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REL-1017 (esmethadone; D-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats.

ABSTRACT: REL-1017 (esmethadone, D-methadone) is the opioid-inactive d-isomer of racemic D,L-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-D-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted. We evaluated lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) Self-administration Study Rats were trained to self-administer oxycodone intravenously (IV) and then were subjected to 3-day substitution tests where saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal with functional observational batteries (FOBs). In the self-administration study, rats treated with saline, vehicle, and all REL-1017 doses showed the typical "extinction burst" pattern of response, characterized by an initial rapid increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated with oxycodone maintained stable self-injection, as expected for reinforcing stimuli. In the withdrawal study, REL-1017 did not engender either morphine or ketamine withdrawal signs over 9 days following abrupt discontinuation of drug exposure. REL-1017 showed no evidence of abuse potential and did not engender withdrawal symptomatology.

SUBMITTER: Henningfield J

PROVIDER: S-EPMC9259683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

Project description:This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.

| S-EPMC10465385 | biostudies-literature

REL-1017 (Esmethadone) Increases Circulating BDNF Levels in Healthy Subjects of a Phase 1 Clinical Study.

Project description:Brain-derived neurotrophic factor (BDNF), a neurotrophin widely expressed in the central nervous system, exhibits important effects on neural plasticity. BDNF has been implicated in the mechanism of action of ketamine, a N-methyl-d-aspartic acid receptor (NMDAR) antagonist with rapid anti-depressant effects in humans. REL-1017 (esmethadone), the d-optical isomer of the racemic mixture d-l-methadone, is devoid of clinically relevant opioid activity at doses expected to exert therapeutic NMDAR antagonistic activity in humans. The present study was conducted to ascertain the effects of oral administration of 25 mg of REL-1017 for 10 days on plasma BDNF in healthy subjects confined to an inpatient unit for a phase 1 clinical trial. We observed an increase in post-treatment BDNF plasma levels compared to pre-treatment levels. Post-treatment, Day 10 BDNF plasma levels ranged from 2 to 17 times pre-treatment levels in the 25 mg REL-1017 treatment group, whereas in the placebo group, BDNF plasma levels remained unchanged (p = 0.028). Diastolic blood pressure decreased significantly in subjects treated with REL-1017, while no effect could be observed in the placebo group. In conclusion, the administration of 25 mg REL-1017 significantly increased BDNF plasma levels and significantly decreased diastolic blood pressure in healthy subjects confined to an inpatient unit for a phase 1 clinical trial.

| S-EPMC8113752 | biostudies-literature

Sprague Dawley rats: A model of successful heart aging.

Project description:Aging is a universal phenomenon involving the whole body and is characterized by metabolic and physiological decline, leading to cardiovascular defects and heart failure. To characterize the molecular basis of physiological cardiac aging, the proteomic profiles of Sprague Dawley rat hearts of 6, 22 and 30 months were analysed by DIGE and immunoblotting. Results indicate changes in myosin binding protein C, aldehyde dehydrogenase, serpins and sirtuin-3 which protects from the opening of the mitochondrial permeability transition pore induced by cyclophilin D increment. Conversely, an increase of fusion, a decrease of mitochondrial fission and the activation of the non-canonical autophagy pathway were observed. These results support the hypothesis of successful aging in this rat model.

| S-EPMC5988506 | biostudies-literature

Sprague Dawley vs Ren-2

Project description:all data from control and diabetic Keywords: other

2005-12-15 | GSE2068 | GEO

Subchronic hepatotoxicity evaluation of 2,3,4,6-tetrachlorophenol in sprague dawley rats.

Project description:Male Sprague Dawley rats were exposed to 2,3,4,6-tetrachlorophenol (TCP) for 5 days, 2 weeks, 4 weeks, or 13 weeks. TCP was administered by gavage at doses of 0, 10, 25, 50, 100, or 200?mg/kg/day. Endpoints evaluated included clinical observations, body weights, liver weights, serum chemistry, blood TCP, gross pathology, and liver histopathology. There were no TCP exposure-related clinical signs of toxicity. Mean body weight decreased 12-22% compared to control in the 100 and 200?mg/kg/day groups. Serum ALT concentrations were increased in rats of the 200?mg/k/day. Liver weight increases were both dose- and exposure time-related and statistically significant at ?25?mg/kg/day. Incidence and severity of centrilobular hepatocytic vacuolation, hepatocyte hypertrophy, and single cell hepatocytic necrosis were related to dose and exposure time. Following 13 weeks of exposure, bile duct hyperplasia and centrilobular and/or periportal fibrosis were observed in rats primarily of the highest TCP dose group. Blood TCP concentrations increased with dose and at 13 weeks ranged from 1.3 to 8.5??g/mL (10 to 200?mg/kg/day). A NOAEL of 10?mg/kg/day was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ?25?mg/kg/day.

| S-EPMC3362204 | biostudies-literature

A gene catalogue of the Sprague-Dawley rat gut metagenome.

Project description:Laboratory rats such as the Sprague-Dawley (SD) rats are an important model for biomedical studies in relation to human physiological or pathogenic processes. Here we report the first catalog of microbial genes in fecal samples from Sprague-Dawley rats. The catalog was established using 98 fecal samples from 49 SD rats, divided in 7 experimental groups, and collected at different time points 30 days apart. The established gene catalog comprises 5,130,167 non-redundant genes with an average length of 750 bp, among which 64.6% and 26.7% were annotated to phylum and genus levels, respectively. Functionally, 53.1%, 21.8%,and 31% of the genes could be annotated to KEGG orthologous groups, modules, and pathways, respectively. A comparison of rat gut metagenome catalogue with human or mouse revealed a higher pairwise overlap between rats and humans (2.47%) than between mice and humans (1.19%) at the gene level. Ninety-seven percent of the functional pathways in the human catalog were present in the rat catalogue, underscoring the potential use of rats for biomedical research.

| S-EPMC5967468 | biostudies-literature

Biopersistence of silver nanoparticles in tissues from Sprague-Dawley rats.

Project description:Silver nanoparticles are known to be distributed in many tissues after oral or inhalation exposure. Thus, understanding the tissue clearance of such distributed nanoparticles is very important to understand the behavior of silver nanoparticles in vivo. For risk assessment purposes, easy clearance indicates a lower overall cumulative toxicity. Accordingly, to investigate the clearance of tissue silver concentrations following oral silver nanoparticle exposure, Sprague-Dawley rats were assigned to 3 groups: control, low dose (100 mg/kg body weight), and high dose (500 mg/kg body weight), and exposed to two different sizes of silver nanoparticles (average diameter 10 and 25 nm) over 28 days. Thereafter, the rats were allowed to recover for 4 months. Regardless of the silver nanoparticle size, the silver content in most tissues gradually decreased during the 4-month recovery period, indicating tissue clearance of the accumulated silver. The exceptions were the silver concentrations in the brain and testes, which did not clear well, even after the 4-month recovery period, indicating an obstruction in transporting the accumulated silver out of these tissues. Therefore, the results showed that the size of the silver nanoparticles did not affect their tissue distribution. Furthermore, biological barriers, such as the blood-brain barrier and blood-testis barrier, seemed to play an important role in the silver clearance from these tissues.

| S-EPMC3734196 | biostudies-literature

Enhancement of the hypothalamic-pituitary-adrenal axis but not cytokine responses to stress challenges imposed during withdrawal from acute alcohol exposure in Sprague-Dawley rats.

Project description:Alcohol withdrawal is associated with reduced activity, increased anxiety, and other signs of distress.The goal of the current studies was to determine whether acute ethanol exposure would alter hypothalamic-pituitary-adrenal (HPA) axis reactivity and cytokine responses to stress challenges imposed during the withdrawal period.Male Sprague-Dawley rats were intubated with 4 g/kg of ethanol to simulate acute binge-like ethanol intake. After characterizing the blood ethanol concentrations (BECs; Experiment 1), exploratory activity in a novel environment was explored at 10, 14 and 18 h after ethanol (Experiment 2) to characterize altered activity patterns indicative of withdrawal. In Experiment 3, rats were exposed to footshock during withdrawal to examine whether prior ethanol exposure would alter cytokine and HPA axis responses to stress. Experiments 4 and 5 investigated HPA axis sensitivity and gene expression changes during restraint imposed during withdrawal.Prior ethanol exposure produced a period of stress hyper-reactivity evidenced by an enhanced HPA axis response (increased corticosterone and adrenocorticotropic hormone) observed during withdrawal. While this hyper-reactivity in response to two different stress challenges (novel environment and restraint) was accompanied by profound behavioral changes indicative of withdrawal, no alterations in cytokine changes evoked by stress were observed.Taken together, these findings provide support for the hypothesis that alcohol withdrawal enhances HPA axis reactivity to stress challenges, though not likely as the result of heightened inflammatory signaling, and may have implications for understanding the mechanisms by which stress impacts relapse drinking in humans.

| S-EPMC3192240 | biostudies-literature

Pharmacokinetic data of synthetic cathinones in female Sprague-Dawley rats.

Project description:The synthetic cathinones methylone, butylone, and pentylone differ from each other through the one carbon lengthening of the ?-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3) while 3,4-methylenedioxymethamphetamine (MDMA) differs from methylone by a single oxygen atom. Studies with MDMA, suggests that there may be male and female pharmacokinetic and pharmacodynamic differences. In the present study, we present the plasma pharmacokinetic data relative to a 20?mg/kg, subcutaneous doses of methylone, butylone and pentylone in female Sprague-Dawley rats. Briefly, plasma samples were collected via a jugular vein cannula, purified, and analyzed using a HPLC system. While we have previously reported on the consistent relationship between structure and pharmacokinetics of these synthetic cathinones in male, Sprague-Dawley rats (Grecco and Sprague, 2016), this data set suggests that there is no consistent relationship of chemical structure and pharmacokinetics of methylone, butylone and pentylone in female Sprague-Dawley rats. The findings from the present study further emphasize the need for the inclusion of female subjects in the pharmacokinetic studies of synthetic cathinones as it is very possible male-female differences may exist in rodent models.

| S-EPMC6226823 | biostudies-other

microRNA profiling of Sprague Dawley organs

Project description:We performed deep sequencing of the miRNAs present in ~20 toxicologically relevant tissues in Sprague Dawley rats and used three independent analysis of the data to determine which miRNAs are tissue specific and tissue enriched.

2016-09-01 | GSE78031 | GEO

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