Dorota Gorska

Effect of acute administration of ethanol on beta-endorphin plasma level in ethanol preferring and non-preferring rats chronically treated with naltrexone.

An ample support can be found in professional literature for the hypothesis that the endogenous opioid system plays an important role in developing a craving for alcohol. It is well established that people with a genetic deficit of beta-endorphin are particularly susceptible to alcoholism. In our study, we looked into the beta-endorphin plasma level of animals with high- and low-risk of alcohol dependency after repeated treatment with naltrexone, the opioid antagonist known to be effective in the treatment of alcoholism. We used the Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) rats and treated them for 10 days with naltrexone in a dose of 2 mg/kg i.p. One hour before blood collection the rats were injected with a single dose of ethanol. A prolonged naltrexone treatment or a single application of ethanol resulted in the increase of the beta-endorphin plasma level. In the WLP rats repeated naltrexone treatment prevents the ethanol-induced increase in beta-endorphin plasma level. In the WHP rats the level of this peptide was similar to it while they were undergoing the naltrexone treatment or had received a single alcohol injection. This finding supports the proposition that the endogenous opioid system plays an important role in developing a craving for alcohol. It is likely that effectiveness of naltrexone in reducing craving for alcohol results from the attenuation of the rewarding properties of ethanol and restoring the beta-endorphin deficit in reward system.

Effect of chronic acamprosate treatment on voluntary alcohol intake and β-endorphin plasma levels in rats selectively bred for high alcohol preference

Our previous studies have shown that repeated acamprosate administration to ethanol-naive Warsaw high preferring (WHP) rats resulted in increased plasma beta-endorphin levels and at least partially prevents increases in levels of this peptide after a single administration of ethanol compared with untreated control rats. The objective of the present study, which included 45 WHP rats, was to continue the past research and investigate the effect of 10-day acamprosate treatment (200 mg/kg p.o.) on alcohol intake using a free-choice procedure and on changes in plasma beta-endorphin levels while alcohol is available, and 10 days after alcohol withdrawal. Voluntary alcohol consumption increases plasma levels of beta-endorphin from 440+/-25 pg/ml to 711+/-57 pg/ml (p=0.0002). After a 10-day of alcohol withdrawal, the levels of this peptide were significantly reduced compared with levels in rats with free access to ethanol (711+/-57 pg/ml vs. 294+/-38 pg/ml, p=0.000001) and in control naive rats (440+/-25pg/ml vs. 294+/-38pg/ml, p=0.044). Chronic treatment with acamprosate increased plasma beta-endorphin levels both in WHP rats with free access to ethanol (440+/-25 pg/ml vs. 616+/-49 pg/ml, p=0.008) and in rats after ethanol withdrawal (440+/-25 pg/ml vs. 620+/-56 pg/ml, p=0.007). In the group with free access to ethanol, there was a significant reduction in mean ethanol intake, from 6.75+/-0.20 g/kg body weight/day to 4.68+/-0.25 g/kg/day. Our results indicate that chronic acamprosate treatment may have beneficial effects, as it increases the beta-endorphin concentration thereby compensating for beta-endorphin deficiency during ethanol withdrawal. As the endogenous opioid system has an important role in the development of craving for alcohol, restoring the alcohol-induced deficits in beta-endorphin levels may be an important factor to prevent craving and maintaining abstinence. We suppose that the anti-craving mechanism of acamprosate that has been reported to abolish excessive glutamate release during alcohol withdrawal may be accompanied by compensation for the beta-endorphin deficiency.

Voluntary alcohol consumption and plasma beta-endorphin levels in alcohol preferring rats chronically treated with levetiracetam: a preliminary study.

Many recent researches have confirmed the effectiveness of antiepileptic drugs in preventing alcohol dependency, whereas our previous study showed that repeated treatment with topiramate, a new antiepileptic drug, was effective in increasing the plasma levels of beta-endorphin (an endogenous opioid peptide) in rats. It is well documented that in humans a genetic deficit of beta-endorphin is often associated with alcohol addiction as alcohol consumption elevates the level of this peptide. The aim of the present study is multifaceted: to investigate the effect of repeated treatment of levetiracetam (50 or 100mg/kg b.w., twice daily) on voluntary alcohol intake in alcohol preferring rats (Warsaw High Preferring; WHP) and to assess changes in plasma beta-endorphin levels while alcohol is available and when it is not available for an extended period of time. We observed a noticeable increase in the levels of beta-endorphin in rats with free access to alcohol whether in a prolonged levetiracetam-treated or vehicle-treated group. However, in the levetiracetam group, a voluntary intake of alcohol diminished in comparison with both the pretreatment period and in comparison with the vehicle-treated rats. A similar increase in the plasma beta-endorphin levels was observed in levetiracetam-treated rats that did not have access to ethanol. This finding lets us to believe that levetiracetam may be a promising medication in treatment of alcohol dependency as its application leads to the increase in the beta-endorphin concentration and ultimately results in reducing deficiency of this peptide.

Effect of repeated treatment with topiramate on the beta-endorphin plasma level in rats selectively bred for high and low alcohol preference

Recent research indicates that topiramate has a role in the treatment of alcohol dependence. Topiramate has multiple mechanisms of action including enhancement of GABA-ergic inhibitory transmission and blocking excitatory glutamate neurotransmission, and modulating voltage-gated sodium and calcium ion channels and inhibiting carbonic anhydrase. In this study, we examined the effect of topiramate on endogenous opioid systems, which have an important role in the development of alcohol dependence. We investigated the beta-endorphin plasma level of animals with high- and low-risks of alcohol dependency after repeated treatment with topiramate. We used the Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) rats, and treated them with topiramate at a dose of 80 mg/kg p.o. for 14 days. In WHP rats treatment with topiramate led to an increase in beta-endorphin plasma levels, which persisted at the same level even after a single injection of alcohol. The level of this peptide with topiramate was lower than in alcohol-injected WHP rats who did not receive topiramate. Beta-endorphin levels in WHP rats after topiramate or topiramate and ethanol treatment were similar to the basal level of this peptide in WLP rats. In WLP rats, topiramate did not prevent the ethanol-induced increase in beta-endorphin plasma level. We propose that administration of topiramate may have different effects on the opioid system involved in dependence according to genetic susceptibilities to alcoholism.

The effects of celiprolol on serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats

BACKGROUND A growing body of evidence suggests that some cardiovascular drugs could modulate the level of proinflammatory cytokines. Therefore, the aim of the present study was to investigate whether celiprolol, a third generation β-adrenoceptor blocker, affects lipopolysaccharide (LPS)-induced serum concentrations of TNF-α, IL-1β, IL-6 in normotensive (WKY) and spontaneously hypertensive (SHR) rats. METHODS Celiprolol (150 mgkg(-1)) or vehicle was administered by gavage once daily for 21 days. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Serum concentrations of proinflammatory cytokines were measured with enzyme-linked immunosorbent assay kits. Additionally, plasma concentrations of total cholesterol, HDL-cholesterol and triglycerides were evaluated. RESULTS In normotensive WKY rats celiprolol did not affect heart rate, blood pressure, or the serum concentrations of triglycerides, total cholesterol or HDL-cholesterol. In hypertensive animals the drug decreased lipid parameters, increased diastolic and mean blood pressure after the first week of administration, and produced a small but significant decrease in heart rate after the first two weeks of the treatment. In both groups of animals, celiprolol decreased LPS-stimulated serum concentration of IL-6 but did not affect levels of TNF-α and IL-1β. CONCLUSIONS It is suggested that the IL-6-modulating properties of celiprolol could provide additional value to the therapeutic effectiveness of the drug in the treatment of hypertension.

Does nebivolol influence serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats

A growing body of evidence suggests that some drugs used in cardiovascular diseases may modulate the level of proinflammatory cytokines. In the present study we examined whether nebivolol, a third generation beta-adrenergic blocker, influences lipopolysaccharide (LPS)-induced serum concentrations of TNF-alpha, IL-1beta, and IL-6 in normotensive (WKY) and spontaneously hypertensive rats (SHR). Nebivolol (5 mg/kg and 10 mg/kg) or vehicle were administered by gavage once a day for 21 days. The drug (5 mg/kg and 10 mg/kg) did not modify LPS-stimulated serum concentrations of TNF-alpha, IL-1beta and IL-6 in normotensive or hypertensive rats and did not affect the total cholesterol and HDL cholesterol level. Nebivolol, at the dose of 10 mg/kg, significantly increased the triglyceride concentration in SHR only. The results were accompanied by a statistically significant decrease in systolic, diastolic and mean blood pressure after 21 days of both of the drug doses. In hypertensive and normotensive rats, nebivolol had a hypotensive activity and neutral effect on lipid profile. In our in vivo model, the immunomodulating effect of the drug was not significant and probably did not depend on hemodynamic action.

Synthesis, pharmacological activity and nitric oxide generation by nitrate derivatives of theophylline

Nitrates of theophylline derivatives — potential nitric oxide (NO) donors — were synthesized by esterification of 7‐hydroxyalkyl theophylline derivatives with fuming nitric acid. The nitrates obtained were tested in‐vitro in reactions with sulfydryl compounds at appropriately adjusted pH and temperature. Under the applied conditions, the synthesized compounds underwent decomposition to release NO, quantified using a polarographic method using a selective isolated (ISO‐NO) sensor. The effects of dyphylline and proxyphylline and their new synthesized nitrates on arterial blood pressure (BP) were measured in spontaneously hypertensive (SH) rats. BP was measured in conscious SH rats using the tail‐cuff method. Both short‐ and long‐term administration of the xanthines tested significantly decreased systolic, diastolic and mean BP. The hypotensive effect of a single dose of nitrate dyphylline on mean BP was greater than that of the parent compound (P = 0.000012; P = 0.000472 at 30 and 60 min post‐dose, respectively), whereas proxyphylline and its nitrate derivative had similar activity. In rats treated with the tested compounds for 9 days twice daily, the decrease in BP persisted for at least 16 h after the last dose. Proxyphylline produced the most marked decrease in diastolic and mean BP. Among the xanthines examined, proxyphylline nitrate had the strongest hypotensive effect when administered in a single dose to animals pretreated with the same compound for 9 days. These results indicate that insertion of a nitrate group weakly modifies the hypotensive action of the studied xanthines in SH rats.