Pellets In Rats Research Articles

Pharmacokinetics and anti-ulcerogenic effects of Zuojin gastric floating bio-adhesive pellets in rats with acetic acid-induced gastric ulcer

Introduction: Zuojin pills(ZP) have been shown to be effective in the treatment of gastric ulcer (GU); however, the efficacy of Zuojin gastric floating bio-adhesive pellets(ZFP) in GU treatment is yet to be evaluated. Methods: The pharmacokinetics(PK) and protective effects of ZFP against acetic acid-induced GU was examined using rat models. Mass spectrometry(MS) analysis was performed using a TSQ LC-MS system. A total of 50male Sprague-Dawley(SD) rats were randomly assigned to five groups: normal, acetic acid-induced, positive control (rabeprazole, 2 mg/kg/day), ZP (500 mg/kg/day), and ZFP (500 mg/kg/day) groups, to elucidate the anti-ulcerogenic effect of ZFP. Results: ZFP prolonged the residence time of the drug (MRT, 10.88 ± 0.93 h; T1/2, 42.83 ± 2.56 h) in rats and promote the effective absorption of the drug with obvious sustained-release properties. Compared with the control group, ZFP treatment for 7 d significantly increased the weight of the rats, significantly reduced ulcer index, increased gastric tissue Superoxide dismutase(SOD) activity, reduced gastric tissue Malondialdehyde(MDA) content, and increased serum IgA, IgM, IgG, and Interleukin-2(IL-2) levels. Additionally, histopathological analysis showed that ZFP treatment reduced inflammatory cell infiltration to mainly the mucosal layer, anda small amount of fibrous scar proliferative repair was observed in the mucosal defect area and the underlying inflammatory granulation tissue. Conclusion: These results indicated that ZFP prolonged the residence time of the drug in rats with sustained-release properties and had an obvious protective effect against acetic acid-induced GU in rats.

Optimization study of combined enteric and time-dependent polymethacrylates as a coating for colon targeted delivery of 5-ASA pellets in rats with ulcerative colitis

Formulation design for colon-specific delivery of 5-aminosalicylic acid (5-ASA) could bring some therapeutic benefits in the treatment of ulcerative colitis (UC).In the current study, a 32 full factorial design was used to predict optimum coating composed of two enteric (poly methacrylic acid, methyl methacrylates 1:2 and 1:1) and time-dependent (poly ethyl acrylate, methyl methacrylate, trimethylammonio ethyl methacrylate chloride 1:2:0.1) polymethacrylates for colon-specific delivery of 5-ASA pellets. A unique coating composition and coating level predicted by the model was applied onto either inulin-free 5-ASA pellets or inulin-bearing 5-ASA pellets and the coated pellets were examined by dissolution test in-vitro. The coated pellets were also tested in a rat model of UC and compared with the a commercially available colonic delivery system of 5-ASA.The ratio of the two enteric polymethacrylates and time-dependet polymethacrylate of 16:64:20 w/w at a coating level of 15% was discovered as the optimum coating for delivery of 5-ASA pellets to the colon. In general, the coated pellets offered a better therapeutic outcome compared to commercially available colonic delivery system of 5-ASA and uncoated pellets in terms of colitis activity index and the colon's tissue enzymes of MDA and GSH.It seems that the coating composed of enteric and pH-dependent polymethacrylates could tune up the rate of drug release from 5-ASA-coated pellets and trigger drug release based on pH and time.

Abstract PO040: Chemoprevention and regression of estrogen-induced atypical endometrial hyperplasia by oral SHetA2 in a rat model

Abstract Introduction: The purpose was to evaluate the chemoprevention efficacy of SHetA2 (NSC 726189) in a rat model of atypical endometrial hyperplasia (AEH). Methods: Female Sprague Dawley rats were ovariectomized, rested for 2 weeks, and subcutaneously implanted with placebo or slow-release estrogen (E2; 1.5 mg/90-day) pellets on the lateral side of the neck. The rats were randomly divided for two studies: 1) AEH prevention, in which SHetA2 treatment was started one day after E2 pellet implantation; 2) AEH regression, in which SHetA2 treatment was started after AEH development (12 weeks after E2 pellet implantation) and continued for 4 weeks. SHetA2 was orally given as a suspension at three different doses of 30, 60 or 90 mg/kg/day. The suspension was prepared by first micronizing SHetA2 powder to < 63 µm and then ultrahomogenizing it in aqueous 30% Kolliphor HS15 until the size of drug particles in suspension was < 20 µm. The presence of AEH in H&E stained uterine sections was evaluated by two pathologists as the study endpoint by the presence of abnormal cells (nuclear enlargement, nuclear membrane irregularities, prominent nucleoli, nuclear hyperchromasia, nuclear pleomorphism, mitotic activity and/or loss of axial polarity) within tissue areas that exhibit at least one of the following features: increased gland to stroma ratio of >1:1, glandular complexity including irregular contours, and cribriform/papillary configurations. Results: E2-treated animals had reduced body weight gain compared to placebo-implanted animals (Repeated Measures ANOVA, p<0.0001). There were no effects of SHetA2 on rat body weights. In the prevention study, uterine to body weight ratios were significantly higher in E2-treated animals compared to placebo (Repeated Measures ANOVA, p<0.0001) and significantly reduced by 30 and 60 mg/kg/day SHetA2 doses (Repeated Measures ANOVA, p=0.0193 and 0.0108, respectively). Also, SHetA2 caused a dose-responsive decrease in AEH incidence in E2-implanted animals from 86.7% (13/15) in the untreated control to 53.3% (8/15), 26.7% (4/15) and 26.7% (4/15) in the 30, 60 and 90 mg/kg/day SHetA2 treatment groups, respectively (Chai Square Analysis p<0.0022). In the regression study, there were no significant differences in uterine to body weight ratios across all groups. Also, SHetA2 caused dose-responsive regression of AEH to normal histology in E2-implanted animals observed by lack of AEH in 18.2% (2/11) of the untreated control group and 83.3% (10/12), 81.8% (9/11) and 75% (9/12) in the 30, 60 and 90 mg/kg/day SHetA2 treatment groups, respectively (Chai Square Analysis p<0.0025). Conclusions: AEH can be induced by implantation of slow-release E2 pellets in ovariectomized rats. SHetA2 significantly prevented AEH development and caused AEH regression to normal endometrium histology in a dose-dependent manner. Further study is warranted to explore the mechanistic chemoprevention action of SHetA2 and translate these findings toward clinical trials. Funding: NCI PREVENT Program Contract HHSN26100008. Citation Format: Vishal Chandra, Rajani Rai, Stan S. Lightfoot, Manolya Kukut Hatipoglu, Lucila Garcia-Contreras, Doris M. Benbrook. Chemoprevention and regression of estrogen-induced atypical endometrial hyperplasia by oral SHetA2 in a rat model [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO040.

Male Offspring of Hyperandrogenemic Female (HAF) Rats Develop Hypertension Beginning at 16 Weeks of Age

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women. It is characterized by hyperandrogenemia, oligo/anovulation, and polycystic ovaries. Children born to women with PCOS often have intrauterine growth restriction (IUGR) or are small for gestational age. This present study was conducted to test the hypothesis that maternal hyperandrogenemia will affect blood pressure (mean arterial pressure (MAP)) in male offspring.Hyperandrogenemia was produced by implantation of 5α‐dihydrotestosterone pellets (DHT; 7.5 mg/90 days, sc) in SD female rats at 4 wks of age (hyperandrogenemic females (HAF)). Control females received placebo pellets. Females were mated with SD males at 10–12 wks of age. Approximately 60% of HAF rats became pregnant, compared to 100% of controls. At 48 hrs, offspring were weighed and measured, and litters were culled to 4 males and 4 females. DHT and control dams were allowed to nurse offspring for 3 wks. Offspring (F1) were left untreated and studied at 4–6 mos (adult) and ≥16 mos (aging).Despite similar litter sizes (n=10–12±2 for HAF and control dams; p=NS), male offspring from HAF dams (F1HAF) weighed significantly less than offspring from control dams (F1contr.): (male F1HAF vs. F1contr: (PN 12 hrs :6.4±0.1 vs. 7.0±0.2g; n=13–15; p<0.05; PN 48 hrs: 7.4±0.3 vs. 8.1±0.1 g; n=13–15; p<0.05). Male F1HAF were also significantly shorter in length (6.2±0.6 vs. 6.8±0.2 cm; n= 15–18, p<0.05) and had smaller head circumference (4.4±0.1 vs. 4.6±0.1 cm; n=12–15) at 48hrs than male F1contr. At 16 wks, fat mass (normalized to BW) was significantly higher in male F1HAF than F1contr (0.07±0.01 vs. 0.06±0.01; p<0.05). MAP (radiotelemetry) was significantly elevated in adult male F1HAF compared to F1contr (121± 3 vs. 113 ± 3 mmHg; n=4–5/grp, p<0.05). DHT levels were significantly lower in male F1HAF than F1contr (57.4±34.9 vs 136.4±55.7 ng/ml; n=7–11/grp; p<0.01). With aging, male F1HAF had higher levels of proinflammatory cytokines than did male F1contr (by Bioplex; n=3–7/grp; all p<0.05): IL‐17a (149.5±39 vs. 32.1±5 pg/ml; p<0.05), IL‐1α (426±159 vs. 138±33 pg/ml), IL‐1β (122.6±36 vs. 36±6 pg/ml), and PAI‐1 (1690±386 vs. 590±63 pg/ml).Male offspring of HAF dams are born with IUGR compared to offspring of control females. As adults, male offspring of HAF dams have lower levels of androgens, increased fat mass, and develop hypertension. With aging, HAF male offspring have higher levels of inflammation than control offspring. These data are important since physicians rarely ask their middle‐aged, hypertensive, overweight male patients with androgen deficiencies if their mothers had PCOS during their pregnancy. With this knowledge, physicians may not only be able to predict which men will suffer from these complications, but may also provide the best therapeutic options for these men.Support or Funding InformationStudies were supported by NIH R01HL135089, R01HL66072, P01HL05971, P20GM121334

Effects of saccharin experience on food consumption, body-weight gain and operant responding for sugar pellets in rats

Effects of saccharin experience on food consumption, body-weight gain and operant responding for sugar pellets in rats

Fluoroscopic Characterization of Colonic Dysmotility Associated to Opioid and Cannabinoid Agonists in Conscious Rats.

Background/AimsGastrointestinal adverse effects have a major impact on health and quality of life in analgesics users. Non-invasive methods to study gastrointestinal motility are of high interest. Fluoroscopy has been previously used to study gastrointestinal motility in small experimental animals, but they were generally anesthetized and anesthesia itself may alter motility. In this study, our aim is to determine, in conscious rats, the effect of increasing doses of 2 opioid (morphine and loperamide) and 1 cannabinoid (WIN 55,212-2) agonists on colonic motility using fluoroscopic recordings and spatio-temporal maps.MethodsMale Wistar rats received barium sulfate intragastrically, 20–22 hours before fluoroscopy, so that stained fecal pellets could be seen at the time of recording. Animals received an intraperitoneal administration of morphine, loperamide, or WIN 55,212-2 (at 0.1, 1, 5, or 10 mg/kg) or their corresponding vehicles (saline, Cremophor, and Tocrisolve, respectively), 30 minutes before fluoroscopy. Rats were conscious and placed within movement-restrainers for the length of fluoroscopic recordings (120 seconds). Spatio-temporal maps were built, and different parameters were analyzed from the fluoroscopic recordings in a blinded fashion to evaluate colonic propulsion of endogenous fecal pellets.ResultsThe analgesic drugs inhibited propulsion of endogenous fecal pellets in a dose-dependent manner.ConclusionsFluoroscopy allows studying colonic propulsion of endogenous fecal pellets in conscious rats. Our method may be applied to the noninvasive study of the effect of different drug treatments and pathologies.

A three-pronged formulation approach to improve oral bioavailability and therapeutic efficacy of two lipophilic drugs with gastric lability.

The aim of present study was to co-administer curcumin (CRM) liquisolid pellets and coated duloxetine hydrochloride (DXH) pellets in rats to treat neuropathic pain (NP) associated with chronic constriction injury (CCI). To formulate liquisolid pellets of CRM, it was first dissolved in Tween-80 and then adsorbed on the porous surface of MCC PH102 and Syloid XDP that were used as carrier and coating materials, respectively. Central composite design was used to optimize the liquisolid formulation. The results of powder X-ray diffraction studies, differential scanning calorimetry, and scanning electron microscopy showed complete solubility of drug in Tween-80 followed by its complete adsorption on the porous surface of Syloid XDP and MCC PH102. Both DXH and liquisolid CRM powders were converted into pellets using extrusion-spheronization. DXH pellets were further coated with Eudragit S100 to bypass the gastric pH. About 32.31-fold increase in dissolution rate of CRM present in liquisolid formulation was observed as compared to its unprocessed form. Similarly, the dissolution profile in 0.1N HCl for Eudragit S100-coated DXH showed complete protection of drug for 2h and complete release after its introduction in buffer medium (0.2M phosphate buffer pH 6.8). he pharmacokinetic studies carried out on rats revealed 7.3-fold increase in bioavailability of CRM present in liquisolid pellets and 4.1-fold increase in bioavailability of DXH present in coated pellets was observed as compared to their unprocessed pellets. This increase in bioavailability of drugs caused significant amelioration of CCI-induced pain in rats as compared to their unprocessed forms. The histological sections showed better improvement in regeneration of nerve fibers in rats.

Prophylactic use of probiotic chocolate modulates intestinal physiological functions in constipated rats.

This study investigated the in vivo prophylactic effect of probiotic chocolate on constipation. Rats were administered chocolate containing 2.5×1010 CFU g-1 of probiotics daily for 4 weeks and treated with loperamide (5 mg kg-1 ) daily at the fourth week of treatment. Probiotic chocolate treatment significantly (P<0.05) increased the intestinal motility, colon length, fecal moisture content and number of excreted fecal pellets in constipated rats. Moreover, quantitative real-time polymerase chain reaction data and histological images also revealed that both probiotic chocolate LYC and BB12 treatments were capable of upregulating the mRNA expression levels of colonic ZO-1, occludin and AQP8, leading to the maintenance of the defensive barrier function in the constipated rats compared with the negative controls. Interestingly, these treatments also modulated gut bacterial populations by increasing the abundance levels of Lactobacillus and Bifidobacterium, as well as reducing the abundance level of Enterobacteriaceae. The present study demonstrated that probiotic chocolate LYC and BB12 could potentially be used as alternative agents for prophylactic constipation. © 2018 Society of Chemical Industry.

Laxative Effects of Taurine on Loperamide-Induced Constipation in Rats.

In the present study, we investigated the laxative effects of taurine in a rat model of loperamide-induced constipation. Rats were divided into six groups of six animals each: normal (NOR), control (CON), loperamide + Dulcolax (5.5mg/kg, p.o.), and loperamide + various doses of taurine (7.5, 15, and 30mg/kg, p.o.). Laxative activity was determined based on body weight, feeding characteristics, fecal properties, gastrointestinal transit (GIT) ratio, and the levels of serum gastrointestinal hormones. Taurine supplementation significantly increased the number, wet weight, and water content of fecal pellets in rats with loperamide-induced constipation. GIT ratio and loperamide-induced serum metabolic parameters, such as gastrin (GAS), motilin (MTL), and somatostatin (SS) significantly changed after supplementation with taurine in loperamide-induced constipated rats. We suggest that taurine had a potent effect against loperamide-induced constipation in part by increasing gastrointestinal motility.

Sex and Feeding Status Differently Affect Natural Reward Seeking Behavior in Olfactory Bulbectomized Rats.

Substance abuse and depression are common psychiatric disorders with a high rate of comorbidity. Both conditions affect differently men and women and preclinical research has showed many sex differences in drug addiction and depression. The most common approach for modeling depression-addiction comorbidity is the combination of the intravenous drug self-administration and the olfactory bulbectomy (OBX) models in rats. Such a combination has revealed enhanced drug-taking and drug-seeking behaviors in OBX rats, but no study has investigated so far potential sex differences in operant responding and motivation for natural reinforcers in OBX rats. This study investigated for the first time operant self-administration of palatable food pellets in male and female OBX rats under different feeding status, i.e., ad libitum vs. restricted food, and schedules of reinforcement, i.e., a continuous ratio schedule fixed ratio 1 (FR1) vs. a complex (FR5(x)) second order schedule of reinforcement. In the FR1 experiment, OBX rats of both sexes exhibited lower operant responding and intake of palatable food pellets than sham-operated controls, with food restriction leading to increased operant responding in both OBX and SHAM groups. Female rats showed higher responding than males but this effect was abolished by the OBX lesion. Similarly, in the (FR5(x)) second order schedule of reinforcement both male and female OBX rats showed lower responding and food intake, with SHAM and OBX females showing higher operant responding than corresponding male groups. Overall, our findings showed that: (i) responding for food was lower in OBX than in SHAM rats under both FR1 and (FR5(x)) schedules of reinforcement; (ii) sex and food restriction affect operant responding for palatable food; and (iii) the suppressing effect of OBX lesion on food intake was consistently present in both sexes and represents the most robust factor in the analysis. This may represent anhedonia which is associated with depressive-like phenotype and palatable food self-administration may serve as a robust behavioral index of anhedonia in the OBX model.

The effect of nicotine pre-exposure on demand for cocaine and sucrose in male rats.

The aim of the present study was to determine how nicotine pre-exposure affects the elasticity of demand for intravenous cocaine and for sucrose pellets in adult male rats. In Experiment 1, demand for cocaine was assessed in rats that had nicotine in their drinking water. Nicotine pre-exposure significantly decreased rats' willingness to defend cocaine consumption as the price (measured as the number of responses per cocaine infusion) increased compared with a control group with no nicotine pre-exposure. That is, nicotine increased the elasticity of demand for cocaine infusions. Experiment 2 repeated the first experiment, but with rats working for sucrose pellets instead of cocaine. Nicotine pre-exposure had no effect on the elasticity of demand for sucrose. This pattern of results suggests that nicotine pre-exposure can reduce the reinforcing effects of cocaine, but not sucrose, in adult male rats.

Kinetics and tissue distribution of bismuth, tin and lead after implantation of miniature shotgun alloy pellets in rats

IntroductionShotgun pellets containing bismuth (Bi) as substitute for lead (Pb) are increasingly being used due to environmental concerns. Information on toxicokinetics of Bi is lacking for the assessment of humans accidentally shot by Bi-containing shotgun alloy pellets. MethodsMale Wistar rats were exposed to miniature alloy pellets containing Bi, tin (Sn) and minor amounts of Pb by implantation in muscle tissues of the hind legs. ResultsThe concentrations of Bi in whole blood and urine increased up to 53 weeks after implantation. The highest concentrations of Sn in whole blood were observed three weeks after implantation, then declining to background levels 53 weeks after implantation. Lead in whole blood increased up to 13 weeks of exposure, and declined for the remaining observation period. Bismuth and Sn accumulated mainly in kidney, but also in liver, testicle and brain. Analytical field emission scanning electron microscopy of post-implant pellets showed depletion of Pb towards the pellet surface. Oxygen and chlorine accumulated in Sn rich lamellas in areas next to the pellet surface. The distribution of Bi remained visually unaffected as compared to pre-implant pellets. ConclusionThe concentration of Bi increased during the whole observation period in blood, urine, kidney, brain, testicle and liver. The decline in the concentrations of Pb and Sn in blood and urine after reaching the peak concentration may be related to alterations in the chemical composition and element distribution of the implanted alloy pellets.

Pharmacological and toxicological investigations of etodolac loaded gum katira microspheres prepared by W1/O/W2 emulsion solvent evaporation technique in rats

ABSTRACT Etodolac is a non-steroidal anti-inflammatory drug (NSAID) and approved by USFDA as a COX2 inhibitor. Although etodolac therapy provides clinical benefits, it is associated with upper gastrointestinal (GI) tract complications also. Etodolac loaded gum Katira microsphere (ELGKM) was prepared by W1/O/W2 emulsion solvent evaporation technique. The gastric irritation properties of orally administered pure etodolac, ELGKM and blank microspheres (without etodolac) were evaluated in experimental rats treated for 6 days. The stomach examination and biochemical investigation of stomach tissue of treated rats indicated that ELGKM formulation remarkably reduced ulcerogenecity as compared to pure etodolac. The anti-inflammatory activities of pure etodolac and ELGKMs were ascertained by the implantation of cotton pellets in rats for 6 days. Based on the results, ELGKMs showed significant anti-inflammatory activities (P<0.01) as compared to control group. The cotton pellets test suggested that ELGKM formulation retained more anti-inflammatory properties among the groups. The hematological changes, biochemical analysis and histopathological studies of subacute toxicity in rats revealed that ELGKM were the effective sustained release formulation in the treatment of chronic pain and inflammation. In conclusion, the physicochemical characterization, pharmacological and toxicological studies suggest that ELGKMs may represent as a potential candidate for sustained drug delivery (10-12 hours) in chronic joint pain related diseases with remarkably diminished gastrointestinal side effects.

Suppressing effect of COR659 on alcohol, sucrose, and chocolate self-administration in rats: involvement of the GABAB and cannabinoid CB1 receptors.

COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABAB receptor. This study evaluated whether COR659 shared with previously tested GABAB PAMs the capacity to reduce alcohol self-administration in rats. Treatment with non-sedative doses of COR659 (2.5, 5, and 10mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABAB PAM, GS39783. Treatment with COR659, but not GS39783, suppressed (a) lever-responding for a sucrose solution (1-3% w/v) in sP rats under the FR4 and PR schedules, (b) lever-responding for a chocolate solution [5% (w/v) Nesquik®] in Wistar rats under the FR10 and PR schedules, and (c) cue-induced reinstatement of chocolate seeking in Wistar rats. Treatment with COR659 was completely ineffective on lever-responding (FR10) for regular food pellets in food-deprived Wistar rats. Pretreatment with the GABAB receptor antagonist, SCH50911, partially blocked COR659-induced reduction of alcohol self-administration, being ineffective on reduction of chocolate self-administration. Pretreatment with the cannabinoid CB1 receptor antagonist, AM4113, fully blocked COR659-induced reduction of chocolate self-administration, being ineffective on reduction of alcohol self-administration. COR659 might exert its behavioral effects via a composite mechanism: (i) positive allosteric modulation of the GABAB receptor, responsible for a large proportion of reduction of alcohol self-administration; (ii) an action at other receptor system(s), including the cannabinoid CB1 receptor, through which COR659 affects seeking and consumption of highly palatable foods.

Preparation and evaluation of gastric adhesive-floating pellets for Bolo leaf phenols

Gastric adhesive-floating pellets for Bolo leaf phenols (BLP) were prepared by extrusion-spheronization method, with chitosan as skeleton bioadhesive material, and stearyl alcohol as help-bleaching agent to evaluate its in vitro adhesivity, floatability and in vivo retention situation, and investigate its in vitro release characteristics. The in vitro adhesivity and floatability were evaluated respectively by in vitro tissue retention method and visual observation method. The retention of pellets in rats was investigated by in vivo tissue retention method and in vivo imaging of small animals. In addition, the in vitro release of p-coumaric acid and caffeic acid as the index components in pellets were evaluated. Results showed that the in vitro adhesivity of the prepared gastric adhesive-floating pellets reached (73.2±3.4)%, and the pellets could float immediately in simulated gastric fluid for more than 12 h; the retention rate of adhesive-floating pellets in rats reached more than 40% after 6 h, while the retention rate of common reference pellets was decreased by 15% as compared with the gastric adhesive-floating pellets, with significant difference (P<0.01); the drug in vitro release time can reach more than 6 h, and the drug release behaviors were lined with Higuchi equation. In vivo and in vitro studies showed that, the gastrointestinal bioadhesive and floating pellets prepared in this study have good bioadhesivity, floatability and good sustained release characteristics.

Progesterone attenuates impulsive action in a Go/No-Go task for sucrose pellets in female and male rats

Impulsivity, or a tendency to act without anticipation of future consequences, is associated with drug abuse. Impulsivity is typically separated into two main measures, impulsive action and impulsive choice. Given the association of impulsivity and drug abuse, treatments that reduce impulsivity have been proposed as an effective method for countering drug addiction. Progesterone has emerged as a promising treatment, as it is associated with decreased addiction-related behaviors and impulsive action. The goal of the present study was to determine the effects of progesterone (PRO) on impulsive action for food: a Go/No-Go task. Female and male rats responded for sucrose pellets during a Go component when lever pressing was reinforced on a variable-interval 30-s schedule. During the alternate No-Go component, withholding a lever press was reinforced on a differential reinforcement of other (DRO) behavior 30-s schedule, where a lever press reset the DRO timer. Impulsive action was operationally defined as the inability to withhold a response during the No-Go component (i.e. the number of DRO resets). Once Go/No-Go behavior was stable, responding between rats treated with PRO (0.5mg/kg) or vehicle was examined. Progesterone significantly decreased the total number of DRO resets in both males and females, but it did not affect VI responding for sucrose pellets. This suggests that PRO decreases motor impulsivity for sucrose pellets without affecting motivation for food. Thus, PRO may reduce motor impulsivity, a behavior underlying drug addiction.

Disulfiram inhibits chocolate self-administration and reinstatement to chocolate seeking in rats

We recently found that the dopamine β-hydroxylase (DBH) inhibitor, nepicastat, reduced chocolate self-administration and reinstatement of chocolate-seeking behavior in free-fed rats and self-administration of regular food pellets in food-restricted rats. Here we show that disulfiram reproduced all these effects but exhibited a considerably different time-course. Wistar rats were trained to lever-respond for a chocolate solution (free-fed rats) or regular food pellets (food-restricted rats) under the Fixed Ratio (FR) 10 (FR10) schedule of reinforcement. Once lever-responding stabilized, rats were exposed to sessions under FR10 and Progressive Ratio (PR) schedule and reinstatement sessions. Acutely administered disulfiram (0, 25, 50, and 100mg/kg, i.p.) inhibited, with similar potency and effectiveness, lever-responding for chocolate solution and regular food pellets under the FR10 schedule. Disulfiram-induced inhibition of lever-responding for chocolate solution and regular food pellets showed a biphasic time-course: an early inhibition at 2h, which subsided within 24h, and a second long-lasting inhibition from 48 to 96h. Administered 48h beforehand, disulfiram reduced lever-responding for chocolate solution under the PR schedule and prevented cue-induced reinstatement of chocolate-seeking behavior. Spontaneous locomotor activity was reduced at 2 but not 48h after disulfiram administration. These results indicate that disulfiram reduced food seeking and consumption elicited by high palatability or appetite. It is suggested that the delayed inhibitory effect of disulfiram is likely mediated by a novel mechanism distinct from blockade of DBH or aldehyde dehydrogenase.

Anti-Inflammatory Activity of Polysaccharide Fraction of Curcuma longa Extract (NR-INF-02).

The aim of the study was to investigate the safety and anti-inflammatory effects of polysaccharide fraction (F1) of Curcuma longa extract (NR-INF-02) in classical rodent models of inflammation. F1 was evaluated for its acute oral toxicity and found to be safe upto 5000 mg/kg body weight in rats. The anti-inflammatory activity of F1 was evaluated in acute (carrageenan - induced paw edema; xylene - induced ear edema) and chronic (cotton pellet - induced granuloma) models of inflammation. The results of the study demonstrated that F1 significantly (p ≤ 0.05) inhibited carrageenan-induced paw edema at 1 h and 3 h at doses of 11.25, 22.5 and 45 mg/kg body weight in rats. Also, F1 at doses of 15.75, 31.5 and 63 mg/kg significantly inhibited the xylene induced ear edema in mice. In a chronic model, F1 at 11.25, 22.5 and 45 mg/kg doses produced significant reduction of wet and dry weights of cotton pellets in rats. Overall results indicated that F1 of NR-INF-02 significantly attenuated acute and chronic inflammation in rodent models. This study emphasizes on the importance of Curcuma longa polysaccharide's role in acute and chronic inflammation.

PC228. Testosterone Replacement Attenuates Hyperplasia Development in an Androgen-Deficient Model of Vascular Injury Independent of Matrix Metalloproteinase Regulation

Clinical and epidemiologic studies have shown low testosterone (TST) is associated with increased risk of vascular disease, yet the molecular mechanisms remain unclear. Matrix metalloproteinases (MMPs) are implicated in dysfunctional remodeling. Our group has previously demonstrated an inverse relationship between TST levels and MMP activity in vitro. We have also demonstrated androgen deficiency (AD)-modulated inflammatory signaling does not influence systemic MMPs in vivo. Here we investigated the role of AD and TST replacement in MMP-modulated remodeling in response to injury. Subphysiological and physiological TST replacement was administered via implanted pellets in aged orchiectomized rats (0.5-5 mg, Table I). Serum TST was determined by enzyme-linked immunosorbent assay. At 14 days, TST replacement rats underwent balloon angioplasty of the left common carotid. Young intact (YI), aged intact (AI), and orchiectomized placebo (Plac) animals served as controls. Carotids were collected 14 days after injury for intima:media (I:M) and MMP quantification. I:M was increased in Plac, sub-physiological, and low-physiological TST animals compared with AI controls (Fig 1) but was decreased with higher physiological TST. Injury-induced expression of MMPs involved in vascular remodeling was not significantly affected by TST status (Table II). AD increased IH development in response to vascular injury while physiological TST replacement attenuated this effect. This attenuation occurs independent of MMP mechanisms known to be heavily involved in vascular remodeling. Future in vivo studies will examine AD and TST replacement in the acute inflammatory response to vascular injury to delineate additional molecular targets. These studies are needed in determining if TST replacement therapy in AD men should be evaluated for attenuation of vascular pathogenesis.Table ISerum TST levels (ng/mL)Baseline14-day post-TSTControlsYI3.82 ± 0.864.38 ± 0.93ControlsAI2.04 ± 0.442.24 ± 0.54Plac0.62 ± 0.210.18 ± 0.02Sub-physiologic0.5 mg0.30 ± 0.040,65 ± 0.04Physiologic2.5 mg0.38 ± 0.082.24 ± 0.37Physiologic5 mg0.63 ± 0.263.87 ± 0.48AI, Aged intact; TST, testosterone; YI, young intact. Open table in a new tab Table II% Intima stainedMMP-2 regulatory pathwayMMP-9 regulatory pathwayMT1-MMPMMP-2TIMP-2MMP-9TIMP-1YI4.2 ± 1.117.5 ± 7.215.8 ± 6.311.7 ± 5.21.3 ± 0.6AI10.0 ± 5.029.6 ± 5.913.3 ± 4.58.5 ± 2.22.0 ± 0.6Plac3.8 ± 1.222.0 ± 6.711.8 ± 5.49.8 ± 2.81.9 ± 0.80.5 mg8.7 ± 3.523.8 ± 3.118.5 ± 5.717.4 ± 4.22.7 ± 0.62.5 mg11.2 ± 4.020.0 ± 4.210.7 ± 3.212.8 ± 2.93.0 ± 0.95 mg9.9 ± 2.930.1 ± 3.211.7 ± 2.023.7 ± 6.63.6 ± 0.6AI, Aged intact; MMP, matrix metalloproteinase; MT1-MMP, membrane type 1-matrix metalloproteinase 1; YI, young intact.P = not significant, n = 5.7. Open table in a new tab

Abstract 284: Testosterone Replacement Attenuates Hyperplasia Development in an Androgen Deficient Model of Vascular Injury Independent of Matrix Metalloproteinase Regulation

Objectives: Clinical and epidemiological studies have shown low testosterone (TST) is associated with increased risk of vascular disease, yet the molecular mechanisms remain unclear. Matrix metalloproteinases (MMPs) are implicated in dysfunctional remodeling. Our group has previously demonstrated an inverse relationship between TST levels and MMP activity in vitro. We have also demonstrated androgen deficiency (AD)-modulated inflammatory signaling does not influence systemic MMPs in vivo. Here we investigated the role of AD and TST replacement in MMP-modulated remodeling in response to injury. Methods: Sub-physiological and physiological TST replacement was administered via implanted pellets in aged orchiectomized rats (0.5-5mg, Table 1). Serum TST was determined by ELISA. At 14d TST replacement rats underwent balloon angioplasty of the left common carotid. Young intact (YI), aged intact (AI), and orchiectomized placebo (Plac) animals served as controls. Carotids were collected 14d post-injury for intima:media (I:M) and MMP quantification. Results: I:M was increased in Plac, sub-, and low-physiological TST animals compared to AI controls, and decreased with higher physiological TST (Fig 1). Injury-induced expression of MMPs involved in vascular remodeling was not significantly affected by TST status (Table 2). Conclusions: AD is associated with hyperplasia development in response to vascular injury while physiological TST replacement attenuated this effect. This attenuation occurs independent of MMP mechanisms known to be heavily involved in vascular remodeling. Future in vivo studies will examine molecular targets involved in AD and the effect of TST replacement in the acute inflammatory response to vascular injury. These studies are needed in determining if TST replacement therapy in AD men should be evaluated for attenuation of vascular pathogenesis.