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.
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.
- MeSH
- dopamin metabolismus MeSH
- GABA MeSH
- kyselina glutamová metabolismus MeSH
- methamfetamin aplikace a dávkování farmakokinetika toxicita MeSH
- mozek účinky léků metabolismus MeSH
- potkani Wistar MeSH
- serotonin metabolismus MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice * MeSH
- zvířata MeSH
- Check Tag
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- corpus striatum účinky léků metabolismus MeSH
- dopamin metabolismus MeSH
- krysa rodu rattus MeSH
- methamfetamin aplikace a dávkování toxicita MeSH
- novorozená zvířata MeSH
- pohlavní dimorfismus * MeSH
- potkani Wistar MeSH
- proteiny přenášející dopamin přes plazmatickou membránu metabolismus MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice chemicky indukované metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cíl: Cílem této normativní studie Mini‑Mental State Examination (MMSE), neuropsychologické metody pro orientační zjištění kognitivního stavu a skríningu kognitivních poruch, je potvrdit zahraniční zjištění o závislosti výkonu v MMSE na věku a vzdělání a poskytnout normativní data české starší populace. Soubor a metodika: Soubor 540 osob ve věku 60 a více let splňujících daná kritéria zařazení, z 12 krajů České republiky, bez suspektní poruchy kognice (na základě anamnézy a výsledků neuropsychologických testů). Soubor byl rozdělen na čtyři skupiny dle věku (mladší, 60–74 let, a starší, 75 a více let) a dle vzdělání (nižší – bez maturity, vyšší – s maturitou a vyšším). Poměr pohlaví byl muži : ženy, 1 : 1. Výsledky: Byl zjištěn významný efekt věku (Pearson r = –0,308) i vzdělání (Cohenovo d = 0,43; oba p < 0,001) na získaný skór v MMSE. Nejhorších výsledků dosahovali starší, méně vzdělaní jedinci (MMSE 26,88; ? 1 SD 24,27–28,48) a nejlepších výsledků mladší vzdělanější (MMSE 28,60; ? 1 SD 26,83–29,62). Závěry: Potvrdili jsme závislost výsledků v MMSE u starších zdravých osob na jejich věku a vzdělání. Z toho vyplývá nutnost ve studiích klinické užitečnosti prověřit užívaný jednotný hraniční skór při odhadu kognitivních poruch, a to především u syndromu demence u různých neurodegenerativních onemocnění. Studie poprvé poskytuje normativní data MMSE na velkém souboru osob z české populace upravená dle věku a vzdělání.
Aim: The aim of this normative study of Mini-Mental State Examination (MMSE) – a neuropsychological method to screen cognitive status and disorders - is to confirm international findings on the effects of age and education on MMSE scores and to obtain normative data for the Czech older population. Sample and methods: The sample consisted of 540 adults of 60 plus years of age meeting the inclusion criteria and without suspected cognitive disorder (based on anamnesis and neuropsychological assessment) from 12 regions of the Czech Republic. The sample was divided into four groups according to their age (younger 60–74, older 75+), and education (lower, higher). Men to women ratio in the sample was 1 : 1. Results: We found a significant effect of age (Pearson r = –0.308) and education (Cohen‘s d = 0.43; both p < 0.001) on MMSE score. The lowest scores were obtained by older, less educated individuals (MMSE 26.88; ? 1 SD 24.27–28.48), the highest scores were obtained by younger, more educated individuals (MMSE 28.60; ? 1 SD 26.83–29.62). Conclusion: We confirmed correlations between MMSE scores and age and education in older, cognitively healthy persons. These results necessitate further investigation of the MMSE clinical utility to determine the cut-off scores for dementia due to different neurodegenerative diseases. The study provides the first normative data from a large sample of the Czech population according to their age and education. Key words: ageing – cognitive functions – screening – dementia syndrome – normal values The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
- MeSH
- kognice * MeSH
- lidé MeSH
- neuropsychologické testy * MeSH
- poruchy paměti * diagnóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- statistika jako téma MeSH
- stupeň vzdělání * MeSH
- věkové faktory * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Since close relationship was shown between drug addiction and memory formation, the aim of the present study was to investigate the effects of interaction between prenatal methamphetamine (MA) exposure and MA treatment in adulthood on spatial and non-spatial memory and on the structure of the N-methyl-D-aspartate (NMDA) receptors in the hippocampus. Adult male rats prenatally exposed to MA (5 mg/kg) or saline were tested in adulthood. Non-spatial memory was examined in the Object Recognition Test (ORT) and spatial memory in the Object Location Test (OLT) and in the Memory Retention Test (MRT) conducted in the Morris Water Maze (MWM), respectively. Based on the type of the memory test animals were injected either acutely (ORT, OLT) or long-term (MWM) with MA (1 mg/kg). After each testing, animals were sacrificed and brains were removed. The hippocampus was then examined in Western Blot analysis for occurrence of different NMDA receptors' subtypes. Our results demonstrated that prenatal MA exposure affects the development of the NMDA receptors in the hippocampus that might correspond with improvement of spatial memory tested in adulthood in the MWM. On the other hand, the effect of prenatal MA exposure on non-spatial memory examined in the ORT was the opposite. In addition, we showed that the effect of MA administration in adulthood on NMDA receptors is influenced by prenatal MA exposure, which seems to correlate with the spatial memory examined in the OLT.
- MeSH
- bludiště - učení účinky léků MeSH
- hipokampus účinky léků metabolismus MeSH
- methamfetamin aplikace a dávkování toxicita MeSH
- náhodné rozdělení MeSH
- potkani Wistar MeSH
- prostorová paměť účinky léků MeSH
- receptory N-methyl-D-aspartátu metabolismus MeSH
- stimulanty centrálního nervového systému aplikace a dávkování toxicita MeSH
- těhotenství MeSH
- western blotting MeSH
- zpožděný efekt prenatální expozice * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- hipokampus účinky léků metabolismus MeSH
- methamfetamin toxicita MeSH
- novorozená zvířata MeSH
- podjednotky proteinů metabolismus MeSH
- potkani Sprague-Dawley MeSH
- receptory N-methyl-D-aspartátu metabolismus MeSH
- signální transdukce účinky léků MeSH
- stárnutí MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- Biochemická lateralita mozku,
- MeSH
- 17-hydroxysteroidní dehydrogenasy izolace a purifikace škodlivé účinky MeSH
- Alzheimerova nemoc MeSH
- diagnostické techniky neurologické trendy využití MeSH
- hipokampus chemie patofyziologie patologie MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- modely nemocí na zvířatech MeSH
- neurodegenerativní nemoci * diagnóza komplikace prevence a kontrola MeSH
- oxid dusnatý izolace a purifikace metabolismus škodlivé účinky MeSH
- oxidační stres fyziologie genetika imunologie MeSH
- potkani Long-Evans MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stárnutí MeSH
- statistika jako téma MeSH
- teoretické modely * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
It has been suggested that Nogo-A, a myelin-associated protein, could play a role in the pathogenesis of schizophrenia and that Nogo-A-deficient rodents could serve as an animal model for schizophrenic symptoms. Since changes in brain laterality are typical of schizophrenia, we investigated whether Nogo-A-deficient rats showed any signs of disturbed asymmetry in cortical N-methyl-d-aspartate (NMDA) receptor-nitric oxide synthase (NOS) pathway, which is reported as dysfunctional in schizophrenia. In particular, we measured separately in the right and left hemisphere of young and old Nogo-A-deficient male rats the expression of NMDA receptor subunits (NR1, NR2A, and NR2B in the frontal cortex) and activities of NOS isoforms [neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) in the parietal cortex]. In young controls, we observed right/left asymmetry of iNOS activity and three positive correlations (between NR1 in the left and NR2B laterality, between NR2B in the right and left sides, and between NR1 in the right side and nNOS laterality). In old controls, we found bilateral decreases in NR1, an increase in NR2B in the right side, and two changes in correlations in the NR1-nNOS pathway. In young Nogo-A-deficient rats, we observed an increase in iNOS activity in the left hemisphere and two changes in correlations in NR1-nNOS and NR2A-eNOS, compared to young controls. Finally, we revealed in old Nogo-A-deficient animals, bilateral decreases in NR1 and one change in correlation between eNOS-iNOS, compared to old controls. Although some findings from schizophrenic brains did not manifest in Nogo-A-deficient rats (e.g., no alterations in NR2B), others did (e.g., alterations demonstrating accelerated aging in young but not old animals, those occurring exclusively in the right hemisphere in young and old animals and those suggesting abnormal frontoparietal cortical interactions in young animals).
- Publikační typ
- časopisecké články MeSH
Methamfetamin (MA) je silný stimulant se schopností vyvolávat psychickou závislost a má neurotoxické vlastnosti. Kromě antagonistů N-methyl-D-aspartátových receptoru jsou amfetaminy jedinou známou skupinou návykových látek, která je spojena s deplecí dopaminu ve striatu. Výsledky animálních pokusů podporují koncept, který říká, že množství D2 receptoru je jednou z determinant souvisejících se závislostí na drogách. Muži a ženy se výrazně liší v užívání a v reakci na MA. Cílem této práce bylo zhodnotit vliv chronického prenatálního podání MA nebo stejného množství fyziologického roztoku (S) v kombinaci s postnatálním podáním MA nebo S u potkanů kmene Wistar (samců/ samic) na dopaminové receptory ve striatu.
Methamphetamine (MA) is a powerful stimulant with a potency to cause psychic addiction and with neurotoxic properties. Except for N-methyl-D-aspartate receptor antagonists, the amphetamines are the only class of addictive drugs known to be associated with striatal dopamine depletion. Animal experiments support the concept that the number of D2 receptors is one of the determinants of a response to drugs of abuse. Men and women differ markedly with regard to their use of, and responses to MA. The purpose of this study was to examine the effect of chronic prenatal exposure of MA or the same volume of saline (S) in combination with chronic administration of MA or S postnatal on Wistar rats (males/females) on dopamine receptors in striatum.
- Publikační typ
- abstrakt z konference MeSH
