The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions.

Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin's/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin's/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.

Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats.

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

Trans-generational neurochemical modulation of methamphetamine in the adult brain of the Wistar rat.

Chronic methamphetamine (METH) abuse has been shown to elicit strong neurotoxic effects. Yet, with an increasing number of children born to METH abusing mothers maturing into adulthood, one important question is how far do the neurotoxic effects of METH alter various neurotransmitter systems in the adult METH-exposed offspring. The purpose of this study was to investigate long-term trans-generational neurochemical changes, following prenatal METH exposure, in the adult Wistar rat brain. METH or saline (SAL-control animals) was administered to pregnant dams throughout the entire gestation period (G0-G22). At postnatal day 90, dopamine, serotonin, glutamate and GABA were measured in the adult brain before (baseline) and after a METH re-administration using in vivo microdialysis and liquid chromatography/mass spectrometry. The results show that METH-exposure increased basal levels of monoamines and glutamate, but decreased GABA levels in all measured brain regions. Acute challenge with METH injection in the METH-exposed group induced a lower increase in the monoamine system relative to the increase in the GABAergic and glutamatergic system. The data show that prenatal METH exposure has strong effects on the monoaminergic, GABAergic and glutamatergic system even when exposure to METH was limited to the prenatal phase. Toxicological effects of METH have therefore longer lasting effects as currently considered and seem to affect the excitatory-inhibitory balance in the brain having strong implications for cognitive and behavioral functioning.

Sex-Dependent Changes in Striatal Dopamine Transport in Preadolescent Rats Exposed Prenatally and/or Postnatally to Methamphetamine.

Methamphetamine (MA) is the most commonly used psychostimulant drug, the chronic abuse of which leads to neurodegenerative changes in the brain. The global use of MA is increasing, including in pregnant women. Since MA can cross both placental and haematoencephalic barriers and is also present in maternal milk, children of chronically abused mothers are exposed prenatally as well as postnatally. Women seem to be more vulnerable to some aspects of MA abuse than men. MA is thought to exert its effects among others via direct interactions with dopamine transporters (DATs) in the brain tissue. Sexual dimorphism of the DAT system could be a base of sex-dependent actions of MA observed in behavioural and neurochemical studies. Possible sex differences in the DATs of preadolescent offspring exposed to MA prenatally and/or postnatally have not yet been evaluated. We examined the striatal synaptosomal DATs (the activity and density of surface expressed DATs and total DAT expression) in preadolescent male and female Wistar rats (31-35-day old animals) exposed prenatally and/or postnatally to MA (daily 5 mg/kg, s.c. to mothers during pregnancy and lactation). To distinguish between specific and nonspecific effects of MA on DATs, we also evaluated the in vitro effects of lipophilic MA on the fluidity of striatal membranes isolated from preadolescent and young adult rats of both sexes. We observed similar changes in the DATs of preadolescent rats exposed prenatally or postnatally (MA-mediated drop in the reserve pool but no alterations in surface-expressed DATs). However, prenatal exposure evoked significant changes in males and postnatal exposure in females. A significant decrease in the activity of surface-expressed DATs was found only in postnatally exposed females sensitized to MA via prenatal exposure. MA applied in vitro increased the fluidity of striatal membranes of preadolescent female but not male rats. In summary, DATs of preadolescent males are more sensitive to prenatal MA exposure via changes in the reserve pool and those of preadolescent females to postnatal MA exposure via the same mechanism. The combination of prenatal and postnatal MA exposure increases the risk of dopaminergic deficits via alterations in the activity of surface-expressed DATs especially in preadolescent females. MA-mediated changes in DATs of preadolescent females could be still enhanced via nonspecific disordering actions of MA on striatal membranes.

Can Anxiety Tested in the Elevated Plus-maze Be Related to Nociception Sensitivity in Adult Male Rats?

Methamphetamine (MA) is one of the most addictive psychostimulant drugs with a high potential for abuse. Our previous studies demonstrated that MA administered to pregnant rats increases pain sensitivity and anxiety in their adult offspring and makes them more sensitive to acute administration of the same drug in adulthood. Because individuals can differ considerably in terms of behaviour and physiology, such as rats that do not belong in some characteristics (e.g. anxiety) to average, can be described as low-responders or high-responders, are then more or less sensitive to pain. Therefore, prenatally MA-exposed adult male rats treated in adulthood with a single dose of MA (1 mg/ml/kg) or saline (1 ml/kg) were tested in the present study. We examined the effect of acute MA treatment on: (1) the anxiety in the Elevated plus-maze (EPM) test and memory in EPM re-test; (2) nociception sensitivity in the Plantar test; (3) the correlation between the anxiety, memory and the nociception. Our results demonstrate that: (1) MA has an anxiogenic effect on animals prenatally exposed to the same drug in the EPM; (2) all the differences induced by acute MA treatment disappeared within the time of 48 hours; (3) there was no effect of MA on nociception per se, but MA induced higher anxiety in individuals less sensitive to pain than in animals more sensitive to pain. In conclusion, the present study demonstrates unique data showing association between anxiety and nociceptive sensitivity of prenatally MA-exposed rats that is induced by acute drug administration.

Effects of psychostimulants on social interaction in adult male rats.

Psychostimulants are known to have a huge impact on different forms of social behaviour. The aim of the present study was to compare the effects of three different psychostimulants [amphetamine, cocaine and 3,4 methylenedimethoxyamphetamine (MDMA)] on social interaction (SI) in adult male rats. The SI test was performed in a familiar arena and under low-stress environmental conditions. Experimental animals received amphetamine (0.5, 1.0, 1.5 mg/kg), cocaine (0.5, 1.0, 1.5, 2.5, 5.0, 10.0 mg/kg) or MDMA (2.5, 5.0, 10 mg/kg) and control animals received saline (1 ml/kg) 45 min before the SI test. Time spent in SI (individual patterns of social behaviour) and nonsocial activities (locomotion and rearing) were video recorded and then analysed offline, with the following results: (a) all doses of amphetamine decreased SI. Specifically, all doses of amphetamine decreased mutual sniffing, and the higher doses also decreased allo-grooming and following behaviours. (b) The higher doses of cocaine decreased SI, especially mutual sniffing, allo-grooming and climbing over. Cocaine at the dose of 5.0 mg/kg increased genital investigation compared with lower doses. (c) All doses of MDMA decreased mutual sniffing and climbing over; the two higher doses decreased allo-grooming behaviour, and only the highest dose decreased following. The two higher doses of amphetamine and all the doses of MDMA increased locomotion and rearing; cocaine did not affect locomotion, but increased rearing at higher doses. In conclusion, the results confirm the well-known finding that psychostimulants suppress SI, but also show novel differences in the effects of psychostimulants on specific patterns of SI.

The effect of prenatal methamphetamine exposure on recognition memory in adult rats.

The use of methamphetamine (MA) among pregnant women is an increasing world-wide health problem. Prenatal MA exposure may cause changes in foetus but the exact effects have remained unclear. The aim of this study is to present the effect of prenatal MA exposure on recognition memory in adult rats. Adult female Wistar rats were injected daily with D-methamphetamine HCl (MA; 5 mg/kg, s.c.) during the entire gestation period. Control females were treated with saline in the same regime. Adult male offspring was administrated acutely by MA (1 mg/kg i.p.) or saline 30 minutes before beginning of an experiment. For testing recognition memory two tasks were chosen: Novel Object Recognition Test (NORT) and Object Location Test (OLT). Our results demonstrate that prenatally MA-exposed animals were worse in NORT independently on an acute administration of MA in adulthood. Prenatally MA-exposed rats did not deteriorate in OLT, but after acute administration of MA in adulthood, there was significant worsening compared to appropriate control. Prenatally saline-exposed offspring did not deteriorate in any test even after acute administration of MA. Our data suggest that prenatal MA exposure in rats cause impairment in recognition memory in adult offspring, but not in spatial memory. In addition, acute administration of MA to controls did not deteriorate either recognition or spatial memory.

Age-related differences in NMDA receptor subunits of prenatally methamphetamine-exposed male rats.

There is accumulating evidence that methamphetamine (MA) is a widely abused drug popular among pregnant women. MA exposure is associated with changes in the function of neurotransmitter systems, namely the dopaminergic, serotonergic and glutamatergic systems. Since N-methyl-D-aspartate receptors (NMDA) are affected by MA-induced glutamate release, we assessed the expression of NMDAR subunits (NR1, NR2A, and NR2B) and postsynaptic density protein 95 (PSD-95), which is connected with NMDAR. We measured the expression of these proteins in adolescent (30 days old) and adult (60 days old) rat males exposed to MA during the entire prenatal period and compared them with the same parameters in age matched saline-exposed rats. There was a significant increase in the NR1 and NR2B subunits in the hippocampus of adult males, but not in adolescent males. We identified a significant change in adult MA-induced rats when compared to adult controls for NR2A and NR2B, while in adolescent MA rats this change was close to the boundary of significance. In summary, our study suggests that prenatal MA exposure is connected with changes in NMDAR subunit expression in adult rats but not in adolescent rats.

Effect of amphetamine on adult male and female rats prenatally exposed to methamphetamine.

The aim of the present study was to examine the cross-sensitization induced by prenatal methamphetamine (MA) exposure to adult amphetamine (AMP) treatment in male and female rats. Rat mothers received a daily injection of MA (5 mg/kg) or saline throughout the gestation period. Adult male and female offspring (prenatally MA- or saline-exposed) were administered with AMP (5 mg/kg) or saline (1 ml/kg) in adulthood. Behaviour in unknown environment was examined in open field test (Laboras), active drug-seeking behaviour in conditioned place preference test (CPP), spatial memory in the Morris water maze (MWM), and levels of corticosterone (CORT) were analyzed by enzyme immunoassay (EIA). Our data demonstrate that in Laboras test, AMP treatment in adulthood increased general locomotion (time and distance travelled) regardless of the prenatal exposure and sex, while AMP increased exploratory activity (rearing) only in prenatally MA-exposed animals. AMP induced sensitization only in male rats, but not in females when tested drug-seeking behaviour in the CPP test. In the spatial memory MWM test, AMP worsened the performance only in females, but not in males. On the other hand, males swam faster after chronic AMP treatment regardless of the prenatal drug exposure. EIA analysis of CORT levels demonstrated higher level in females in all measurement settings. In males, prenatal MA exposure and chronic adult AMP treatment decreased CORT levels. Thus, our data demonstrated that adult AMP treatment affects behaviour of adult rats, their spatial memory and stress response in sex-specific manner. The effect is also influenced by prenatal drug exposure.

Impact of altered environment and early postnatal methamphetamine exposure on serotonin levels in the rat hippocampus during adolescence.

BACKGROUND: Methamphetamine (MA) is a highly abused psychostimulant across all age groups including pregnant women. Because developing brain is vulnerable by the action of drugs, or other noxious stimuli, the aim of our study was to examine the effect of early postnatal administration of MA alone or in combination with enriched environment (EE) and/or stress of separate housing, on the levels of serotonin (5HT) in the hippocampus of male rat pups at three stages of adolescence (postnatal day (PND) 28, 35 and 45). MA (5 mg/kg/ml) was administered subcutaneously (sc) to pups (direct administration), or via mothers' milk between PND1 and PND12 (indirect administration). Controls were exposed saline (SA). Pups were exposed to EE and/or to separation from the weaning till the end of the experiment. RESULTS: On PND 28, in sc-treated series, EE significantly increased the muted 5HT in SA pups after separation and restored the pronounced inhibition of 5HT by MA. No beneficial effect of EE was present in pups exposed to combination of MA and separation. 5HT development declined over time; EE, MA and separation had different effects on 5HT relative to adolescence stage. CONCLUSIONS: Present study shows that MA along with environment or housing affect 5HT levels, depending on both the age and the method of application (direct or indirect). These findings extend the knowledge on the effects of MA alone and in combination with different housing conditions on the developing brain and highlight the increased sensitivity to MA during the first few months after birth.

Gender differences in behavioral changes elicited by prenatal methamphetamine exposure and application of the same drug in adulthood.

The aim of the present study was to compare the response to sub-chronic application of methamphetamine (MA) in adulthood in male and female rats prenatally exposed to the same drug. The spontaneous locomotor activity and exploratory behavior of adult male and female rats prenatally exposed to 5 mg/kg MA or saline (SAL) were tested in a Laboras apparatus (Metris B.V., Netherlands) for five consecutive days, 1 hr daily. MA 1 mg/kg or SAL were used as a challenge prior to testing. Our results showed that rats prenatally exposed to MA were more sensitive to sub-chronic administration of MA in adulthood than prenatally SAL-exposed rats. However, this sensitizing effect of prenatal MA exposure was manifested differently in males and females. In contrast, prenatal MA exposure decreased baseline locomotion in females. This study indicates that gender plays an important role in the sensitivity to MA during prenatal development and in adulthood.

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.

Perinatal Stress and Methamphetamine Exposure Decreases Anxiety-Like Behavior in Adult Male Rats.

Methamphetamine (MA) is an illicit synthetic psychostimulant drug, and its abuse is growing worldwide. MA has been reported as the primary drug of choice, by drug-abusing women, during pregnancy. Since MA easily crosses the placental barrier, the fetus is exposed to MA in a similar fashion to the mother. This study aimed to evaluate the effect of long-term perinatal stressors and drug exposure on anxiety-like behavior in adult male rats using the open field test (OF) and elevated plus maze (EPM). Dams were divided into three groups according to drug treatment during pregnancy: controls (C), saline-SA [subcutaneous (s.c.), 1 ml/kg], and MA (s.c., 5 mg/kg). Litters were divided into four groups according to postnatal stressors: non-stressed controls (N), maternal separation (S), maternal cold water stress (W), and maternal separation plus maternal cold water stress (SW). Forty-five minutes before testing (in both OF and EPM), one-half of adult male rats received an (s.c.) injection of MA and the other half received an SA injection. Prenatal MA/stress exposure did not affect anxiety-like behavior in adult male rats in both tests. In the OF, an acute MA dose in adulthood increased the time spent in the central disk area, decreased time spent in the corners, and decreased time spent immobile and grooming. Also, postnatal stress increased time spent in the central disk area, decreased time spent in corners, and increased mobility compared to controls. All groups of rats exposed to postnatal stressors spent significantly less time in the closed arms of the EPM compared to controls. Overall, our results indicate that early postnatal stress and a single acute MA administration in adulthood decreases the parameters of anxiety-like behavior in adult male rats regardless of prenatal MA exposure. Moreover, postnatal stress via maternal separation impacts the effect of acute MA administration in adulthood. Long-term postnatal stress may thus result in improved adaptation to subsequent stressful experiences later in life.

The Impact of Neonatal Methamphetamine on Spatial Learning and Memory in Adult Female Rats.

The present study was aimed at evaluating cognitive changes following neonatal methamphetamine exposure in combination with repeated treatment in adulthood of female Wistar rats. Pregnant dams and their pups were used in this study. One half of the offspring were treated indirectly via the breast milk of injected mothers, and the other half of pups were treated directly by methamphetamine injection. In the group with indirect exposure, mothers received methamphetamine (5 mg/ml/kg) or saline (1 ml/kg) between postnatal days (PD) 1-11. In the group with direct exposure, none of the mothers were treated. Instead, progeny were either: (1) treated with injected methamphetamine (5 mg/ml/kg); or (2) served as controls and received sham injections (no saline, just a needle stick) on PD 1-11. Learning ability and memory consolidation were tested on PD 70-90 in the Morris Water Maze (MWM) using three tests: Place Navigation Test, Probe Test, and Memory Recall Test. Adult female progeny were injected daily, after completion of the last trial of MWM tests, with saline or methamphetamine (1 mg/ml/kg). The effects of indirect/direct neonatal methamphetamine exposure combined with acute adult methamphetamine treatment on cognitive functions in female rats were compared. Statistical analyses showed that neonatal drug exposure worsened spatial learning and the ability to remember the position of a hidden platform. The study also demonstrated that direct methamphetamine exposure has a more significant impact on learning and memory than indirect exposure. The acute dose of the drug did not produce any changes in cognitive ability. Analyses of search strategies (thigmotaxis, scanning) used by females during the Place Navigation Test and Memory Recall Test confirmed all these results. Results from the present study suggested extensive deficits in learning skills and memory of female rats that may be linked to the negative impact of neonatal methamphetamine exposure.

Methamphetamine and sleep impairments: neurobehavioral correlates and molecular mechanisms.

Methamphetamine is a potent and highly addictive psychostimulant, and one of the most widely used illicit drugs. Over recent years, its global usage and seizure have been on a rapid rise, with growing detrimental effects on mental and physical health, and devastating psychosocial impact pressing for intervention. Among the unwanted effects of methamphetamine, acute and long-term sleep impairments are of major concern, posing a significant therapeutic challenge, and a cause of addiction relapse. Unraveling mechanisms and functional correlates of methamphetamine-related sleep and circadian disruption are, therefore, of key relevance to translational and clinical psychiatry. In this article, we review the mounting evidence for the acute and long-term impairements of sleep-wake behavior and circadian activity caused by single or recurring methamphetamine usage and withdrawal. Factors contributing to the severity of sleep loss and related cognitive deficit, with risks of relapse are discussed. Key molecular players mediating methamphetamine-induced dopamine release and neuromodulation are considered, with wake-promoting effects in mesolimbic circuits. The effects on various sleep phases and related changes in dopamine levels in selected subcortical structures are reviewed and compared to other psychostimulants with similar action mechanisms. A critical appraisal is presented of the therapeutic use of modafinil, countering sleep, and circadian rhythm impairments. Finally, emerging knowledge gaps and methodical limitations are highlighted along with the areas for future research and therapeutic translation.

Challenge dose of methamphetamine affects kainic acid-induced seizures differently depending on prenatal methamphetamine exposure, sex, and estrous cycle.

Even though it is obvious that glutamate plays an important role in the effect of psychostimulants on seizures, the role of non-NMDA receptors remains uncertain. The aim of the present study was to determine whether acute methamphetamine (MA) administration changes sensitivity to seizures induced with kainic acid in prenatally MA-exposed adult rats. Adult male and female rats (prenatally MA exposed, prenatally saline exposed, and controls) were divided into groups that received a challenge dose (1mg/kg) of MA and groups that did not receive the MA challenge (saline injected). Systemic administration of 15 mg/kg kainic acid was used as a seizure model. Our results demonstrated that a single injection of MA (1mg/kg) affects kainic acid-induced seizures differently depending on prenatal exposure, sex, and female estrous cycle. Even though daily injections of MA (5mg/kg) in maternal rats did not have a long-term effect on susceptibility to seizures induced with kainic acid in adult progeny, sensitivity to the challenge dose of MA differed between the prenatal exposure groups.

Effect of prenatal and postnatal methamphetamine exposure on nociception in adult female rats.

The aim of the present study was to determine effects of methamphetamine (MA) exposure and cross-fostering on thermal nociceptive thresholds in different estrous phases in adult female rats. Rat mothers were exposed daily to injection of MA (5 mg/kg) or saline for 9 weeks: prior to impregnation, throughout gestation and lactation periods. Dams without any injections were used as an absolute control. On postnatal day 1, pups were cross-fostered so that each mother raised four pups of her own and eight pups from the mothers with the other two treatments. Offspring females were tested in adulthood (85-90 days) for thermal nociception as latency [s] of withdrawal reaction of forelimbs, hind limbs, and tail. Our results showed that prenatal MA exposure did not affect the nociception in adulthood, while postnatal MA exposure (i.e., MA administration to lactating mothers) had pro-nociceptive effects. The effect of postnatal MA exposure was apparent in both, fore- and hind limbs, while the latency to tail withdrawal reaction was the same among the groups. In addition, the pro-nociceptive effect of postnatal MA exposure did not depend on estrous cycle. This study indicates that postnatal but not prenatal exposure to MA affects nociception in adult female rats. However, it is still not clear whether the pro-nociceptive effect of postnatal MA exposure is linked to direct action of MA on neuronal organization, or to indirect action of MA mediated by impaired maternal care.

Influence of Prenatal Methamphetamine Abuse on the Brain.

Methamphetamine (MA), a psychostimulant, has become a serious problem in recent years. It is one of the most widely abused psychostimulants in the world. In the Czech Republic, ecstasy is the most commonly used non-cannabis drug, followed by hallucinogenic fungi, LSD, MA, cocaine, and finally heroin. The prevalence of the usage of all addictive substances is highest in the age category of 15-34. Approximately 17.2% of registered drug addicts, both male and female, in the Czech Republic use MA as their first-choice drug. This group consists mostly of women who are unemployed and addicted to MA (85%). Almost half of the addicted women switched to MA from other drugs in the course of pregnancy. Psychostimulants such as amphetamine and its synthetic derivate MA induce feelings of calm and happiness by suppressing anxiety and depression. When MA is abused for longer periods, it mimics symptoms of mania and can lead to the development of psychosis. MA is often abused for its anorectic effect, its simple preparation, and compared to heroin and cocaine, its low price. There are significant differences in the susceptibility of users to the stimulant, with reactions to MA fluctuating from person to person. Molecular mechanisms related to the variable response among users might represent an explanation for increased addiction-associated bipolar disorder and psychosis. Currently, there is limited information regarding genetic mechanisms linked to these disorders and the transmission of drug addiction. As such, animal models of drug addiction represent significant sources of information and assets in the research of these issues. The aim of this review is to summarize the mechanism of action of methamphetamine and its effect on pregnant addicted women and their children, including a detailed description of the anatomical structures involved.

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.

Prenatal Exposure to Methamphetamine: Up-Regulation of Brain Receptor Genes.

Methamphetamine (METH) is a widespread illicit drug. If it is taken by pregnant women, it passes through the placenta and just as it affects the mother, it can impair the development of the offspring. The aim of our study was to identify candidates to investigate for changes in the gene expression in the specific regions of the brain associated with addiction to METH in rats. We examined the various areas of the central nervous system (striatum, hippocampus, prefrontal cortex) for signs of impairment in postnatal day 80 in experimental rats, whose mothers had been administered METH (5 mg/kg/day) during the entire gestation period. Changes in the gene expression at the mRNA level were determined by two techniques, microarray and real-time PCR. Results of two microarray trials were evaluated by LIMMA analysis. The first microarray trial detected either up-regulated or down-regulated expression of 2189 genes in the striatum; the second microarray trial detected either up-regulated or down-regulated expression of 1344 genes in the hippocampus of prenatally METH-exposed rats. We examined the expression of 10 genes using the real-time PCR technique. Differences in the gene expression were counted by the Mann-Whitney U-test. Significant changes were observed in the cocaine- and amphetamine-regulated transcript prepropeptide, tachykinin receptor 3, dopamine receptor D3 gene expression in the striatum regions, in the glucocorticoid nuclear receptor Nr3c1 gene expression in the prefrontal cortex and in the carboxylesterase 2 gene expression in the hippocampus of prenatally METH-exposed rats. The microarray technique also detected up-regulated expression of trace amine-associated receptor 7 h gene in the hippocampus of prenatally METH-exposed rats. We have identified susceptible genes; candidates for the study of an impairment related to methamphetamine addiction in the specific regions of the brain.