RESUMO
Ionising radiation causes secondary tumours and/or enduring cognitive deficits, especially in children. Proton radiotherapy reduces exposure of the developing brain in children but may still cause some lasting effects. Recent observations show that ultra-high dose rate radiation treatment (≥40 Gy/s), called the FLASH effect, is equally effective at tumour control but less damaging to surrounding tissue compared with conventional dose rate protons (0.03-3 Gy/s). Most studies on the FLASH effect in brain and other tissues with different radiation modalities (electron and photon radiation), show FLASH benefits in these preclinical rodent models, but the data are limited, especially for proton FLASH, including for dose, dose rate and neurochemical and neurobehavioural outcomes. Tests of neurocognitive outcomes have been limited despite clinical evidence that this is the area of greatest concern. The FLASH effect in the context of proton exposure is promising, but a more systematic and comprehensive approach to outcomes is needed.
Assuntos
Terapia com Prótons , Animais , Encéfalo , Elétrons , Humanos , Prótons , RoedoresRESUMO
Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 flox ) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y ) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8 -/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8 -/y mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8-/y mice.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , Disfunção Cognitiva/genética , Creatina/deficiência , Proteínas de Membrana Transportadoras/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Animais , Encéfalo/metabolismo , Encefalopatias Metabólicas Congênitas/metabolismo , Disfunção Cognitiva/metabolismo , Creatina/genética , Creatina/metabolismo , Medo/fisiologia , Aprendizagem/fisiologia , Masculino , Aprendizagem em Labirinto , Proteínas de Membrana Transportadoras/metabolismo , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Camundongos , Camundongos Knockout , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismoRESUMO
Phosphodiesterase-1b (Pde1b) is highly expressed in striatum, dentate gyrus, CA3 and substantia nigra. In a new Floxed Pde1b × CreCMV global knockout (KO) mouse model, we show an immobility-resistance phenotype that recapitulates that found in constitutive Pde1b KO mice. We use this new mouse model to show that the resistance to acute stress-induced depression-like phenotype is not the product of changes in locomotor activity or reactivity to other stressors (learned helplessness, novelty suppressed feeding or dexamethasone suppression), and is not associated with anhedonia using the sucrose preference test. Using tamoxifen inducible Cre, we show that the immobility-resistant phenotype depends on the age of induction. The effect is present when Pde1b is Reduced from conception, P0 or P32, but not if reduced as adults (P60). We also mapped regional brain expression of PDE1B protein and of the Cre driver. These data add to the suggestion that PDE1B may be a target for drug development with therapeutic potential in depression alone or in combination with existing antidepressants.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Depressão/genética , Fenótipo , Estresse Psicológico/genética , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Depressão/fisiopatologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/fisiopatologiaRESUMO
Phosphodiesterases (PDEs) are a superfamily of intracellular second messenger cyclic nucleotide hydrolyzing enzymes composed of 12 families. The Pde4 family has been implicated in depression and cognition, and PDE4 inhibitors have been evaluated as antidepressants and possible cognitive enhancers. Pde4d(-/-) mice show an antidepressant phenotype and learning enhancement on some tests, but not others as do mice treated with PDE4 inhibitors. Here, we report for the first time the behavioral phenotype of a new Pde4d knock-down (KD) rat model of PDE4D deficiency. Consistent with other data on PDE4D deficiency, Pde4d KD rats showed depression resistance in the Porsolt forced swim test and hyperreactivity of the acoustic startle response with no differential response on prepulse inhibition, suggesting no sensorimotor gating defect. Pde4d KD rats also exhibited a small exploratory activity reduction but no difference following habituation, and no enhanced spatial learning or reference memory in the Morris water maze. A selective improvement in route-based learning in the Cincinnati water maze was seen as well as enhanced contextual and cued fear conditioning and a more rapid rate of cued extinction from their higher freezing level that declined to wild-type (WT) levels only after â¼20 extinction trials. The rat model confirms Pde4d's role in depression but not in spatial learning or memory enhancement and shows for the first time higher fear conditioning and altered extinction compared with controls. The new model provides a tool by which to better understand the role of PDE4D in neuropsychiatric disorders and for the development of alternate treatment approaches.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Depressão/enzimologia , Aprendizagem em Labirinto/fisiologia , Animais , Comportamento Animal/fisiologia , Encéfalo/enzimologia , Condicionamento Clássico/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Depressão/genética , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Atividade Motora/genética , Ratos , Reflexo de Sobressalto/genéticaRESUMO
Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reactive oxygen species during metabolic processes. Various species--including humans and other primates--suffer mutations in the GULO gene encoding L-gulono-γ-lactone oxidase; GULO is the rate-limiting enzyme in the biosynthesis of ascorbate, an important cellular antioxidant. Animals lacking the ability to synthesize vitamin C develop scurvy without dietary supplementation. The Gulo-/- knockout (KO) mouse requires oral supplemental vitamin C; without this supplementation the animal dies with a scorbutic condition within several weeks. Vitamin C is known to be most abundant in the brain, where it is believed to play important roles in neuroprotection, neurotransmission and neuromodulation. We therefore hypothesized that ascorbate deficiency in Gulo-/- KO mice might lead to an abnormal behavioral phenotype. We established the amount of ascorbate in the drinking water (220 ppm) necessary for generating a chronic low-ascorbate status in the brain, yet clinically the mice appeared healthy throughout 100 days postpartum at which time all behavioral-phenotyping tests were completed. Compared with Gulo+/+ wild-type littermates, ascorbate-deficient Gulo-/- mice were found to be less active in moving in their environment; when in water, these mice swam more slowly in some tests, consistent with a mild motor deficit. We found no evidence of cognitive, anxiety or sensorimotor-gating problems. Despite being less active, Gulo-/- mice exhibited exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, point to developmental ascorbate deficiency causing long-term striatal dysfunction.
Assuntos
Deficiência de Ácido Ascórbico/enzimologia , Deficiência de Ácido Ascórbico/genética , Comportamento Animal/fisiologia , L-Gulonolactona Oxidase/deficiência , Animais , Animais Recém-Nascidos , Ácido Ascórbico/genética , Deficiência de Ácido Ascórbico/fisiopatologia , Modelos Animais de Doenças , Feminino , L-Gulonolactona Oxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , GravidezRESUMO
Methamphetamine (MA) is an abused stimulant which can result in cognitive deficits and monoamine depletions. Animal models of neurotoxic MA exposure show reductions in dopamine, serotonin, and their associated transporters. MA abuse can result in long-term attention, working memory, and executive function deficits in humans and deficits in route-based egocentric learning, novel object recognition, and novel odor preference in rodents. MA has also been shown to affect brain-derived neurotrophic factor (BDNF) in humans and rodents. This experiment examined the effects of a MA binge dosing regimen (10 mg/kg x 4 at 2 h intervals, s.c.) in Sprague-Dawley rats on BDNF, tropomyosin receptor kinase B (TrkB), and tyrosine hydroxylase (TH) mRNA expression, and plasma corticosterone. Tissues were collected 1, 7, and 24 h following the last MA dose. Expression of BDNF and TrkB mRNA was analyzed using in situ hybridization with cRNA probes. Frontal, parietal, and entorhinal cortical BDNF mRNA expression were increased by MA exposure at all time-points. Increases in BDNF mRNA were also seen in the hippocampal CA1, prefrontal cortex (PFC), piriform cortex, and locus coeruleus but only at specific times. TrkB mRNA expression was modified in several subregions of the hippocampus as well as in PFC and striatum. TH mRNA was increased at the 1 h time-point in the substantia nigra pars compacta with no differences noted at the other times. Corticosterone levels were increased at all three time-points. The findings suggest that BDNF and its receptor may be upregulated as a compensatory mechanism after MA exposure.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Metanfetamina/farmacologia , Receptor trkB/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Corticosterona/sangue , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkB/genéticaRESUMO
Methamphetamine (MA) induces multiple effects in rats including alterations to corticosterone (CORT) and adrenocorticotropic hormone (ACTH). This effect is age dependent showing a U-shaped function similar to that of other stressors during the stress hyporesponsive period. Neonatal MA treatment leads to adult learning and memory impairments, but whether these are related to MA-induced CORT release is unknown. Here in, four methods were tested in neonatal rats previously established in adult rats for inhibiting stress-induced CORT release: inhibiting synthesis (metyrapone (MET) or ketoconazole (KTZ)) or surgically by adrenalectomy or adrenal autotransplantation (ADXA). Pretreatment on postnatal day 11 with MET or KTZ prior to four doses of 10 mg/kg of MA initially suppressed MA-induced increases in plasma CORT, but 24 h later, even with additional inhibitor treatment, a large CORT increase was seen which exceeded that of MA alone. Adrenalectomy blocked MA-induced increases in CORT but caused a secondary effect on brain serotonin (5-HT) and dopamine (DA), causing greater reductions than those caused by MA alone. ADXA inhibited MA-induced CORT release without causing a 24-h CORT increase and did not produce additional effects on brain 5-HT or DA. Neonatal ADXA is a new model for developmental drug or stress experiments designed to test the role of CORT in mediating early effects on later outcomes.
Assuntos
Encéfalo/efeitos dos fármacos , Corticosterona/sangue , Metanfetamina/farmacologia , Serotonina/metabolismo , Glândulas Suprarrenais/transplante , Adrenalectomia , Hormônio Adrenocorticotrópico/sangue , Animais , Animais Recém-Nascidos , Corticosterona/antagonistas & inibidores , Corticosterona/biossíntese , Dopamina/metabolismo , Feminino , Cetoconazol/farmacologia , Masculino , Metirapona/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Serotonin (5-HT) is involved in many developmental processes and influences behaviors including anxiety, aggression, and cognition. Disruption of the serotonergic system has been implicated in human disorders including autism, depression, schizophrenia, and ADHD. Although pharmacological, neurotoxin, and dietary manipulation of 5-HT and tryptophan hydroxylase has added to our understanding of the serotonergic system, the results are complicated by multiple factors. A newly identified ETS domain transcription factor, Pet-1, has direct control of major aspects of 5-HT neuronal development. Pet-1 is the only known factor that is restricted in the brain to 5-HT neurons during development and adulthood and exerts dominant control over 5-HT neuronal phenotype. Disruption of Pet-1 produces an approximately 80% loss of 5-HT neurons and content and results in increased aggression in male Pet-1(-/-) mice [Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Neuron 37:233-247]. We hypothesized that Pet-1(-/-) mice would also exhibit changes in anxiety and cognition. Pet-1(-/-) mice were hypoactive which may have affected the observed lack of anxious behavior in the elevated zero maze and light-dark test. Pet-1(-/-) mice, however, were more defensive during marble burying and showed acoustic startle hyper-reactivity. No deficits in spatial, egocentric, or novel object recognition learning were found in Pet-1(-/-) mice. These findings were unexpected given that 5-HT depleting drugs given to adult or developing animals result in learning deficits [Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Brain Res 760:68-73; Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Eur J Neurosci 16:491-500; Vorhees CV, Schaefer TL, Williams MT (2007) Synapse 61:488-499]. Lack of differences may be the result of compensatory mechanisms in reaction to a constitutive knock out of Pet-1 or 5-HT may not be as important in learning and memory as previously suspected.
Assuntos
Ansiedade/psicologia , Cognição/fisiologia , Plasmocitoma/genética , Serotonina/fisiologia , Animais , Depressão/psicologia , Comportamento Exploratório , Feminino , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Fenótipo , Reconhecimento Psicológico , Reflexo de Sobressalto , Filtro Sensorial/fisiologiaRESUMO
PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.
Assuntos
Comportamento Animal/fisiologia , Química Encefálica/genética , Camundongos Knockout , Diester Fosfórico Hidrolases/deficiência , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Química Encefálica/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1 , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout/genética , Camundongos Knockout/metabolismo , Camundongos Knockout/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Fenciclidina/farmacologia , Fatores Sexuais , NataçãoRESUMO
Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Diester Fosfórico Hidrolases/metabolismo , Comportamento Espacial/efeitos dos fármacos , Análise de Variância , Animais , Ansiedade/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1 , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Feminino , Hipercinese/enzimologia , Hipercinese/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Diester Fosfórico Hidrolases/genética , Transdução de Sinais/fisiologia , Comportamento Espacial/fisiologiaRESUMO
The view that methamphetamine is neurotoxic to dopaminergic and serotonergic axon terminals has been based largely on biochemical and histological studies. In the present study, methamphetamine-induced structural damage to axons was quantified using a sensitive sandwich enzyme-linked immunosorbent assay developed for the detection of the cleaved form of the cytoskeletal protein tau. The administration of a monoamine-depleting regimen of methamphetamine (4 x 10 mg/kg, i.p. every 2 hours for a total of four injections) produced a time-dependent increase in the concentration of cleaved tau in the striatum. Maximal concentrations of cleaved tau were detected 3 days following methamphetamine administration. Cleaved tau concentrations also were significantly elevated in the dorsal hippocampus and, to a lesser extent, in the prefrontal cortex of methamphetamine-treated rats. Maintenance of rats in a cold (4 degrees C) environment not only prevented the methamphetamine-induced depletion of striatal dopamine and serotonin but also prevented the methamphetamine-induced increase in striatal cleaved tau concentrations. The novel findings from this study are supportive of the view that methamphetamine produces acute structural damage to neurons that may lead to the long-term neurotoxic effects of repeated, high-dose administration of the drug and that cleaved tau reliably quantifies the time-dependent neurotoxic effects of methamphetamine.
Assuntos
Química Encefálica/efeitos dos fármacos , Encéfalo/metabolismo , Metanfetamina/toxicidade , Proteínas tau/metabolismo , Animais , Proteínas do Citoesqueleto/metabolismo , Humanos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
D-Fenfluramine, a serotonin releaser, was administered to neonatal rats on postnatal days 11-20 (a stage of hippocampal development analogous to third trimester human ontogeny). As adults, the D-fenfluramine-treated offspring exhibited dose-related impairments of sequential and spatial learning and reference memory in the absence of sensorimotor impairments. Procedures to minimize stress and to control for other performance effects prior to testing for spatial learning demonstrated that nonspecific factors did not account for the selective effects of D-fenfluramine on learning and memory. Developmental D-fenfluramine-induced spatial and sequential learning deficits are similar to previous findings with developmental MDMA treatment. By contrast, recent findings with developmental D-methamphetamine treatment showed spatial learning deficits while sparing sequential learning. The spatial learning effects common to all three drugs suggest that they may share a common mechanism of action, however, the effects are not related to long-lasting changes in hippocampal 5-HT levels as no differences were found in adulthood. Whether the cognitive deficits are related to the effects of substituted amphetamines on corticosteroids, other aspects of the 5-HT system, or some unidentified neuronal substrates is not known, but the data demonstrate that these drugs are all capable of inducing long-term adverse effects on learning.
Assuntos
Fenfluramina/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Feminino , Hipocampo/metabolismo , Humanos , Aprendizagem/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Gravidez , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Taxa de SobrevidaRESUMO
Thalidomide-induced embryopathy has been known for four decades, however, the drug has been reintroduced for human use in a number of countries, including the United States. In utero thalidomide exposure in humans is associated with central nervous system (CNS) effects in addition to the well-known limb, ear and other malformations. Despite knowledge of these CNS effects, not a single experimental study could be found that examined thalidomide for possible developmental neurobehavioral effects. In the present experiment, gravid Sprague-Dawley rats were treated with either thalidomide (100 mg/kg by gavage) or vehicle (propylene glycol) on embryonic days E7-18 and allowed to deliver and raise their own offspring. The offspring were evaluated in a series of neurobehavioral tests (reflexes, locomotor activity, startle reactivity and learning in the Morris and Cincinnati water mazes). There was a small reduction in maternal weight among thalidomide-treated dams during midgestation. Thalidomide offspring showed increased preweaning mortality and male-specific, late onset reduction in growth that persisted until the end of the study. Male thalidomide offspring showed significant increases in errors and latency in the multiple-T Cincinnati water maze. Although rats are refractory to thalidomide-induced teratogenesis, the present results suggest that thalidomide selectively impairs offspring survival and growth and at least one type of learning among male offspring.
Assuntos
Comportamento Animal/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Teratogênicos/toxicidade , Talidomida/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/psicologia , Orientação/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Olfato/efeitos dos fármacos , Natação/fisiologiaRESUMO
Use of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has increased dramatically in recent years, yet little is known about its effects on the developing brain. Neonatal rats were administered MDMA on days 1-10 or 11-20 (analogous to early and late human third trimester brain development). MDMA exposure had no effect on survival but did affect body weight gain during treatment. After treatment, body weight largely recovered to 90-95% of controls. MDMA exposure on days 11-20 resulted in dose-related impairments of sequential learning and spatial learning and memory, whereas neonatal rats exposed on days 1-10 showed almost no effects. At neither stage of exposure did MDMA-treated offspring show effects on swimming ability or cued learning. Brain region-specific dopamine, serotonin, and norepinephrine changes were small and were not correlated to learning changes. These findings suggest that MDMA may pose a previously unrecognized risk to the developing brain by inducing long-term deleterious effects on learning and memory.
Assuntos
3,4-Metilenodioxianfetamina/administração & dosagem , Alucinógenos/administração & dosagem , Deficiências da Aprendizagem/induzido quimicamente , Transtornos da Memória/induzido quimicamente , Fatores Etários , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Reação de Fuga/efeitos dos fármacos , Feminino , Injeções Subcutâneas , Deficiências da Aprendizagem/diagnóstico , Deficiências da Aprendizagem/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/diagnóstico , Transtornos da Memória/fisiopatologia , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Taxa de SobrevidaRESUMO
Studies in both humans and animals demonstrate that D,L- and D-fenfluramine (D,L-FEN and D-FEN, respectively) can activate the hypothalamic-pituitary-adrenal axis following an acute dose. No data exist showing a prolonged effect of either drug, although two studies have hinted at increased adrenal activity. There are also considerable differences in the literature pertaining to the neurotoxic effects of D,L- and D-FEN. Some possible explanations for these differences include: activation of different neurotransmitter systems, the temperature at which the animals were maintained during exposure, or the substance sampled in each study. We investigated the effects of either D,L-FEN or D-FEN on pituitary, adrenal, and gonadal hormones 72 h after drug exposure. Furthermore, using a dosing regimen adapted from studies on methamphetamine (e.g., four times every 2 h in a single day) known to produce elevations in glial fibrillary acidic protein (GFAP) under hyperthermic conditions, we examined the effects of D- and D,L-FEN (15 mg/kg, four times) on GFAP content when the animals were dosed at ambient temperatures of 21 or 32 degrees C. Approximately fivefold increases of corticosterone and threefold increases of aldosterone were found 72 h later under resting conditions following both D- and D,L-FEN. Nonetheless, when animals were dosed with D-FEN at 32 degrees C, no significant elevation in corticosterone was detected. No effect was observed for ACTH, testosterone, or GFAP following D- or D,L-FEN treatment. These data suggest that: (1) FEN treatment causes prolonged elevations in adrenal cortical hormones; (2) FEN-treated animals displayed hormonal characteristics similar to animals undergoing a chronic stressor as suggested by no difference in ACTH titers; (3) D,L-FEN treatment or D-FEN treatment (as reported previously) is not similar to other substituted amphetamines in that it does not increase GFAP, even under hyperthermic conditions.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Aldosterona/sangue , Astrócitos/metabolismo , Encéfalo/metabolismo , Corticosterona/sangue , Fenfluramina/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Testosterona/sangue , Animais , Astrócitos/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Fatores de TempoRESUMO
D-Methamphetamine (D-MA) treatment during the neonatal period has been shown to induce acoustic startle hyperreactivity and Morris maze spatial learning deficits, but not to significantly affect Cincinnati maze sequential learning. In order to characterize the internal dose in these experiments, MA was measured in plasma and brain of neonatal rats at one of two ages, and using one of three dose schedules, two of which were selected to be representative of those used in previously published neurobehavioral studies. Plasma parameters showed few age and dose-frequency effects; however, brain concentrations showed more consistent age-dependent effects. Brain area under the concentration (AUC) values were consistently higher, regardless of dosing schedule, in offspring treated on postnatal day (P) 1 compared to those treated on P11. Previous results with the multiple-dose schedules have shown that Morris maze spatial learning deficits only occur in those exposed beginning on P11, whereas acoustic startle hyperreactivity is associated with exposure beginning on either P1 or P11. The pharmacokinetic parameters did not predict the long-term spatial learning and memory effects of neonatal MA administration, nor are they well correlated to the acoustic startle effects. The plasma concentrations obtained in rats are within the range for human MA abusers based on extrapolations from human low-dose values to those expected for heavy users.
Assuntos
Encéfalo/metabolismo , Metanfetamina/farmacocinética , Animais , Animais Recém-Nascidos , Área Sob a Curva , Injeções Subcutâneas , Metanfetamina/administração & dosagem , Metanfetamina/sangue , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: The long-term neurochemical effects produced by the repeated administration of methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) are well documented; however, the functional consequences have not been clearly defined. OBJECTIVE: The present study was designed to investigate whether rats treated with a monoamine-depleting regimen of MA or MDMA exhibit disturbances in locomotor activity during the diurnal and nocturnal cycles. METHODS: Rats were treated with the vehicle or a monoamine-depleting regimen of MA or MDMA (10 mg/kg, IP, every 2 h for four injections on a single day). One week after drug treatment, the rats were placed in residential activity chambers and their locomotor activity was monitored for the next 7-day/night cycles. RESULTS: MA-treated rats exhibited depletions of striatal dopamine and serotonin content of approximately 70%, whereas MDMA-treated rats showed depletions of striatal serotonin content of approximately 50%. Rats treated with MA demonstrated a significant reduction in diurnal, but not nocturnal, locomotor activity, whereas MDMA-treated rats exhibited significant reductions in both diurnal and nocturnal locomotor activity. Analysis of the difference in activity between the nocturnal and diurnal cycles revealed that MA-treated animals exhibited a significantly greater change in activity as compared to that observed in vehicle- and MDMA-treated rats. CONCLUSIONS: Although it is unknown whether the adaptations in locomotor activity observed in MA- and MDMA-treated rats are due to the loss of dopamine and/or serotonin, these data suggest that the administration of a monoamine-depleting regimen of MA or MDMA results in alterations in light-cycle-dependent locomotor activity.
Assuntos
3,4-Metilenodioxianfetamina/análogos & derivados , 3,4-Metilenodioxianfetamina/farmacologia , Ritmo Circadiano , Dopaminérgicos/farmacologia , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Monoaminas Biogênicas/metabolismo , Ritmo Circadiano/fisiologia , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
The administration of a neurotoxic regimen of methamphetamine (MA) produces an acute elevation in the extracellular concentrations of dopamine and glutamate in the striatum and a long-term depletion of striatal dopamine content in rats. The intent of the present study was to determine whether attenuation of the MA-induced increase in extracellular glutamate would prevent the depletion of striatal dopamine. Male rats were treated with MA (10 mg/kg, i.p.) or vehicle every 2 h for four injections and concomitantly perfused intrastriatally with either artificial cerebrospinal fluid or lubeluzole (300 microM), a novel neuroprotectant that has been shown to prevent the increase in extracellular glutamate after the induction of neocortical infarct in rats. Lubeluzole significantly attenuated the MA-induced increase in extracellular glutamate in the striatum without affecting the MA-induced increase in extracellular dopamine or the MA-induced hyperthermic response. Nevertheless, lubeluzole did not prevent the long-term depletion of striatal dopamine produced by a neurotoxic regimen of MA. These results suggest that the MA-induced depletion of striatal dopamine may not be dependent on the increased extracellular concentration of striatal glutamate.
Assuntos
Dopamina/metabolismo , Interações Medicamentosas/fisiologia , Ácido Glutâmico/metabolismo , Metanfetamina/toxicidade , Neostriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Tiazóis/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Masculino , Neostriado/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismo , Veratridina/farmacologiaRESUMO
A neurotoxic regimen of methamphetamine (MA) produces long-term depletions in neostriatal dopamine and serotonin concentrations. In addition to evidence of dopaminergic and serotonergic neurotoxicity, there is evidence of MA-induced behavioral changes. In this regard, stereotypic behavior elicited by MA is greater in rats treated previously with a neurotoxic regimen of MA than in control animals. The present study was designed to determine whether the enhanced stereotypy observed in MA-treated rats is due to the MA-induced loss of dopamine (neurotoxicity) or to the repeated exposure to MA (sensitization). Rats were treated with MA (10 mg/kg every 2 h for four injections) or vehicle at either a normal (24 degrees C) room temperature or a cold (4 degrees C) room temperature, which has been shown to attenuate the MA-induced loss of dopamine. Stereotypy was assessed 7 days after treatment. Rats that had received a neurotoxic regimen of MA at 24 degrees C exhibited 49% and 45% reductions in neostriatal dopamine and serotonin concentrations, respectively, whereas rats treated with MA at 4 degrees C had no significant neurochemical depletions. Stereotypy elicited by MA (5.0 mg/kg) was significantly greater in rats treated with a neurotoxic regimen of MA regardless of the initial treatment temperature. In addition, an injection of apomorphine (0.5 mg/kg) elicited an enhanced stereotypic response in MA-treated rats. These data suggest that the augmented stereotypic behavior observed in rats treated with a neurotoxic regimen of MA is not due to the loss of dopamine, but rather the manifestation of behavioral sensitization, possibly due to an increase in dopamine receptor sensitivity.
Assuntos
Encéfalo/efeitos dos fármacos , Metanfetamina/toxicidade , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Comportamento Estereotipado/efeitos dos fármacos , Animais , Apomorfina/farmacologia , Encéfalo/citologia , Encéfalo/metabolismo , Temperatura Baixa/efeitos adversos , Dopamina/metabolismo , Masculino , Neostriado/citologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Serotonina/metabolismo , Comportamento Estereotipado/fisiologiaRESUMO
Treatment with methamphetamine (MA) on postnatal days P11-20 induces adult spatial learning and memory deficits without affecting monoamine levels in various brain regions. In this study, we examined the pituitary and adrenal response of animals administered MA four times daily on P11, P11-15, or from P11 to P20. Corticosterone (CORT) and adrenocorticotropin hormone (ACTH) levels were assessed over a 1-hour period following MA exposure. On P11, MA produced marked elevations of both CORT and ACTH; this is during the stress hyporesponsive period (SHRP). On P15 and P20, the maximal effect of MA on CORT titers was observed at 30 min, with lower, but still significantly increased, levels at 60 min compared to controls. Males receiving MA on P15 had higher levels of ACTH than did control males, while no differences were noted among females. On P20, MA treatment resulted in higher levels of ACTH relative to vehicle-injected controls, but levels were not different from controls that were only weighed at each drug administration. MA treatment inhibited body, but not brain weight gain, resulting in hippocampal weights that were heavier in the MA-treated animals when expressed as a percent of body weight. The elevations of adrenal steroids by MA, during late phases of hippocampal neurogenesis, may contribute to neuronal alterations that are later manifested in deficits of learning and memory.