An overview of the methamphetamine effect on male sexual behavior and reproductive system.

Drug addiction and its effect on the behavior and development of children has become a serious problem in our society. Methamphetamine (MA) is one of the most abused psychostimulants in the Czech Republic, and its abuse is rising worldwide. Previous studies have demonstrated the adverse long-term effects of maternal drug abuse on rat offspring. However, the father's contribution as a parent and donor of half of the genetic information is unclear. Previous studies of other psychostimulant drugs indicate that long-term application of MA to adult male rats may induce changes in their reproductive system and lead to changes in rat pup functional and behavioral development. Therefore, the present review aimed to investigate the effect of MA administration on reproductive toxicity and sexual behavior of adult male rats, as well as the impact of paternal MA exposure on behavioral development and locomotor activity in rat offspring.

Levels of BDNF and NGF in adolescent rat hippocampus neonatally exposed to methamphetamine along with environmental alterations.

Neurotrophins are proteins included in development and functioning of various processed in mammalian organisms. They are important in early development but as well as during adulthood. Brain - derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been previously linked with many psychiatric disorders such as depression and addiction. Since during postnatal development, brain undergoes various functional and anatomical changes, we included preweaning environment enrichment (EE), since enrichment has been linked with improved function and development of the several brain structure such as hippocampus (HP), in which we monitored these changes. On the other hand, social isolation has been linked with depression and anxiety-like behavior, therefore postweaning social isolation has been added to this model as well and animal were exposed to this condition till adolescence. We examined if all these three factors had impact on BDNF and NGF levels during three phases of adolescence - postnatal days (PDs) 28, 35 and 45. Our results show that EE did not increase BDNF levels neither in control or MA exposed animals and these results are similar for both direct and indirect exposure. On the other side, social separation after weaning did reduce BDNF levels in comparison to standard housing animals but this effect was reversed by direct MA exposure. In terms of NGF, EE environment increased its levels only in indirectly exposed controls and MA animals during late adolescence. On the other hand, social separation increased NGF levels in majority of animals.

Methamphetamine, neurotransmitters and neurodevelopment.

Methamphetamine (MA), as massively abused psychoactive stimulant, has been associated with many neurological diseases. It has various potent and neurotoxic properties. There are many mechanisms of action that contribute to its neurotoxic and degenerative effects, including excessive neurotransmitter (NEU) release, blockage of NEU uptake transporters, degeneration of NEU receptors, process of oxidative stress etc. MA intoxication is caused by blood-brain barrier disruption resulted from MA-induced oxidation stress. In our laboratory we constantly work on animal research of MA. Our current interest is to investigate processes of MA-induced alteration in neurotransmission, especially during development of laboratory rat. This review will describe current understanding in role of NEUs, which are affected by MA-induced neurotoxicity caused by altering the action of NEUs in the central nervous system (CNS). It also briefly brings information about NEUs development in critical periods of development.

Does paternal methamphetamine exposure affect the behavior of rat offspring during development and in adulthood?

Methamphetamine (MA) is one of the most abused psychostimulants in the Czech Republic and worldwide. Previous studies have demonstrated the adverse effects of maternal drug abuse. However, the father's contribution as a parent and donor of the half genetic information is unclear. The present study aimed to examine the effect of paternal MA exposure on behavioral development and locomotor activity in rat offspring. MA was administrated subcutaneously for 30 days at a dose of 5 mg/kg to adult male rats. The impact of paternal MA exposure on rat pups was investigated using behavioral tests during development and locomotor activity tests in adulthood. Prior to testing, adult offspring were exposed to an acute challenge dose of MA (1 mg/kg) to examine the possible sensitizing effect of the paternal treatment. Our results found no significant differences in behavioral development or locomotor activity in adulthood of offspring linked to paternal MA application. These results differ from the effects induced by maternal MA application. Further, our results demonstrated a significant increase in locomotor activity on the Laboras test after acute MA application. When comparing sex differences, females showed more activity than males in adulthood, whereas males were more active during development.

Can prenatal methamphetamine exposure be considered a good animal model for ADHD?

Attention-deficit/hyperactivity disorder (ADHD) is a mental disorder with a heterogeneous origin with a global incidence that continues to grow. Its causes and pathophysiological mechanisms are not fully understood. It includes a combination of persistent symptoms such as difficulty in concentration, hyperactivity and impulsive behavior. Maternal methamphetamine (MA) abuse is a serious problem worldwide, it can lead to behavioral changes in their offspring that have similarities with behavioral changes seen in children with ADHD. There are several types of ADHD animal models, e.g. genetic models, pharmacologically, chemically and exogenously induced models. One of the exogenously induced ADHD models is the hypoxia-induced model. Our studies, as well as those of others, have demonstrated that maternal MA exposure can lead to abnormalities in the placenta and umbilical cord that result in prenatal hypoxia as well as fetal malnutrition that can result in irreversible changes to experimental animals. Therefore, the aim the present study was to compare the cognitive impairments in MA exposure model with those in established model of ADHD - prenatal hypoxia model, to test whether MA exposure is a valid model of ADHD. Pregnant Wistar rats were divided into four groups based on their gestational exposure to MA: (1) daily subcutaneous injections of MA (5 mg/kg), (2) saline injections at the same time and volume, (3) daily 1-hr hypoxia (10 % O2), and (4) no gestational exposure (controls). Male rat offspring were tested for short-term memory in the Novel Object Recognition Test and the Object Location Test between postnatal days 35 and 40. Also their locomotor activity in both tests was measured. Based on the present results, it seems that prenatal MA exposure is not the best animal model for ADHD since it shows corresponding symptoms only in certain measures. Given our previous results supporting our hypothesis, more experiments are needed to further test possible use of prenatal MA exposure as an animal model of the ADHD.

Methamphetamine exposure during the first, but not the second half of prenatal development, affects social play behavior.

Methamphetamine (MA), as a psychostimulant drug that crosses the placental barrier, may disrupt the development of social play. The present study aims to examine the effect of prenatal MA (5 mg/kg) exposure during the first (gestational day (GD) 1-11) or second (GD 12-22) halves of prenatal development of rats on social play behavior. To investigate an acute effect of MA on social play in adulthood, juvenile rats were exposed to a dose of 1 mg/kg MA or saline on the test day and tested for social play for 15 min. Prenatal exposure to MA during GD 1-11 increased social play behavior during 5-10 min interval of the test in males but not females. Prenatal MA during GD 12-22 did not influence social play in males nor females. However, social play occurred to a greater extent in GD 12-22 groups compared with GD 1-11. Acute exposure to MA eliminated playful behavior in all groups and decreased social exploration in GD 1-11. Our results suggest that manipulation of prenatal development during the first half of the gestational period has a greater impact on social play behavior than during the second half.

Review of long-term consequences of maternal methamphetamine exposure.

Methamphetamine is one of the most abused hard drugs in the Czech Republic. Its popularity is high not only in Eastern Bloc of Europe but is growing in other countries around the world, including the United States. In addition, methamphetamine abuse increases in drug addicts during pregnancy. Although research into the long-term effects of prenatal methamphetamine exposure has been ongoing for many years, the exact mechanism of action and factors that may influence the effect of this drug are still not fully understood. There have been many studies that investigated the effects of addictive substances on the behavior and cognitive function of individuals during adolescence. Some studies have shown prenatal or perinatal influences, e.g. drugs, stress, hypoxia, and malnutrition, can affect drug sensitivity or drug-seeking behavior in adulthood. However, when these factors are most impactful, i.e. prenatal vs. perinatal, and which stages of the prenatal and perinatal periods are the most sensitive to these factors is not yet clear. Our laboratory specializes in research on the effects of drugs (especially methamphetamine) on rat mothers and their offspring during postnatal development, adolescence, and adulthood. This review summarizes our past results on the long-term effects of methamphetamine on the mother and her offspring, its mechanism of action, the role of maternal care, the possible emergence of long-term sensitization, and the critical neurodevelopmental periods for methamphetamine exposure.

Effect of methamphetamine exposure on sexual behavior and locomotor activity of adult male rats.

Drug addiction and its consequences on social life and behavior is currently a worldwide problem. Methamphetamine (MA) is one of the most abused psychostimulants in the Czech Republic. MA elevates mood, increases concentration, reduces appetite, and promotes weight loss. However, high doses and long-term abuse can induce psychosis, hallucinations, paranoia, violent behavior, and can lead to cardiovascular problems. Regarding its high prevalence and negative impact on health and social life, MA needs to be fully investigated. Previous studies have demonstrated the impairing effect of MA drug abuse on female behavior. However, MA's influence on male sexual behavior is not entirely clear. The aim of this study was to examine the effect of MA exposure on sexual behavior and spontaneous locomotor activity of adult male rats. MA was administrated subcutaneously at a dose of 5 mg/kg daily for a period of 30 days. The control group was exposed to saline (SA) at the same time and same volume. At the end of the application period, exposed male rats were paired with non-treated female rats, and their behavior was recorded for 2 h. Sexual mating behavior was described in terms of mounting frequency, intromission frequency, ejaculation frequency, sniffing time, intromission latency and the post-ejaculatory interval. Spontaneous locomotor activity in postnatally exposed male rats was studied using the Laboras apparatus. Acute doses of MA (1 mg/kg) or SA were administrated to probe the sensitizing effect of previous chronic MA exposure. Afterward, the animal was placed in an unknown environment and monitored for 1 h. Behavior was automatically evaluated using Laboras software by analyzing the following parameters: duration of locomotion (s), duration of immobility (s), rearing (vertical exploratory behavior), time spent grooming (s), average speed (mm/s), and distance traveled (m). Our results indicate that MA administration has a negligible effect on the sexual behavior of adult male rats. However, more experiments have to be performed to examine the influence of MA exposure on spermatogenesis and the behavior of offspring. Data from the Laboras test showed that MA exposure has a significant effect on locomotor activity in both acute as well as subchronic MA application. In conclusion, our results show that administration of MA in adult male rats does not affect sexual performance and motivation but does increase locomotor and exploratory activity in an unknown environment.

ADHD symptoms induced by prenatal methamphetamine exposure.

Methamphetamine is commonly used psychostimulant in the Czech Republic and is often abused by pregnant women. Methamphetamine may cause abnormalities in placenta and umbilical cord that results in hypoxia and malnutrition. ADHD is a mental disorder with a heterogeneous origin. The number of patients suffering from ADHD is growing. The pathophysiological mechanisms causing ADHD have not yet been clarified. There are very few rat models for ADHD and include genetic models, chemically induced models (ethanol, nicotine, PCBs, 6-hydroxydopamine lesion) or environmentally induced models (anoxia). The aim of the present study was to test prenatal methamphetamine exposure (5 mg/kg) as a potential novel animal model for ADHD. We found that adult male offspring prenatally exposed to methamphetamine presented hyperactivity while exploring novel environments. Together with cognition changes found in our previous studies, these might represent symptoms similar to those seen in ADHD. More experiments are planned to investigate our hypothesis.

What is the role of subcutaneous single injections on the behavior of adult male rats exposed to drugs?

Psychostimulants, as well as cannabinoids, have been shown to significantly affect a great variety of behaviors in both humans and laboratory animals. Our previous studies have repeatedly demonstrated that the application of the vehicle for psychostimulants, i.e. saline, to control groups, generated different behavioral test results compared to absolute naive controls (i.e. without any injection). Therefore, our present study has set three goals: (1) to evaluate the effect of three different psychostimulant drugs, (2) to evaluate the effect of three doses of delta 9-tetrahydrocannabinol (THC), and (3) to evaluate the effect of saline and ethanol injections vs sham injections and no injection on spontaneous behavior of adult male rats. The LABORAS test (Metris B.V., Netherlands) was used to examine spontaneous locomotor activity and exploratory behavior in an unknown environment over 1 h. In Experiment 1, psychostimulant drugs were tested: single subcutaneous (s.c.) injections of amphetamine (5 mg/kg), cocaine (5 mg/kg), and 3,4-methylenedioxymethamphetamine (MDMA) (5 mg/kg) were applied prior to testing. Control animals received the same volume (1 ml/kg) of s.c. saline. In Experiment 2, the effect of three doses of THC (1, 2, and 5 mg/kg, s.c.) were examined. An s.c. injection of vehicle (ethanol) was used as a control. In Experiment 3, injections of saline and ethanol were compared to the group receiving a sham s.c. injection and to a group of absolute "naive" controls. Our results demonstrated that (1) all psychostimulants increased locomotion time, distance traveled, and speed while decreasing immobility time of adult male rats relative to saline controls. The most prominent effect was associated with MDMA; (2) The effect of THC was dose-dependent and was most apparent within the first 10 min of the LABORAS test. (3) With regard to the effect of injection: absolute controls (without injection) compared to animals injected with ethanol, saline, or sham-injected displayed reduced immobility time, traveled longer distances, and had increased speed. In conclusion, our data showed drug dependent behavioral changes in adult male rats after application of psychostimulants and cannabinoids. Our findings also suggest that not only drugs but the actual single injection per se also affects the behavior of laboratory animals in an unknown environment. This effect seems to be associated with the acute stress associated with the injection.

Does prenatal methamphetamine exposure induce sensitization to drugs in adulthood?

Behavioral sensitization is defined as augmented psychomotor activity, which can be observed after drug re-administration following withdrawal of repeated drug exposure. It has been shown that abuse of one drug can lead to increased sensitivity to certain other drugs. This effect of developed general drug sensitivity is called cross-sensitization and has been reported between drugs with similar as well as different mechanisms of action. There is growing evidence that exposure to drugs in utero not only causes birth defects and delays in infant development, but also impairs the neural reward pathways, in the brains of developing offspring, in such a way that it can increase the tendency for drug addiction later in life. This review summarizes the results of preclinical studies that focused on testing behavioral cross-sensitization, after prenatal Methamphetamine exposure, to drugs administered in adulthood, with both similar and different mechanisms of action. Traditionally, behavioral sensitization has been examined using the Open field or the Laboras Test to record locomotor activity, and the Conditioned Place Preference and Self-administration test to examine drug-seeking behavior. However, it seems that prenatal drug exposure can sensitize animals not only to the locomotor-stimulating and conditioning effects of drugs, but may also be responsible for modified responses to various drug effects.

Olfactory bulbectomy in methamphetamine-treated rat mothers induces impairment in somatic and functional development of their offspring.

Olfactory bulbectomy in rodents is considered a putative model of depression. Depression is often associated with drug addiction. Our previous studies demonstrated that methamphetamine (MA) administration to rat mothers affects both, mothers and their pups. The aim of the present study was to examine the effect of bulbectomy, as a model of depression, and MA administration on behavior of rat mothers and postnatal development of their pups. Adult female Wistar rats were randomly divided into two groups: bulbectomized (OBX) and sham-operated (SH). A period of 20 days was allowed for the development of the depressive-like phenotype. Animals were tested in the motor activity test and 2 % sucrose preference for anhedonia and hyperactive locomotor response to a novel environment, respectively. After then females were impregnated. Pregnant females were exposed to daily subcutaneous (s.c.) injection of MA (5 mg/kg) or saline (SA) during the entire gestation period. Postnatally, maternal behavior and pup development was examined. The effect of a challenge dose of MA (1 mg/kg, s.c.) on behavior was further examined in adult male offspring. Our results showed no differences in the maternal behavior as a matter of bulbectomy, only OBX rats slept more than all the SH controls. Pups from OBX mothers were born with lower birthweight and gained less weight during the postnatal development than pups from SH controls. Both, bulbectomy and MA administration, delayed the eyes opening. As a matter of functional development of the pups, maternal OBX procedure impaired the performance in the Bar-holding test, but only in saline group. OBX/SA group was the worst in the Bar-holding test relative to all the other groups. In addition, pups from OBX mothers dropped more boluses during the Bar-holding test, suggesting that they were more stressed. In adult male offspring, bulbectomy increased immobility only in the SA/SA group. Prenatal MA exposure increased locomotion, while decreasing immobility. In addition, challenge dose of MA in adulthood increased distance traveled, locomotion, rearing, and average and maximal velocity, while decreasing immobility and grooming. In conclusion, our results suggest that depressive-like phenotype of rat mothers induces impairment in somatic and functional development of their male offspring.

Effects of perinatal stress and drug abuse on maternal behavior and sensorimotor development of affected progeny.

Methamphetamine (MA) is an addictive psychostimulant with significant potential for abuse. Previous rat studies have demonstrated that MA use during pregnancy impairs maternal behavior and induced delayed development of affected pups. The offspring of drug-addictive mothers were often neglected and exposed to neonatal stressors. The present study therefore examines the effect of perinatal stressors combined with exposure to prenatal MA on the development of pups and maternal behavior. Dams were divided into three groups according to drug treatment during pregnancy: controls (C); saline (SA, s.c., 1 ml/kg); MA (s.c., 5 mg/ml/kg). Litters were divided into four groups according to postnatal stressors: controls (N); maternal separation (S); maternal cold-water stress (W); maternal separation plus cold-water stress (SW). The pup-retrieval test showed differences among postnatally stressed mothers and non-stressed controls. The righting reflex on a surface revealed delayed development of pups prenatally exposed to MA/SA and postnatal stress. Negative geotaxis and Rotarod results confirmed that the MA group was the most affected. Overall, our data suggests that a combination of perinatal stress and prenatal MA can have a detrimental effect on maternal behavior as well as on the sensorimotor development of pups. However, MA exposure during pregnancy seems to be the decisive factor for impairment.

Morphine decreases social interaction of adult male rats, while THC does not affect it.

The aim of the present study was to compare effect of three low doses of morphine (MOR) and delta9-tetrahydrocannabinol (THC) on social behavior tested in Social interaction test (SIT). 45 min prior to testing adult male rats received one of the drugs or solvents: MOR (1; 2.5; 5 mg/kg); saline as a solvent for MOR; THC (0.5; 1; 2 mg/kg); ethanol as a solvent for THC. Occurrence and time spent in specific patterns of social interactions (SI) and non-social activities (locomotion and rearing) was video-recorded for 5 min and then analyzed. MOR in doses of 1 and 2.5 mg/kg displayed decreased SI in total. Detailed analysis of specific patterns of SI revealed decrease in mutual sniffing and allo-grooming after all doses of MOR. The highest dose (5 mg/kg) of MOR decreased following and increased genital investigation. Rearing activity was increased by lower doses of MOR (1 and 2.5 mg/kg). THC, in each of the tested doses, did not induce any specific changes when compared to matching control group (ethanol). However, an additional statistical analysis showed differences between all THC groups and their ethanol control group when compared to saline controls. There was lower SI in total, lower mutual sniffing and allo-grooming, but higher rearing in THC and ethanol groups than in saline control group. Thus, changes seen in THC and ethanol groups are seemed to be attributed mainly to the effect of the ethanol. Based on the present results we can assume that opioids affect SI more than cannabinoid.

The effect of neonatal maternal stress on plasma levels of adrenocorticotropic hormone, corticosterone, leptin, and ghrelin in adult male rats exposed to acute heterotypic stressor.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is important for maintenance of homeostasis during stress. Recent studies have shown a connection between the HPA axis and adipose tissue. The present study investigated the effect of acute heterotypic stress on plasma levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), leptin, and ghrelin in adult male rats with respect to neonatal maternal social and physical stressors. Thirty rat mothers and sixty of their male progeny were used. Pups were divided into three groups: unstressed control (C), stressed by maternal social stressor (S), stressed by maternal social and physical stressors (SW). Levels of hormones were measured in adult male progeny following an acute swimming stress (10 min) or no stress. ELISA immunoassay was used to measured hormones. The ACTH and CORT levels were significantly increased in all groups of adult progeny after acute stress; however, CORT levels were significantly lower in both neonatally stressed groups compared to controls. After acute stress, plasma leptin levels were decreased in the C and SW groups but increased in the S group. The data suggest that long-term neonatal stressors lead to lower sensitivity of ACTH receptors in the adrenal cortex, which could be a sign of stress adaptation in adulthood. Acute stress in adult male rats changes plasma levels of leptin differently relative to social or physical neonatal stressors.

The effect of combined treatment of opioids with methylphenidate on nociception in rats and pain in human.

Methylphenidate hydrochloride (MPH/Ritalin) is a stimulant used for off-label management of cancer-related fatigue and sedation; however, its use in pain treatment is still relatively rare. This study 1) compares the antinociceptive effect of MPH and its combination with morphine (MOR) in adult male Wistar rats after a single administration of MPH, MOR or their combination, and 2) compares the analgesic effects of opioids and Ritalin combined therapy with opioid monotherapy in patients with cancer pain. To objectively assess physical activity during a three-week monitoring period, patients were equipped with Actiwatch Score Actigraph. Patients performed daily evaluations of pain intensity and frequency, and the extent to which pain interfered with their daily life. Our research with rats supports the evidence that MPH in lower doses has the ability to enhance the analgesic properties of morphine when the two drugs are used in combination. Results from the patient arm of our study found that short-term treatment had no significant effect on intensity or frequency of pain, however it decreased the overall burden of pain; the combined treatment of opioid and Ritalin also showed anti-sedation effects and resulted in mild improvement in one of our patient's quality of life.

Does effect from developmental methamphetamine exposure on spatial learning and memory depend on stage of neuroontogeny?

Psychostimulants, including methamphetamine (MA), have neurotoxic effect, especially, if they are targeting CNS during its critical periods of development. The present study was aimed to examine cognitive changes after prenatal and neonatal MA treatment in combination with chronic MA exposure in adulthood of male rats. Eight groups of male rats were tested in adulthood: males whose mothers were exposed to MA (5 mg/kg) or saline (SA, 1 ml/kg) during the first half of gestation period (GD 1-11), the second half of gestation period (GD 12-22) and neonatal period (PD 1-11). In addition, we compared indirect neonatal application via the breast milk with the group of rat pups that received MA or SA directly by injection (PD 1-11). Males were tested in adulthood for cognitive changes in the Morris Water Maze (MWM). MWM experiment lasted for 12 days: Learning (Day 1-6), Probe test (Day 8) and Retrieval Memory test (Day 12). Each day of the MWM animals were injected with MA (1 mg/kg) or SA (1 ml/kg). Prenatal MA exposure did not induce changes in learning abilities of male rats, but neonatal exposure to MA leads to an increase search errors and latencies to find the hidden platform. Prenatal and also neonatal MA exposure impaired cognitive ability to remember the position of the platform in Retrieval Memory test in adulthood. Animals exposed to the prenatal treatment within the second half of gestation (ED 12-22) swam longer, slower and spent more time to find the hidden platform in Retrieval Memory test than animals exposed throughout other periods. The present study demonstrated that stage of development is crucial for determination the cognitive deficits induced by prenatal or neonatal MA exposure.

How various drugs affect anxiety-related behavior in male and female rats prenatally exposed to methamphetamine.

Different forms of anxiety-related behavior have been reported after a single drug use of many abused substances, however, less is known about how males and females are affected differently from exposure to various drugs. Furthermore, chronic prenatal methamphetamine (MA) exposure was shown to predispose the animal to an increased sensitivity to drugs administrated in adulthood. Using the Elevated plus-maze test (EPM), the first aim of the present study was to examine how male and female rats are affected by acute drug treatment with subcutaneously (s.c.) administrated (a) MA (1mg/kg); (b) drugs with a similar mechanism of action to MA: amphetamine (AMP, 1mg/kg), cocaine (COC, 5mg/kg), 3,4-methylenedioxymethamphetamine (MDMA, 5mg/kg); and (c) drugs with different mechanisms of action: morphine (MOR, 5mg/kg), and Δ 9-tetrahydrocannabinol (THC, 2mg/kg). The second aim was to determine if prenatally MA-exposed (5mg/kg) animals show an increased sensitivity to adult drug treatment. The parameters analyzed were divided into two categories: anxiety-related behavior and anxiety-unrelated/exploratory behavior. Our results showed in female rats a decreased percentage of the time spent in the closed arms (CA) after MA, and an increased percentage of the time spent in the open arms (OA) after MA, AMP, and COC treatment, indicating an anxiolytic-like effect. In females, MDMA and THC treatment increased the percentage of the time spent in the CA. An increased percentage of the time spent in the CA was also seen after MOR treatment in females as well as in males, indicating an anxiogenic-like effect. As far as the interaction between prenatal MA exposure and adult drug treatment is concerned, there was no effect found. In conclusion, it seems that: (a) in some cases female rats are more vulnerable to acute drug treatment, in terms of either anxiogenic- or anxiolytic-like effects; (b) prenatal MA exposure does not sensitize animals to the anxiety-related effects of any of the drugs.

Drug sensitization induced by prenatal methamphetamine exposure.

Women, who abuse drugs during pregnancy, expose not just themselves but also their developing fetus to impairing effects, which can have potentially harmful and even long-term effects on the exposed children. For some years, methamphetamine (MA) has dominated the illicit drug market in the Czech Republic and Slovakia; additionally this drug is on the rise worldwide. It is one of the most accessible drugs, and in many cases the first choice drug for many drug-addicted pregnant women; in part due to its anorectic and stimulant effects. These women are rarely aware of the consequences of their behavior and their pregnancy is hardly ever a good enough reason for giving up drug use. These findings are supported by many experimental studies that show the damaging effects of maternal MA exposure on their offspring. There is growing evidence that exposure to MA in utero not only causes birth defects and delays in infant development, but also impairs the brain reward neural pathways of a developing offspring in such a way, that it could increase the predisposition for drug addiction later in life. Previously published animal studies have shown that offspring of mothers exposed to MA during pregnancy are more sensitive to MA when they encounter this drug later in adulthood. With respect to increased sensitivity, the term of sensitization has been introduced. It is defined as augmented psychomotor activity, which can be observed after drug re-administration following discontinuation of repeated drug exposure, and has been demonstrated to develop not only after repeated drug administration in adulthood, but also after chronic prenatal exposure. Results from our studies have shown that prenatal MA exposure can influence the sensitivity to the effects of some drugs, given as a challenge, in adulthood, specifically to those with a similar action mechanism. Our findings indicate that cross-sensitization between prenatal MA exposure and adult drug treatment cannot be simply termed as a general drug addiction, since it seems that the mechanism by which a drug impairs specific neurotransmitter systems plays an important role. The study findings show that although the offspring of MA-addicted mothers have altered sensitivity to certain drugs in adulthood, they do not display increased active drug-seeking behavior. Therefore, if we extrapolate the results to humans, it appears that there is a relatively little risk that a person, whose mother abused MA during pregnancy, will actively seek out drugs.

Gender differences in the effect of adult amphetamine on cognitive functions of rats prenatally exposed to methamphetamine.

Psychostimulants have been shown to affect brain regions involved in the process of learning and memory consolidation. It has been shown that females are more sensitive to the effects of drugs than males. The aim of our study was to investigate how prenatal methamphetamine (MA) exposure and application of amphetamine (AMP) in adulthood would affect spatial learning of adult female and male rats. Mothers of the tested offspring were exposed to injections of MA (5mg/kg) or saline (SA) throughout the entire gestation period. Cognitive functions of adult rats were evaluated in the Morris Water Maze (MWM) tests. Adult offspring were injected daily with AMP (5mg/kg) or SA through the period of MWM testing. Our data from the MWM tests demonstrates the following. Prenatal MA exposure did not change the learning ability of adult male and female rats. However, AMP administration to adult animals affected cognitive function in terms of exacerbation of spatial learning (increasing the latency to reach the hidden platform, the distance traveled and the search error) only in female subjects. There were sex differences in the speed of swimming. Prenatal MA exposure and adult AMP treatment increased the speed of swimming in female groups greater than in males. Overall, the male subjects showed a better learning ability than females. Thus, our results indicate that the adult AMP treatment affects the cognitive function and behavior of rats in a sex-specific manner, regardless of prenatal exposure.