Project description:Methamphetamine (METH) is a widely abused illicit amphetamine that causes acute biochemical and molecular changes in the brain. However, there are very few studies that have investigated the long-term effects of a single METH exposure in adult animals. The purpose of this study was thus to determine the consequences of a single injection of METH (10) mg/kg) on the biochemical and transcriptional effects of a second challenge injection of the drug (2.5 mg/kg) given one month later. Towards that end, we measured monoamine levels and gene expression by microarray and quantitative PCR analyses in the nucleus accumbens (NAc) of 4 groups of rats: saline-pretreated and saline-challenged (SS); saline-pretreated and METH-challenged (SM); METH-pretreated and saline-challenged (MS); and METH-pretreated and METH-challenged (MM). The rats were euthanized 2 hours after the acute challenge injection and NAc samples were harvested. The acute METH challenge caused increases in NAc DA and HVA levels in both the SM and MM groups. Microarray analyses revealed that an injection of METH (2.5 mg/kg) produced acute changes (1.8-fold; p < 0.01) in the expression of 418 (358 up-, 60 downregulated) genes including several immediate early genes (IEGs) such as Arc, c-fos, and fosB in the SM group. Several neuropeptides including Cart, Crf (Crh), and vasopressin were upregulated in that group. Injection of the higher dose of METH (10 mg/kg) did not influence monoamine levels but caused changes in 510 (345 up-, 165 downregulated) transcripts measured one month later (MS group). This list included Cart and Crf but not any IEGs. The MM group showed changes in 774 (572 up-, 202 downregulated) genes that also included vasopressin, Cart, and Crf whose expression was enhanced by the second METH injection. Quantitative PCR confirmed the METH-induced changes in the expression of the neuropeptides. We also confirmed the METH-induced potentiation of Crf expression in the METH-pretreated group. These observations suggest that a single injection of a moderate dose of METH can produce long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crf expression also suggest that a single injection of a moderate METH dose can cause prolonged dysregulation in the endogenous stress system in the rat brain. 24 samples. SS (4), SM (6), MS (7), MM (7)

Project description:Methamphetamine (METH) is a widely abused illicit amphetamine that causes acute biochemical and molecular changes in the brain. However, there are very few studies that have investigated the long-term effects of a single METH exposure in adult animals. The purpose of this study was thus to determine the consequences of a single injection of METH (10) mg/kg) on the biochemical and transcriptional effects of a second challenge injection of the drug (2.5 mg/kg) given one month later. Towards that end, we measured monoamine levels and gene expression by microarray and quantitative PCR analyses in the nucleus accumbens (NAc) of 4 groups of rats: saline-pretreated and saline-challenged (SS); saline-pretreated and METH-challenged (SM); METH-pretreated and saline-challenged (MS); and METH-pretreated and METH-challenged (MM). The rats were euthanized 2 hours after the acute challenge injection and NAc samples were harvested. The acute METH challenge caused increases in NAc DA and HVA levels in both the SM and MM groups. Microarray analyses revealed that an injection of METH (2.5 mg/kg) produced acute changes (1.8-fold; p < 0.01) in the expression of 418 (358 up-, 60 downregulated) genes including several immediate early genes (IEGs) such as Arc, c-fos, and fosB in the SM group. Several neuropeptides including Cart, Crf (Crh), and vasopressin were upregulated in that group. Injection of the higher dose of METH (10 mg/kg) did not influence monoamine levels but caused changes in 510 (345 up-, 165 downregulated) transcripts measured one month later (MS group). This list included Cart and Crf but not any IEGs. The MM group showed changes in 774 (572 up-, 202 downregulated) genes that also included vasopressin, Cart, and Crf whose expression was enhanced by the second METH injection. Quantitative PCR confirmed the METH-induced changes in the expression of the neuropeptides. We also confirmed the METH-induced potentiation of Crf expression in the METH-pretreated group. These observations suggest that a single injection of a moderate dose of METH can produce long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crf expression also suggest that a single injection of a moderate METH dose can cause prolonged dysregulation in the endogenous stress system in the rat brain.

Project description:Background: Vitamin D deficiency is associated with cardiac hypertrophy and heart failure, and vitamin D therapy prevents the progression of cardiac hypertrophy in animal models. Here, we examine whether vitamin D therapy regresses pre-existing cardiac hypertrophy, and prevents the progression to heart failure. Methods and Results: When male Dahl salt-sensitive (DSS) rats are fed a high salt (HS) diet, all rats develop cardiac hypertrophy after 5 weeks (H). Thereafter, rats were treated with vehicle (V), paricalcitol (PC, an active vitamin D analog at 200ng, IP 3x/wk), enalapril (EP, 90ug/day), and PC+EP. All groups were continued on the HS diet and evaluated after 4 weeks of therapy. The PC and PC+EP, but not the V and EP-only groups, showed significant regression of pre-existing cardiac hypertrophy. The signs of decompensated heart failure were evident in the vehicle-treated group; these heart failure parameters significantly improved with PC, EP or PC+EP therapy. The expression of PKCe, which is regulated by Ca2+ and known to stimulate cardiac hypertrophy, was significantly increased in the vehicle group, and PC, EP or PC+EP effectively decreased PKCe activation. We also observed normalization of genetic alterations during progression to heart failure with PC treatment. Conclusions: PC treatment resulted in both the regression of pre-existing cardiac hypertrophy, and the attenuation of the progression to heart failure, compared to improvement in progression to heart failure by EP alone. These beneficial findings in the heart were associated with inhibition of PKCe activation, and reversal of gene alterations. Male Dahl salt-sensitive rats (Harlan Sprague–Dawley, Somerville, NJ) were bred and fed a normal diet until 6 weeks of age. To generate pressure overload cardiac hypertrophy, they were then fed a high salt (6%NaCl) diet for the next 5 weeks. Data for baseline hypertrophic group (H) was obtained at the end of 11 weeks. Among H group animals, they were divided as follows and treated for an additional 4 weeks: 1) continuation of the HS diet with vehicle injection (H+V); 2) continuation of the HS diet with paricalcitol (19-nor-1,25-(OH)2 D2) (PC) (200ng IP 3x/wk) injection (H+PC); 3) continuation of the HS diet with low dose enalapril (EP), an angiotensin-converting enzyme inhibitor, infusion via osmotic pump and vehicle injection (H+EP+V); and 4) continuation of the HS diet with low dose EP infusion via osmotic pump and PC (200ng IP 3x/wk) injection (H+EP+PC). PC was prepared with 95% propylene glycol and 5% ethyl alcohol solution and administered three times a week on Monday, Wednesday, and Friday for 4 consecutive weeks. Vehicle groups received vehicle injections on the same schedule. Two groups of rats were implanted with pumps to deliver EP for 4 weeks. Since the reduction in blood pressure (BP) from high doses of EP would have effects on cardiac hypertrophy and progression to heart failure, we used low dose EP at 90ug/day, a maximum dose that did not significantly decrease BP in these rats, to study the effects of EP and PC that are independent of BP.

Dataset Information

Time course expression data from Brown Norway rat livers treated with nevirapine or galactosamine or both

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets