substances mediated this association or that fetal growth or maternal age moderated this association. Regression analyses also indicated that birth weight (BW), but not birthlength (BL), head circumference (HC) or other substance use, mediated the association between prenatal exposure to cocaine and heart rate. CONCLUSIONS: These results suggest that cocaine exposure is associated with physiological regulation at 4-8 weeks of age and highlight the importance of considering level of exposure when assessing infant outcomes.     

Effect of maternal weight during pregnancy on offspring muscle strength response to resistance training in late adulthood

Purpose

Maternal obesity can unfavorably influence offspring body composition, muscle strength, and possibly muscle’s adaptability to training, but the human studies are scarce. Therefore, we aimed to investigate the effect of maternal obesity on offspring muscle strength responses to resistance training intervention in elderly frail women.

Psychosocial maternal stress during pregnancy affects serum corticosterone, blood immune parameters and anxiety behaviour in adult male rat offspring

Exposure to prenatal stress can impair the behavioural and hormonal development in mammals. However, the consequences for the immune system are rarely investigated and there is only limited evidence that naturalistic prenatal stressors do also have the potential to affect the offspring. Thus, by using a social conflict model in female Long-Evans rats, we investigated the effects of prenatal social stress on several behavioural, hormonal and immunological parameters. Offspring from stressed and non-stressed pregnant females were housed in pairs after weaning, and tested at an age of 4-6 months. Prenatally stressed (PS) males were more active in the elevated plus-maze test as indicated by significantly more frequent entries into the open arms compared to prenatal control males (PC). In addition, PS males had significantly lower serum corticosterone concentrations under basal conditions as well as after ACTH-challenge. The basal number of total leukocytes was significantly lower in the PS group due to significantly lower lymphocyte counts. In particular, the CD4+ T-helper cell subset was affected. The lymphocyte proliferation to pokeweed mitogen was lower in PS males. Because some of the present findings do not correspond to previous studies using conventional stressors, we assume that the nature of the stressor plays an important role for pregnancy outcome and behaviour and physiology of the offspring in later life.     

Deficiency of SHP1 leads to sustained and increased ERK activation in mast cells, thereby inhibiting IL-3-dependent proliferation and cell death

SHP-1 plays an important role for the regulation of signaling from various hematopoietic cell receptors. In this study, we examined IL-3-induced cell proliferation and IL-3 depletion-induced apoptosis in bone marrow-derived mast cells (BMMC) established from motheaten (me) that lack SHP-1 expression, viable motheaten (me^v) expressing phosphatase-deficient SHP-1, and wild-type (WT) mice. When BMMC were stimulated with IL-3, increased ERK activation was evident in resting state and sustained in me-BMMC relative to WT-BMMC. ERK is known to be involved in the regulation of cell proliferation and apoptosis in some cells. In accordance with sustained ERK activation, apoptosis was decreased in me- and me^v-BMMC compared with WT-BMMC. In contrast to the predicted role of ERK as a pro-survival molecule, IL-3-induced cell proliferation was much lower in me- and me^v-BMMC than WT-BMMC. Stimulation with lower concentration of IL-3 or addition of PD98059, a MEK inhibitor, to the culture resulted in the suppression of decreased apoptosis and cell proliferation in me- and me^v-BMMC. Collectively, these results suggest that SHP-1 positively regulates IL-3-dependent mast cell proliferation and apoptosis by inhibiting ERK activity through its phosphatase activity. Furthermore, our results indicate that ERK would act as a negative regulator for cell proliferation and induce apoptosis when its activity is highly increased.