Marie Pometlová

Postnatal development of rat pups is altered by prenatal methamphetamine exposure

There are studies showing that drug abuse during pregnancy may have impairing effect on progeny of drug-abusing mothers. Methamphetamine (MA) is one of the most common illicit drugs throughout the world. The purpose of the present study was to assess the effect of prenatal MA exposure on postnatal development of rat pups before the time of separation from their mothers. Female rats were injected with MA (5 mg/kg daily) for the duration of their pregnancy. Pups were then tested throughout the lactation period. They were weighed daily and the ano-genital distance was measured on postnatal day (PD) 1. Development of postural motor reaction was tested by righting reflex on surface between PD 1 and 12, and righting reflex in mid-air after PD 12 until successfully accomplished. On PD 15 homing test was examined as a test of pup acute learning. On PD 23 sensory-motor coordination was examined using the rotarod and bar-holding tests. Additionally, the markers of physical maturation, such as eye opening, testes descent in males and vaginal opening in females were also recorded. The birth weight in prenatally MA-exposed pups was lower than in controls or saline-exposed pups regardless of sex. There were no changes induced by prenatal MA exposure in weight gain or in sexual maturation. In righting reflexes, we demonstrated that pups exposed prenatally to MA were slower in righting reflex on surface and that they accomplished the test of righting reflex in mid-air later than controls or saline-exposed pups. The performance of homing test was not affected by prenatal drug exposure. The sensory-motor coordination was impaired in prenatally MA-exposed pups when testing in the rotarod test. Also, the number of falls in the bar-holding test was higher in MA-exposed pups than in controls. There were no sex differences in any measures. Thus, the present study demonstrated that prenatal MA exposure impairs development of postural motor movements of rat pups during the first 3 weeks after birth, while not affecting physical or sexual maturation.

Age-specific N-methyl-D-aspartate-induced seizures: perspectives for the West syndrome model.

Summary: Purpose: With intraperitoneal N‐methyl‐D‐aspartate (NMDA; 15–200 mg/kg) administration, we attempted to develop an animal model of age‐specific West syndrome to serve for testing of putative anticonvulsant drugs and to determine the mechanisms of this disorder.

Prenatal morphine exposure differentially alters learning and memory in male and female rats.

The present study tested the hypothesis that exposure to morphine on prenatal days 11-18 impairs performance on tasks requiring learning and memory in adult male and female rats. In Experiment 1, a symmetrical maze was used to measure learning. In Experiment 2, an eight-arm radial maze was used to assess working spatial memory. The results of Experiment 1 demonstrated that prenatal morphine exposure reduces the time needed to complete the trials, but does not affect the accuracy of performance in male rats. In contrast, prenatal drug treatment had no effects on either the time or the accuracy of performance in female rats. In Experiment 2, both male and female morphine-exposed rats needed more time to complete regular trials (no delay) than controls; however, morphine exposure in male rats did not affect performance on tasks requiring memory, measured with delay trials, but hindered it in ovariohysterectomized (OVX) female rats. In OVX females, replacement injections of both estrogen and progesterone restored the impairment of performance on delay trials produced by prenatal morphine exposure. Thus, the present study demonstrates that prenatal morphine exposure differentially alters performance of adult male and female rats on tasks requiring learning and spatial memory.

Effect of methamphetamine exposure and cross-fostering on sensorimotor development of male and female rat pups

The present study tested the hypothesis that cross-fostering influences the development of rat pups. Mothers were exposed daily to injection of methamphetamine (M) (5 mg/kg) or saline for 9 weeks: 3 weeks prior to impregnation, throughout gestation and lactation periods. Control females animals without any injections were used. On postnatal day (PD) 1, pups were cross-fostered so that each mother received four pups of her own and eight pups from the mothers with the other two treatments. Offspring were tested for sensorimotor development in preweaning period by using tests of: negative geotaxis, tail pull, righting reflexes, rotarod and bar-holding. Further, the pups were weighed daily. Our results showed that birth weight in prenatally M-exposed pups was lower than in control or saline-exposed pups. Prenatally M-exposed pups gained less weight than control or saline-exposed pups regardless of postnatal treatment and sex. Further, our data demonstrated that prenatal and postnatal M exposure impairs sensorimotor functions in most of the tests. On the other hand, the negative effect of prenatal M exposure was partially suppressed in prenatally M-exposed pups by cross-fostering to control dams. Our hypothesis that cross-fostering may affect postnatal development of pups was confirmed.

The effect of methamphetamine on social interaction of adult male rats

The effect of psychostimulants on social behavior still remains unclear. Therefore the aim of the present study was to assess the effect of low doses of methamphetamine (MA) on social interaction (SI) in adult male rats. Rats were tested in three environmental conditions: (1) dimly lit, familiar environment, (2) dimly lit, unfamiliar environment and (3) intensely lit, unfamiliar environment considered to be low, middle and high stress, respectively. In each condition different set of animals was used. Rats were always divided into five groups. Control (without injection), saline (with 1 ml/kg saline injection) and three MA groups (doses: 0.5, 1 and 1.5mg/kg). Injections were applied 30 min prior to testing. Always a pair of unfamiliar rats of the same treatment group was tested. Their behavior was video recorded for 5 min in an open field. Times spent by SI (following, climbing, genital investigation, etc.) and non-social behavior (locomotion, rearing) were analyzed using a two-way ANOVA (drug treatment x stress condition). Our data demonstrate that all doses of MA, reduced SI. In addition, the unfamiliarity of the arena increased exploratory behavior (locomotion and rearing) in all treatment groups, while the SI was affected by the environmental condition only in controls or saline-treated rats, but not in MA-treated groups. In conclusion, our data demonstrate that MA administration impairs SI in dose- and stress condition-specific manner, however, some of our results may be due to increase locomotion and rearing induced by MA.

Responsiveness to methamphetamine in adulthood is altered by prenatal exposure in rats

Methamphetamine (MA) is a drug causing potent psychomotor activation. The aim of the present study was: (1) to assess the effect of prenatal and acute MA administration on behavior in adult male rats and (2) to find out if the prenatal exposure to MA increases sensitivity to acute MA application in adulthood. Behavior of adult male rats prenatally exposed to MA (5mg/kg) or saline was tested in Open field (OF) and Elevated plus maze (EPM). Subcutaneously administered MA (1mg/kg) or saline were used as challenge in adulthood, 30 min prior to testing. Our results showed that prenatal MA did not have an effect on baseline behavior in either of the tests. By contrast, acute MA increased overall psychomotor activity by increasing locomotion and exploratory behavior and decreasing comforting behavior. Moreover, adult rats prenatally exposed to MA exhibited increased sniffing and decreased rearing after acute MA dose in adulthood relative to prenatally saline-exposed rats. In addition, while acute MA application decreased anxiety in rats prenatally exposed to MA, rats prenatally exposed to saline were less sensitive to the anxiolytic effects of MA. Our results indicate that changes caused by prenatal exposure to psychostimulants may become apparent as different reactivity to drugs of abuse when an individual encounters them later in life. In addition, we found that the anxiolytic effect of acute MA (1mg/kg) probably depends also on the reactivity to stress and the activity of hypothalamo-pituitary-adrenal axis.

Sex differences in social interaction of methamphetamine-treated rats.

Our previous study showed that single injection of methamphetamine decreases social interaction (SI) in a dose-dependent manner that was further affected by stressful environment conditions. The aim of this study was to examine the effect of methamphetamine and its interaction with gonadal hormones on SI. Adult male and female rats were gonadectomized and assigned to testosterone-treated and oil-treated groups in male rats and estradiol-treated and oil-treated groups in female rats, respectively. Hormones were administered 30 min before each habituation in the open field. All four hormonal groups were further divided to control (without injection), saline (1 ml/kg saline injection), and methamphetamine (1 mg/kg) groups. Injections were applied 30 min before the SI test. The total duration and the total number of SI and nonsocial behavioral patterns were assessed. This study showed that an acute methamphetamine administration in a dose of 1 mg/kg decreased different types of SI in both sexes. In contrast, the same dose of methamphetamine increased locomotion and rearing behavior in male and female rats. The frequency and/or duration of SI (especially mutual sniffing and allogrooming) was lower in adult female rats relative to gonadectomized male rats, but locomotion was increased in female relative to male rats regardless of the presence or absence of gonadal hormones. In conclusion, this study is novel especially because it examines SI in both sexes in relation to the presence or absence of gonadal hormones.

Do the effects of prenatal exposure and acute treatment of methamphetamine on anxiety vary depending on the animal model used

The aim of the present study was an evaluation of prenatal exposure to acute methamphetamine (MA) treatment on manifestations of anxiety. Anxiety was evaluated in adult animals in three different experimental models: the Elevated plus-maze (EPM), Social interaction test (SIT) and Ultrasound vocalization (USV). Female rats were administered saline (S) or MA (5 mg/kg) daily throughout their entire gestation period. The male progeny, in adulthood, were administered with challenge dose of S or MA (1 mg/kg) prior to evaluation of anxiety. The study demonstrated that prenatal MA exposure increased the anxiogenic effect on evaluated behaviour patterns in the USV model and to a lesser degree in the EPM model. In addition, the acute MA challenge in adulthood decreased the time spent during social interaction suggesting an anxiogenic effect in the SIT model as well. On the other hand, some of the evaluated parameters (e.g. the number of head-dipping in the EPM and number of dropped boluses in the SIT) also suggest MA-induced anxiolytic effects. Sensitization to a MA challenge was apparent in several parameters of the EPM (e.g. increased number of entries to the closed arms, increased stretched attend postures and increased approach-avoid conflicts) and SIT (total social interaction and following). The present data demonstrate that prenatal MA exposure and adult challenge of the same drug have diverse effects on animal behaviour that depends on the type of anxiety model used.

Effect of methamphetamine exposure and cross-fostering on cognitive function in adult male rats.

The aim of our study was to examine the effect of prenatal methamphetamine (MA) exposure and cross-fostering on cognitive functions of adult male rats tested in Morris water maze (MWM). Rat mothers were exposed daily to injection of MA (5mg/kg) or saline for 9 weeks: prior to impregnation, throughout gestation and lactation periods. Females without any injections were used as an absolute control. On postnatal day 1, pups were cross-fostered so that each mother raised 4 pups of her own and 8 pups from the mothers with the other two treatments. Four types of tests were used: (1) Place navigation test (Learning), (2) Probe test (Probe), (3) Retention memory test (Memory) and (4) Visible platform task. Our results demonstrate that the prenatal exposure to MA does not impact learning and memory, while postnatal exposure to MA shows impairments in cognition. In the test of learning, all animals fostered to MA-treated dams had longer latencies, bigger search error and used lower spatial strategies than the animals fostered to control or saline-treated mother, regardless of prenatal exposure. Regardless of postnatal exposure, the animals prenatally exposed to saline swam faster in all the tests than the animals prenatally exposed to MA and controls, respectively. This study indicates that postnatal but not prenatal exposure to MA affects learning in adult male rats. However, it is still not clear whether these impairments are due to a direct effect of MA on neuronal structure or due to an indirect effect of MA mediated by impaired maternal care.

Does Prenatal Methamphetamine Exposure Induce Cross-sensitization to Cocaine and Morphine in Adult Male Rats?

The aim of the present study was to examine the cross-sensitization induced by prenatal methamphetamine (MA) exposure to challenge dose of cocaine or morphine. Rat mothers received a daily injection of MA (5 mg/kg) or saline throughout the gestation period. Adult male offspring (prenatally MA- or saline-exposed) were divided to groups with challenge doses of saline (1 ml/kg), cocaine (5 mg/kg) or morphine (5 mg/kg). Behavior in unknown environment was examined in Laboras, nociception in Plantar test, and active drug-seeking behavior in conditioned place preference (CPP). Our data demonstrate that cocaine increased the exploratory activity in Laboras test in prenatally saline-exposed, but decreased it in prenatally MA-exposed rats. An analgesic effect of cocaine was demonstrated only by the tail withdrawal and it was independent of the prenatal drug exposure. CPP test showed that prenatal MA exposure induced rather tolerance than sensitization to cocaine. In contrast to cocaine effects, morphine decreased rearing activity in both, prenatally MA-exposed and saline-exposed rats, and locomotion only in prenatally MA-exposed rats in the Laboras. In the Plantar test, the results demonstrated that morphine had an analgesic effect in prenatally saline-exposed rats but this effect was suppressed in prenatally MA-exposed rats. In the CPP test morphine induced drug-seeking behavior, which however was not affected by prenatal drug exposure. Thus, our data demonstrate that there is a cross-effect between prenatal MA exposure and the challenge dose of other drug in adulthood, however drug-seeking behavior is not increased by prenatal MA exposure as we expected.