RESUMO
BACKGROUND: COVID-19 restrictions have significantly limited access to in-person educational and healthcare services for all, including individuals with intellectual and developmental disabilities (IDDs). The objectives of this online survey that included both national and international families were to capture changes in access to healthcare and educational services for individuals with IDDs that occurred shortly after restrictions were initiated and to survey families on resources that could improve services for these individuals. METHODS: This was an online survey for caregivers of individuals with (1) a genetic diagnosis and (2) a neurodevelopmental diagnosis, including developmental delay, intellectual disability, autism spectrum disorder or epilepsy. The survey assessed (1) demographics, (2) changes in access to educational and healthcare services and (3) available and preferred resources to help families navigate the changes in service allocation. RESULTS: Of the 818 responses (669 within the USA and 149 outside of the USA), most families reported a loss of at least some educational or healthcare services. Seventy-four per cent of parents reported that their child lost access to at least one therapy or education service, and 36% of respondents lost access to a healthcare provider. Only 56% reported that their child received at least some continued services through tele-education. Those that needed to access healthcare providers did so primarily through telemedicine. Telehealth (both tele-education and telemedicine) was reported to be helpful when available, and caregivers most often endorsed a need for an augmentation of these remote delivery services, such as 1:1 videoconference sessions, as well as increased access to 1:1 aides in the home. CONCLUSIONS: COVID-19 restrictions have greatly affected access to services for individuals with syndromic IDDs. Telehealth may provide opportunities for delivery of care and education in a sustainable way, not only as restrictions endure but also after they have been lifted.
RESUMO
The neurotoxic heavy metal trimethyltin (TMT) primarily damages neurons of the hippocampus and limbic areas of the temporal lobe, and causes a dose-dependent decrease in the polysialated form of the neural cell adhesion molecule (PSA-NCAM) in the mouse hippocampus. In the current study, we attempted to associate deficits in spatial learning following TMT exposure at various stages in learning with changes in levels of NCAM-180 and PSA-NCAM in both the hippocampus and frontal cortex. Mice were treated with TMT either before or after training on a spatial learning paradigm and examined for changes in NCAM and PSA-NCAM 12h later. In the first set of experiments, male BALB/c mice were injected with TMT (2.25 mg/kg) or saline i.p. and tested 24-168 h later using hidden and visible versions of the water maze, as well as light avoidance and motor activity. Mice in both treated and control groups which demonstrated a significant improvement in water maze performance also showed an elevation in hippocampal PSA-NCAM at all time points examined. TMT exposure impaired spatial learning and blocked learning-induced elevations in PSA-NCAM expression 24-96 h post-treatment, but these deficits disappeared by 168 h post-treatment. Mice exposed to TMT during reconsolidation of spatial learning (after repeated water maze training) demonstrated a mild and transient difference in escape latency compared to saline exposed mice. TMT administration during this period did not result in the attenuation of PSA-NCAM expression observed when animals were exposed before training. These results confirm a specific role for PSA-NCAM in acquisition and consolidation of spatial memory.
Assuntos
Comportamento Animal/efeitos dos fármacos , Molécula L1 de Adesão de Célula Nervosa/biossíntese , Ácidos Siálicos/biossíntese , Compostos de Trimetilestanho/toxicidade , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Western Blotting , Química Encefálica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora/efeitos dos fármacosRESUMO
We have previously shown that coadministration of the dopamine (DA) agonist phentermine plus the serotonergic agonist fenfluramine suppresses alcohol intake and withdrawal seizures in rats. In the present study, phentermine and the serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (5-HTP), were administered alone, or in combination, to rats fed on a 6% alcohol-containing diet or an isocaloric control diet. Following a 9-h withdrawal period from the alcohol-containing diet, phentermine enhanced the effects of 5-HTP on both reduction of alcohol withdrawal seizures as well as changes in striatal serotonin. Food intake was monitored for 24 h after drug treatment, and neurochemical measures were examined at various time points. Phentermine alone reduced food intake in all diet conditions, but this anorectic effect was followed by hyperphagia in control rats. Phentermine plus 5-HTP reduced the consumption of the alcohol-containing diet, while its effects on consumption of control diets were mixed. In vivo microdialysis in rat nucleus accumbens revealed that phentermine increased extracellular DA, whereas 5-HTP caused marked elevations in extracellular 5-HT. Coadministration of phentermine and 5-HTP evoked simultaneous elevations in extracellular DA and 5-HT that mirrored the effects of each drug alone. Collectively, these findings show that coadministered phentermine plus 5-HTP is effective in reducing alcohol intake and suppressing alcohol withdrawal seizures. These therapeutic actions may be related to elevations in synaptic DA and 5-HT in critical brain regions.
Assuntos
5-Hidroxitriptofano/uso terapêutico , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Convulsões por Abstinência de Álcool/tratamento farmacológico , Monoaminas Biogênicas/metabolismo , Estimulantes do Sistema Nervoso Central/uso terapêutico , Fentermina/uso terapêutico , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Depressores do Sistema Nervoso Central/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Etanol/efeitos adversos , Masculino , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
Developmental exposure to methylmercury (MeHg) induces a spectrum of neurological impairment characterized by cognitive disturbance, sensory/motor deficit, and diffuse structural abnormalities of the brain. These alterations may arise from neural path-finding errors during brain development, resulting from disturbances in the function of morphoregulatory guidance molecules. The Eph family of tyrosine kinase receptors and their ligands, the ephrins, guide neuronal migration and neurite pathfinding mainly via repulsive intercellular interactions. The present study examined the effects of MeHg on mRNA and protein expression profiles of Ephs and ephrins in the P19 embryonal carcinoma (EC) cell line and its neuronal derivatives. Undifferentiated control P19 cells displayed low- to undetectable levels of mRNA for ephrins or Ephs, with the sole exception of EphA2 which was highly expressed. Upon differentiation into neurons, the ephrin expression increased progressively through day 10. Similarly, expression of the Ephs, including EphsA3, -A4, -A8, -B2, -B3, -B4, and -B6, increased significantly. In contrast, EphA2 expression decreased in day 2, 6 and 10 control neurons. Treatment with MeHg did not affect the expression of mRNA for ephrins or Ephs in undifferentiated P19 cells. However, treatment of differentiating neurons with MeHg for 24 h caused consistent increases in ligand mRNA expression, particularly ephrin-A5, -A6, -B1, and -B2. Similarly, MeHg induced variable increases in mRNA expression of receptors EphA2, -A3, -B3, and -B6. A trend toward a concentration-response relationship was observed for the alterations in Eph receptor mRNA expression although increases at the low and mid concentrations did not reach statistical significance. Immunoblots for ligand and receptor proteins mirrored the increases in the mRNA levels at the 0.5 and 1.5 microM MeHg concentrations but showed decreased protein levels compared to controls at the 3.0 microM concentration. Alterations in the Eph/ephrin family of repulsion molecules may represent an important mechanism in developmental MeHg neurotoxicity.
Assuntos
Efrinas/biossíntese , Compostos de Metilmercúrio/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neurônios/fisiologia , Receptores da Família Eph/biossíntese , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células-Tronco de Carcinoma Embrionário , Efrinas/genética , Humanos , Immunoblotting , Hibridização In Situ , Ligantes , Neurônios/efeitos dos fármacos , Ensaios de Proteção de Nucleases , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/análise , RNA Neoplásico/biossíntese , Receptores da Família Eph/genéticaRESUMO
The Eph family tyrosine kinase receptors and their ligands have been linked to axon guidance and topographic mapping of the developing central nervous system. More specifically, the EphA5 receptor has been shown to play a role in development of hippocamposeptal, retinotectal and thalamocortical projections. Recently, a line of transgenic mice was developed which expresses a truncated EphA5 receptor lacking a functional tyrosine kinase domain. In a previous study, axonal tracing revealed that medial hippocampal axons in this strain projected laterally and ventrally away from their normal target area. In the current study, both transgenic and wild-type controls were evaluated in unconditioned (rotorod and locomotor activity) and conditioned (water maze and active avoidance) behavior tasks which tested hippocampal and striatal functioning. Compared to controls, the transgenic strain did not show differences in rotorod motor activity but did show a transient deficit in spatial navigation ability and a consistent impairment in active avoidance. The dominant-negative mutant receptor also resulted in a decrease in striatal dopamine and serotonin concentrations with no change in hippocampal monoamines. Collectively, these data suggest that animals expressing a truncated EphA5 receptor show deficits related to striatal functioning.
Assuntos
Química Encefálica/genética , Encéfalo/metabolismo , Dopamina/metabolismo , Genes Dominantes/genética , Receptor EphA5/biossíntese , Serotonina/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Encéfalo/fisiopatologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Regulação para Baixo/genética , Feminino , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Atividade Motora/genética , Mutação/genética , Receptor EphA5/genéticaRESUMO
The role of both monoamine synthesis and monoamine oxidase inhibition in mediating the fenfluramine-induced damage to serotonin neurones was examined; as pretreatment agents, both alpha-methyl-para-tyrosine (AMPT) and parachlorophenylalanine (PCPA) were used to deplete dopamine and serotonin, respectively, while clorgyline and deprenyl were used to inhibit monoamine oxidase types A and B. While both AMPT and deprenyl did not alter fenfluramine induced serotonin or 5-hydroxyindoleacetic acid (5-HIAA) depletion in any area, PCPA did partially reduce the serotonin depletion in the hippocampus and hypothalamus. Although pretreatment with clorgyline did not significantly alter fenfluramine-induced serotonin depletion, it did produce a 65% mortality rate in animals treated with both drugs. Both PCPA and clorgyline significantly increased the depletion of striatal 5-HIAA concentration consequent to fenfluramine; however, these drugs also produced a long-term depletion of striatal 5-HIAA when administered alone, therefore, the changes seen after the coadministration with fenfluramine may be viewed as additive. Finally, acute PCPA pretreatment attenuated the rapid rise in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (homovanillic acid) induced by fenfluramine, and acute clorgyline reversed the drop in serotonin and rise in 5-HIAA induced by fenfluramine. These results indicate that the rapid increase in dopamine activity induced by fenfluramine is partially dependent on serotonin concentration and release and that the mechanism of fenfluramine-induced toxicity is unlike that of the other substituted amphetamines.
Assuntos
Corpo Estriado/efeitos dos fármacos , Fenfluramina/toxicidade , Inibidores da Monoaminoxidase/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Serotonina/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Clorgilina/farmacologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Interações Medicamentosas , Fenclonina/farmacologia , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Selegilina/farmacologia , Antagonistas da Serotonina/farmacologia , Triptofano/farmacologia , alfa-Metiltirosina/farmacologiaRESUMO
The effect of an amphetamine-induced depletion of striatal dopamine on active and passive avoidance responding of rats was examined. Sixteen animals received two sets of 4 injections each of 15 mg/kg d-amphetamine, administered at 2 hr intervals with each set delivered one week apart. One week after the last injection, animals were given 50 consecutive active avoidance trials in a shuttle box. Animals treated with amphetamine exhibited a 50%, depletion of striatal dopamine and showed a slower learning curve, as evidenced by significantly fewer avoidances and a slower escape latency during trials 21-30. Both groups demonstrated a 90% avoidance rate by trials 41-50. A separate group of rats was treated as above and trained for several weeks on the active avoidance procedure. Haloperidol (0.01-0.10 mg/kg intraperitoneally) dose-dependently decreased avoidance number and increased avoidance and escape latency in both groups, an effect that was exaggerated in those animals previously treated with amphetamine. Finally, these animals were tested in the same apparatus using a passive avoidance procedure. The amphetamine treatment produced a significantly higher mean number of avoidances in this procedure compared to saline-treated animals during trials 1-20. These results suggest that the impairment in conditioned avoidance following amphetamine treatment is due to a motoric, rather than a cognitive deficit.
Assuntos
Anfetamina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Dopamina/deficiência , Animais , Cognição/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Haloperidol , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The drug combination of phentermine plus fenfluramine has been used clinically in both the treatment of obesity and alcoholism. The aim of the current study was to assess the interaction of the two drugs on consumption of both an alcohol-containing and a nonalcoholic diet. Furthermore, the efficacy of the drug combination on suppression of withdrawal seizures was determined. Animals were either maintained on a 6% alcohol-containing diet, free-fed an isocaloric control, or pair-fed the control diet. It was observed that, with regard to body weight growth curves, alcohol provides about 2.5 kcal/g. Both phentermine and fenfluramine caused a decrease in consumption 1 h after administration; however, during the next 23 h, 4 mg/kg phentermine significantly increased consumption of all diets. At doses of 1 and 2 mg/kg, fenfluramine selectively reduced consumption of the alcohol-containing diet as compared to the isocaloric diets. Lower doses of fenfluramine blocked the increases in consumption induced by phentermine. Furthermore, in animals fed the nonalcoholic diet, the drug combination of 2 mg/kg fenfluramine plus 8 mg/kg phentermine produced a 63-82% reduction in consumption, an effect not seen when either drug was administered alone. This greater than additive effect was also seen in the earlier time periods in animals pair-fed the control diet. Neurochemical analysis from these animals revealed that the alcohol-dependent animals displayed a significant reduction of DOPAC and 5-HIAA levels in the striatum, frontal cortex, and hypothalamus after a 9-h withdrawal period, further implicating the serotonergic and dopaminergic systems in mediation of withdrawal symptoms and alcohol craving. Finally, 8 mg/kg phentermine plus 8 mg/kg fenfluramine completely abolished alcohol withdrawal seizures, compared to a 78% rate in saline treated rats. In conclusion, the coadministration of phentermine plus fenfluramine produced a moderate reduction of alcohol consumption and was completely effective at reducing alcohol withdrawal seizures.
Assuntos
Consumo de Bebidas Alcoólicas/terapia , Convulsões por Abstinência de Álcool/tratamento farmacológico , Depressores do Apetite/uso terapêutico , Fenfluramina/uso terapêutico , Fentermina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Consumo de Bebidas Alcoólicas/efeitos adversos , Animais , Depressores do Apetite/farmacologia , Interações Medicamentosas , Quimioterapia Combinada , Ingestão de Alimentos/efeitos dos fármacos , Fenfluramina/farmacologia , Masculino , Fentermina/farmacologia , Ratos , Ratos Long-Evans , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
The Eph family tyrosine kinase receptors and their ligands have been implicated in axon guidance and neuronal migration during development of the nervous system. In the current study, we aim to characterize the nature of changes in EphB1 receptor expression following increases or decreases in dopamine activity. Neonatal mice (P3) were injected with 6-hydroxydopamine and allowed 13 days to recover. These animals show a profound depletion of dopamine in all areas assayed, with a corresponding dose-dependent decrease in EphB1 expression. Day 3 pups were also injected either chronically (P3-P16) or acutely (P3 only) with cocaine to determine how enhancing dopamine signaling would affect EphB1 signal density. It was found that both treatments significantly increased expression of EphB1 in the cortex, striatum and substantia nigra. Finally, animals were treated prenatally (E15-E17) with cocaine and sacrificed on P7. These animals also showed an increase in EphB1 signal density, but only in the dopaminergic terminal areas in the cortex and striatum. These studies indicate that dopamine activity regulates developmental expression of the tyrosine kinase receptor EphB1.
Assuntos
Dopamina/metabolismo , Proteínas de Membrana/genética , Transdução de Sinais/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/análise , Animais , Animais Recém-Nascidos , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Corpo Estriado/química , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/análise , Inibidores da Captação de Dopamina/farmacologia , Efrina-B1 , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Ácido Homovanílico/análise , Hibridização In Situ , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Oxidopamina , Gravidez , RNA Mensageiro/análise , Transdução de Sinais/efeitos dos fármacos , Substância Negra/química , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , SimpatolíticosRESUMO
In a previous study in which a single 2.5 mg/kg (15.4 micromol/kg) s. c. dose of nicotine effected a transient, lung-specific induction of cytochrome P-450 (CYP) 1A1 in the rat, a dose-response study and assessment of the lung specificity of the induction was limited by toxicity of the acute parenteral nicotine exposure. In the present study, we examined the dose-CYP1A1/2 induction response relationship and the tissue specificity of the induction by orally administered nicotine, which lacks the toxicity of the parenterally administered drug. Nicotine, administered in a nutritionally balanced liquid diet, at a level of 20 (low), 60 (medium), or 200 (high) mg/kg of diet, induced CYP1A1 in the lung and kidney in a dose-dependent manner and in the liver at the high nicotine dose only, whereas CYP1A2 was induced in the liver dose-dependently and in the kidney at the high nicotine dose only. The high nicotine dose up-regulated mRNA level in the three tissues examined, but with the lung being the most responsive to the up-regulation. Induction of the CYP1A1-preferential activity ethoxyresorufin O-deethylase by the low, medium, and high nicotine diets was 1.9-, 4.9-, and 21.6-fold, respectively, in the lung, 1.4-, 1.7-, and 15.9-fold, respectively, in the kidney, and 1.7-, 2.9-, and 5.1-fold, respectively, in the liver. Similarly, albeit to lower extents, the dietary alkaloid induced the CYP1A2-preferential activity methoxyresorufin O-demethylase in all three tissues dose-dependently. Plasma nicotine concentration correlated neither with the dietary nor intake dose of the alkaloid nor with tissue levels of CYP1A, especially with the high-dose diet. Plasma nicotine levels at which CYP1A induction was maximal were comparable to those reported in smokers, suggesting that nicotine may induce CYP1A1 in humans.
Assuntos
Citocromo P-450 CYP1A1/biossíntese , Rim/enzimologia , Fígado/enzimologia , Pulmão/enzimologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Northern Blotting , Western Blotting , Cotinina/sangue , Citocromo P-450 CYP1A1/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Dieta , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Indução Enzimática/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Nicotina/sangue , Agonistas Nicotínicos/sangue , Oxirredutases/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Long-EvansRESUMO
1. Male Swiss Webster mice were administered a series of amphetamine injections preceded by either saline or L-DOPA. 2. This injection regimen was performed for either one, two or three consecutive weeks and neurotoxic effects of the drugs were determined one week later. 3. Amphetamine treatment for two weeks produced a greater striata-dopaminergic lesion that treatment for only one week. Three weeks of treatment did not exacerbate the lesion, indicating that the damage had reached maximal levels. 4. L-DOPA pretreatment did not significantly alter any of the toxic effects of the amphetamine. Therefore, some dopaminergic neurons may be resistant to the toxic effects of amphetamine.
Assuntos
Encéfalo/metabolismo , Dextroanfetamina/toxicidade , Dopamina/metabolismo , Levodopa/toxicidade , Neurotoxinas/toxicidade , Serotonina/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Benserazida/farmacologia , Encéfalo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Interações Medicamentosas , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Ácido Homovanílico/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Especificidade de Órgãos , Fatores de TempoRESUMO
The goal of the present study was to determine if enhancement of tryptophan levels in a nutritionally balanced liquid diet would affect alcohol intake in a two-bottle choice procedure. Furthermore. the monoaminergic agonists amphetamine, phentermine (dopaminergic- and noradrenergic-releasing drugs), and fenfluramine (a serotonin releaser) were administered to determine if these drugs reduced alcohol intake in animals fed the tryptophan-enhanced diet compared to those fed an alcohol-containing diet without added tryptophan. Amphetamine 0.5 and 2 mg/kg and phentermine 4 mg/kg selectively reduced alcohol intake in animals fed the tryptophan-enhanced diet; higher doses also reduced alcohol intake in animals fed the control alcohol diet. Three hours after drug administration, phentermine 2 and 4 mg/kg produced increases in consumption of the nonalcoholic diet in animals fed the control diet without affecting consumption in animals fed the tryptophan-enhanced diet. Finally, animals in the tryptophan-enhanced group gained less weight than those animals fed an identical diet without the added tryptophan. Neurochemical analysis revealed that the tryptophan-fed groups showed increased 5-HIAA concentrations and serotonin turnover in the striatum. hypothalamus, and frontal cortex compared to animals fed the control diet. The tryptophan-alcohol group also showed almost double the tryptophan levels in the hypothalamus compared to the tryptophan-isocaloric group. These results indicate that, whereas increasing tryptophan levels by itself was not sufficient to alter consumption of an alcohol-containing diet, the administration of monoaminergic agonists significantly interacted with tryptophan in a dose-dependent manner to reduce intake of an alcohol-containing diet without reducing intake of an isocaloric diet.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Depressores do Apetite/uso terapêutico , Dopamina/metabolismo , Alimentos Formulados , Serotonina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Triptofano/uso terapêutico , Anfetamina/uso terapêutico , Animais , Córtex Cerebral/química , Corpo Estriado/química , Dopamina/análise , Fenfluramina/uso terapêutico , Hipotálamo/química , Fentermina/uso terapêutico , Ratos , Ratos Long-Evans , Serotonina/análiseRESUMO
To determine if rats would consume nicotine at psychoactive levels, a nutritionally balanced diet with 0, 20, 60, or 200 mg of nicotine tartrate per kg of diet was provided. Diet consumption and body weight differences were recorded for 14 days after which, following 16 hr of withdrawal, animals were given access to a two-bottle choice of the previously presented diet and a nicotine-free diet. Spontaneous horizontal motor activity was recorded 8, 16, and 24 hr after withdrawal. By Day 14, all animals showed a significant increase in diet consumption and significant weight gain compared to Day 1. Animals consumed an average of 2.1, 6.8, or 19.5 mg/kg/day of nicotine on the low, medium, and high-nicotine diets, respectively. However, animals receiving the high-nicotine diet consumed less diet and gained less weight than the control, low, and medium nicotine groups. During only the first 4 hr of the two-bottle choice (16-20 hr postwithdrawal), the high-nicotine group consumed significantly higher amounts of nicotine base than the other groups, but also consumed more of the control diet during the first 2 hr. In a replicate experiment, animals receiving the medium-nicotine diet showed an increased consumption of the nicotine diet and increased preference for nicotine following a 14-day exposure compared to the control-fed animals and compared to a baseline preference test. Also, this group showed differences in locomotor activity consistent with other studies using an injection regimen or subcutaneuos pumps to induce dependence. Finally, animals in all three groups exhibited high plasma nicotine and cotinine (a major nicotine metabolite) levels. Because animals in all groups tolerated the diet well, gained weight, selected the nicotine diet in a choice test, and showed withdrawal symptoms, we conclude that the liquid diet proved to be a satisfactory method of inducing nicotine dependence in rats.
Assuntos
Nicotina/farmacologia , Psicotrópicos/farmacologia , Tabagismo , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Cotinina/sangue , Dieta , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Nicotina/administração & dosagem , Nicotina/sangue , Psicotrópicos/administração & dosagem , Ratos , Ratos Long-Evans , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
The effect of ginseng total saponin (GTS) on amphetamine (AMPH)-induced disruption of fixed-interval (FI) responding in rats was examined. GTS (50 mg/kg) significantly improved the temporal responding impaired by 2 mg/kg of AMPH. A higher dose of 100 mg/kg GTS disrupted performance when given alone; this disruption was reversed by a low dose of AMPH (0.5 mg/kg) and tolerance developed to the effects of GTS with its repeated administration. Neurochemical analysis revealed that GTS (50 mg/kg) attenuated the increase in striatal dopamine caused by AMPH leading to the conclusion that brain dopamine may partially mediate the behavioral effects of GTS.
Assuntos
Anfetaminas/farmacologia , Comportamento Animal/efeitos dos fármacos , Panax/química , Plantas Medicinais , Saponinas/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Dopaminergic neurons in the substantia nigra and ventral tegmental area project to the caudate putamen and nucleus accumbens/olfactory tubercle, respectively, constituting mesostriatal and mesolimbic pathways. The molecular signals that confer target specificity of different dopaminergic neurons are not known. We now report that EphB1 and ephrin-B2, a receptor and ligand of the Eph family, are candidate guidance molecules for the development of these distinct pathways. EphB1 and ephrin-B2 are expressed in complementary patterns in the midbrain dopaminergic neurons and their targets, and the ligand specifically inhibits the growth of neurites and induces the cell loss of substantia nigra, but not ventral tegmental, dopaminergic neurons. These studies suggest that the ligand-receptor pair may contribute to the establishment of distinct neural pathways by selectively inhibiting the neurite outgrowth and cell survival of mistargeted neurons. In addition, we show that ephrin-B2 expression is upregulated by cocaine and amphetamine in adult mice, suggesting that ephrin-B2/EphB1 interaction may play a role in drug-induced plasticity in adults as well.
Assuntos
Dopamina/fisiologia , Proteínas de Membrana/fisiologia , Mesencéfalo/fisiologia , Animais , Morte Celular/fisiologia , Cocaína/farmacologia , Corpo Estriado/metabolismo , Dextroanfetamina/farmacologia , Efrina-B1 , Efrina-B2 , Camundongos , Camundongos Endogâmicos , Vias Neurais/fisiologia , Neuritos/fisiologia , Neurônios/fisiologia , Substância Negra/citologia , Substância Negra/fisiologia , Tegmento Mesencefálico/citologia , Tegmento Mesencefálico/fisiologiaRESUMO
The effect of ginseng total saponin (GTS) on amphetamine (AMPH)-induced disruption of fixed-interval (Fl) responding in rats was examined. GTS (50 mg/kg) significantly improved the temporal responding impaired by 2 mg/kg of AMPH. A higher dose of 100 mg/kg GTS disrupted performance when given alone; this disruption was reversed by a low dose of AMPH (0.5 mg/kg) and tolerance developed to the effects of GTS with its repeated administration. Neurochemical analysis revealed that GTS (50 mg/kg) attenuated the increase in striatal dopamine caused by AMPH leading to the conclusion that brain dopamine may partially mediate the behavioral effects of GTS.
RESUMO
Previous studies have reported the use of combined serotonergic and dopaminergic agonists in the treatment of obesity and alcoholism. Along these lines, phentermine plus fenfluramine has been suggested as a possible clinical treatment for alcohol craving. To determine the neurochemical effects of a combined treatment of phentermine plus fenfluramine, animals were injected subcutaneously with saline, phentermine 12 mg/kg, fenfluramine 16 mg/kg, or a combination of phentermine plus fenfluramine. One hour after injection, animals were sacrificed and neurochemical analysis performed. Furthermore, separate groups of animals were given the same injections 8 times, 12 hours apart, to determine the effects on body weight and to detect a possible exacerbation of fenfluramine induced toxicity. The drug combination produced a significant rise in dopamine in the striatum, greater than that seen with either drug alone. Furthermore, the addition of phentermine reduced the fenfluramine induced rise in striatal 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindolacetic acid (5-HIAA). Phentermine plus fenfluramine combination produced a greater weight loss than either drug alone, however, it did not produce a significantly greater drop in striatal serotonin or 5-HIAA levels above that induced by fenfluramine alone. Thus, while previous studies report the potentiated neurotoxicity of phentermine plus fenfluramine over fenfluramine alone, the present study does not indicate that such an effect occurs following an administration regimen analogous to that of patients treated with the drug combination.
Assuntos
Adrenérgicos/toxicidade , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Dopaminérgicos/toxicidade , Fenfluramina/toxicidade , Fentermina/toxicidade , Serotoninérgicos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Sinergismo Farmacológico , Fenfluramina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Fentermina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismoRESUMO
Experiments were carried out with a nutritionally balanced diet to test the response of rats to levels of ethanol between 0% and 6%, and to different levels and sources of protein and amino acid supplements in relation to alcohol utilization and withdrawal seizures. The high-calorie/high-carbohydrate liquid diet was well tolerated when the alcohol level was less than 30% of total calories, or 4.5% of diet. When alcohol was provided at 6% of diet, or 33% of total calories, growth and withdrawal seizure rates were negatively affected in comparison with the lower ethanol levels, even though ethanol consumption (in g/kg/day) was not different. The 6% alcohol diet was then altered through the addition of more protein calories, from 13% to 20%. This supplementation improved growth rate of the animals and reduced the rate of withdrawal seizures. The improvement from the additional protein was observed with both casein and soy protein, and was not attributable to any one or even several amino acids that might serve as transmitter precursors. A mixture of all essential amino acids representing the difference in amino acids between 13% and 20% casein protein calories was an effective as the equivalent amount of intact protein. The nonessential amino acids equivalent to 7% casein protein calories, when added to the 13% protein calories diet, increased the rate of withdrawal seizures, presumably by exacerbating the protein deficiency in the 13% protein diet. It was concluded that a 1000-1200 kcal/kg diet with 20% kcal from protein and 50% kcal from carbohydrate provides an optimal nutrient balance for efficient utilization of a 6% ethanol liquid diet for rats.