Biomedical subjects

Philippe De Witte

Publications and source records attributed to Philippe De Witte.

17 recordsLinked to original sources

PubMed2007

Functional characteristics of TauA binding protein from TauABC Escherichia coli system.

Although TauA shares few common characteristics with other known periplasmic binding protein, TauA is a putative periplasmic binding protein, part of tauABCD gene cluster involved in sulfonate transport in sulphate starvation condition. This protein was expressed in E. coli BL 21 and purified before to assess its binding functionalities. Measurement of K (d) value (mean 11.3 nM) by binding/dialysis studies revealed high affinity and specificity with taurine and also indicated that TauA possessed a unique binding site for its ligand. Comparisons with other periplasmic binding proteins suggests TauA plays a major role in ABC transport system and could be ideal candidate to serve as taurine catcher in biological fluids.

ATP-Binding Cassette Transporters↗

PubMed2006

SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats.

This study investigated the effect of the new CB1 cannabinoid receptor antagonist, SR147778, on ethanol preference in chronically alcoholized Wistar rats. In study 1, SR147778, at doses of 0.3, 1, or 10 mg/kg/day (mg/kg/d) intraperitonealy (ip), was administered during chronic pulmonary ethanol intoxication for 30 days. The rats were then exposed to a two-bottle choice (ethanol 10% v/v vs. water) for at least 30 days. Neither 0.3 nor 1 mg/kg/d had any effect on ethanol preference. In contrast, the high dose induced a significant transient increase in ethanol intake between days 6 and 10. In study 2, SR147778, at doses of 0.3, 1, or 10 mg/kg/d ip, was administered during the free-choice period after chronic alcoholization. Both ethanol preference and intake were significantly reduced only for 1 and 10 mg/kg/d. These results reinforce the hypothesis that the cannabinoid CB1 receptor is part of the neural substrate mediating alcohol intake and the motivational properties of alcohol. When these results are compared with those obtained with SR141716 (Rimonabant) on ethanol preference, we observed that (1) coadministration of 10 mg/kg/d SR147778 during chronic alcoholization induced a shorter transient increase of ethanol intake than Rimonabant and (2) SR147778 treatment during the free-choice period at doses of 1 and 10 mg/kg/d decreased ethanol intake more dramatically than SR141716 which, furthermore, continued for the duration of the free choice.

Alcoholism↗

PubMed2006

Nicotine-induced changes of glutamate and arginine in naive and chronically alcoholized rats: an in vivo microdialysis study.

The effects of nicotine, when administered either acutely or chronically, at doses of 0.15, 0.3 or 0.6 mg/kg, on the release of glutamate and arginine in the rat nucleus accumbens have been studied in microdialysis experiments. Glutamate release significantly increased after acute nicotine injection, 0.3 mg/kg, which was accentuated if there was a priming regime of saline for the previous 27 days. This is possibly related to the rewarding effects of nicotine. Five hours after cessation of chronic oral nicotine administration, there were significant increases in glutamate content, which was possibly reflective of a withdrawal process. Significant decreases in nucleus accumbens arginine release were evident, between 1 and 2 h, after chronic nicotine administration. When nicotine was co-administered to rats during chronic ethanol intoxication, at either 0.15 mg/kg or 0.3 mg/kg doses, glutamate release did not increase during the first 12 h of withdrawal. However, a decrease in arginine microdialysate content was still observed with all nicotine doses. The nicotine-induced changes in glutamate and arginine release in nucleus accumbens highlights the complex neuropharmacological interactions evoked by this compound and also identified its possible modulating effect on glutamate release during the initial stages of chronic ethanol withdrawal.

Alcohol-Induced Disorders, Nervous System↗

PubMed2006

Glutamic acid in withdrawal and weaning in patients classified according to Cloninger's and Lesch's typologies.

AIMS: Though glutamic acid is well known as a working excitatory in the CNS, its impact on the modulation of alcohol withdrawal symptoms and withdrawal fits are not yet clear. The study has been undertaken to examine the levels of glutamic acid in chronic alcohol-dependent patients at different stages of alcohol withdrawal and weaning and to examine any existence of any differences according to Cloninger's and Lesch's typologies. PATIENTS AND METHODS: One hundred and fifty-nine alcohol-dependent patients were assessed according to Cloninger's and Lesch's typologies and related to abstinence duration, age, and gender. Blood samples were taken for mean corpuscular volume (MCV), gamma-glutamyltransferase (GGT) and glutamic acid, in order to find primarily any differences in glutamic acid according to the typologies, age, abstinence duration, and liver damage. RESULTS: There was no significant association between Cloninger's and Lesch's typologies. Cloninger's types 1 and 2 had an equal distribution of GGT and duration of abstinence, while Lesch's type I had more patients with high GGT, and more patients who were sober for a maximum of 2 days. Unlike in Lesch's types, glutamic acid levels did not differ according to Cloninger's types, as significantly higher glutamic acid values were found in Lesch's types I and IV. Glutamic acid values did not differ significantly in different age groups. CONCLUSIONS: Our study findings of varying glutamic acid levels seen in Lesch's typology, higher in types I and IV than in types II and III, are of significant clinical value and can be interpreted differently, as in type I high levels of glutamic acid is seen as a kindling phenomenon, while in type IV elevated levels might be related to either compulsivity of frequent repetition of drinking or withdrawal.

Adult↗

PubMed2005

Production of reactive oxygen species following acute ethanol or acetaldehyde and its reduction by acamprosate in chronically alcoholized rats.

The salicylate trap method, combined with microdialysis, has been used to validate whether reactive oxygen species, particularly hydroxyl radicals, ((*)OH), are generated in the hippocampus of male Wistar rats after acute intraperitoneal administration of either ethanol, 2 and 3 g/kg, or acetaldehyde, 200 mg, or during the initial stages of ethanol withdrawal after chronic ethanol intoxication. Salicylate (5 mM) was infused into the hippocampus via the microdialysis probe and the products of its metabolism by hydroxyl radical, particularly 2,3-dihydroxybenzoic acid (2,3-DHBA) as well as 2,5-dihydroxybenzoic acid (2,5-DHBA) assayed by HPLC (High Pressure Liquid Chromatography). Acetaldehyde, 200 mg/kg, and the higher acute dose of ethanol, 3 g/kg, induced transitory increases in 2,3-DHBA and 2,5-DHBA microdialysate content. At the cessation of four weeks of chronic ethanol intoxication, (by the vapour inhalation method), the mean blood alcohol level was 1.90 g/l. Significant increases of microdialysate 2,3-DHBA and 2,5-DHBA levels were assayed 3 h after alcohol withdrawal which were sustained for a further 5 and 1 h 40 min respectively. Oral administration of Acamprosate, 400 mg/kg/day, during the chronic ethanol intoxication procedure prevented the increased formation of 2,3- and 2,5-DHBA by comparison to rats chronically ethanol intoxicated alone.

Acamprosate↗

PubMed2005

Nicotine increases microdialysate brain amino acid concentrations and induces conditioned place preference.

The action of nicotine on the nicotinic receptor-mediated release of inhibitory and excitatory acids in the nucleus accumbens, NAC, of freely moving rats was studied in order to clarify their effects' on reinforcing behavior as estimated by conditioned place preference (CPP). Using the technique of microdialysis, intraperitoneal (i.p.) injections of nicotine (0.15-0.3-0.6 mg/kg), significantly increased aspartate, glutamate, arginine, taurine, and alanine microdialysate content in the nucleus accumbens. The same doses of nicotine were able to elicit a reinforcing effect in a CPP paradigm which was probably associated with the increased brain levels of excitatory acids triggering additional dopamine release in the mesolimbic system.

Amino Acids↗

PubMed2005

Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action.

Acamprosate is an abstinence-promoting drug widely used in the treatment of alcohol dependence but which has a mechanism of action that has remained obscure for many years. Recently, evidence has emerged that this drug may interact with excitatory glutamatergic neurotransmission in general and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular. These findings provide, for the first time, a satisfactory, unifying hypothesis that can bring together and explain the diverse neurochemical effects of acamprosate. Glutamic acid is involved in several aspects of alcohol dependence and withdrawal, many of which can be modified by acamprosate. For example, during chronic exposure to alcohol, the glutamatergic system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn. The surge in glutamic acid release that occurs following alcohol withdrawal can be attenuated by acamprosate. The elevated extracellular levels of glutamic acid observed in withdrawal, together with supersensitivity of NMDA receptors, may expose vulnerable neurons to excitotoxicity, possibly contributing to the neuronal loss sometimes observed in chronic alcohol dependence. In vitro studies suggest that the excitotoxicity produced by ethanol can effectively be blocked by acamprosate. Moreover, glutamatergic neurotransmission plays an important role in the acquisition of cue-elicited drinking behaviours, which again can be modulated by acamprosate. In conclusion, the glutamatergic hypothesis of the mechanism of action of acamprosate helps explain many of its effects in human alcohol dependence and points the way to potential new activities, such as neuroprotection, that merit exploration in the clinic.

Acamprosate↗

PubMed2004

Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic alcohol administration combined with repeated re-exposures and withdrawals.

AIMS: The cannabinoid CB1 receptor antagonist, SR141716A, differentially affects the ethanol preference of chronically alcoholized rats when administered during cycles of ethanol exposure and withdrawal. In this study, ethanol preference was investigated in chronically alcoholized rats that underwent regular withdrawal periods during which the brain cannabinoid CB(1) receptor antagonist, SR141716A, was administered. METHODS: The cannabinoid receptor antagonist SR141716A, 3 or 10 mg/kg/day, was administered i.p. to Wistar rats at the conclusion of a 4-week period of chronic alcoholization, as they commenced a cycle of alcohol withdrawal for 10 days followed by a period of 10 days chronic ethanol exposure. In a second set of experiments, an additional cycle of ethanol withdrawal and re-exposure was given. Preference for ethanol versus water started at the end of the first or second chronic ethanol re-exposure for a period of at least 30 days. RESULTS: In rats pretreated with the higher dose of SR141716A, ethanol preference during free choice was significantly increased after two ethanol re-exposures. In contrast, pretreatment with the lower SR141716A dose induced no significant change in ethanol intake during the free choice followed by either one or two ethanol re-exposures. CONCLUSIONS: SR141716A, 10 mg/kg/day dose, induced a significant increase in ethanol preference which was dependent on both the number of ethanol withdrawals and chronic ethanol re-exposures, while 3 mg/kg/day had no significant effect on ethanol preference.

Administration, Inhalation↗

PubMed2004

Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol.

Long-term exposure to ethanol leads to an imbalance in different excitatory and inhibitory amino acids. When ethanol consumption is reduced or completely stopped, these imbalances in different amino acids and neurotransmitters are behaviorally expressed in the form of ethanol withdrawal. Glutamate, a major excitatory amino acid, and GABA, a major inhibitory amino acid, are responsible, at least partly, for ethanol withdrawal symptoms. The hypofunction of GABAA receptors and enhanced function of NMDA receptors are suggested to be responsible for the increase in the behavioral susceptibility during ethanol withdrawal. This imbalance between receptors may be exacerbated by repeated withdrawal. Because multiple and repeated periods of chronic ethanol consumption and withdrawal often occur in alcohol abusers, animal studies on the neurochemical changes in different amino acids following chronic ethanol treatment (CET) that is interrupted by repeated ethanol withdrawal episodes may be of clinical relevance for the development of treatment strategies. Brain glutamate increases during the first cycle of ethanol withdrawal, and this increase is much higher during the third cycle of ethanol withdrawal. The elevated glutamate released in the hippocampus during the first cycle of ethanol withdrawal episode was exacerbated in subsequent withdrawal episodes. Acamprosate, a drug used during human alcohol detoxification, is able to completely block the glutamate increase observed during the first as well as the third withdrawal of ethanol. In ethanol-naïve rats, there was no change in the glutamate microdialysate content after an acute ethanol injection. However, when repeated ethanol injections were cued with a vinegar stimulus that had previously been associated with the same ethanol injection, a significant increase in glutamate microdialysate content was assayed. Furthermore, when the cue was omitted, the ethanol injection induced no changes in glutamate microdialysate content in rats that had been previously ethanol conditioned. By comparison, a saline injection had no effect on extracellular glutamate concentration in rats naïve for ethanol as well as in rats daily administered with repeated ethanol injections that were not paired with the cue. It appears probable that these conditioned responses by extracellular glutamate concentrations may participate in the environmental cue-induced conditioned cravings for ethanol that are thought to be related to the high frequency of relapse in detoxified alcoholics.

Alcoholism↗

PubMed2003

Role of catalase in ethanol-induced conditioned taste aversion: a study with 3-amino-1,2,4-triazole.

Recent studies involved acetaldehyde, the first ethanol metabolite, in both the rewarding and aversive effects of ethanol consumption. Brain acetaldehyde is believed to originate mainly from local brain metabolism of ethanol by the enzyme catalase. Therefore, the inhibition of catalase by 3-amino-1,2,4-triazole (aminotriazole) may help to clarify the involvement of acetaldehyde in ethanol's hedonic effects. In the present study, multiple doses of both ethanol and aminotriazole were used to investigate the effects of catalase inhibition on ethanol-induced conditioned taste aversion (CTA). A separate microdialysis experiment investigated the effects of aminotriazole pretreatment on the time course of brain ethanol concentrations. Ethanol induced a dose-dependent CTA with a maximal effect after conditioning with 2.0 g/kg ethanol. Aminotriazole pretreatments dose-dependently potentiated the CTA induced by 1.0 g/kg ethanol. However, aminotriazole pretreatments did not alter the CTA induced by higher ethanol doses (1.5 and 2.0 g/kg) probably because a maximal aversion for saccharin was already obtained without aminotriazole. The results of the microdialysis experiment confirmed that the effects of aminotriazole cannot be attributed to local alterations of brain ethanol levels. The present study argues against a role for brain acetaldehyde in ethanol's aversive effects but in favor of its involvement in ethanol rewarding properties.

Acetaldehyde↗

PubMed2003

Role of acetaldehyde in ethanol-induced conditioned taste aversion in rats.

RATIONALE: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. OBJECTIVES: The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. METHODS: A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. RESULTS: Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. CONCLUSIONS: The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA.

Acetaldehyde↗

PubMed2003

Excitatory and inhibitory amino acid changes during repeated episodes of ethanol withdrawal: an in vivo microdialysis study.

Changes in amino acid levels in the hippocampus during repeated ethanol withdrawal were studied. Wistar rats were made ethanol-dependent by 4-week vapour inhalation. After this first cycle of chronic ethanol treatment, rats underwent repeated and alternate cycles of 24 h of withdrawal followed by 1 week of chronic ethanol treatment. The microdialysis technique was used together with high-performance liquid chromatography and electrochemical detection to separate and quantify different amino acids such as aspartate, glutamate, arginine, taurine, alanine and gamma-aminobutyric acid. During the first cycle of ethanol withdrawal, increases in glutamate, taurine and alanine levels were observed. During the third withdrawal period, further increases were detected in aspartate, glutamate, taurine and alanine in the comparison with levels in the control group. However, the arginine level during the third withdrawal period decreased when compared to that after the first withdrawal period. The results of this study demonstrate that excitatory amino acid levels increased with subsequent withdrawal periods.

Animals↗

PubMed2003

Systemic osmotic manipulations modulate ethanol-induced taurine release: a brain microdialysis study.

In recent microdialysis studies, increased extracellular concentrations of taurine after high ethanol dose administration were identified in various rat brain regions. The mechanisms by which ethanol caused these increases in extracellular taurine concentration remained unclear but could be related to ethanol-induced cell swelling. The aim of the current study was to investigate whether changes in the body osmotic state modulate the effects of ethanol on brain extracellular taurine concentrations. In several groups of rats, brain hypoosmotic or hyperosmotic states were superimposed on acute ethanol (2.0-g/kg) injections, and extracellular taurine concentrations within the nucleus accumbens were assessed by using an intracerebral microdialysis procedure. A hypoosmotic state was obtained by systemic administration of water while hyperosmotic states were induced by intraperitoneal injections of hypertonic saline solutions (1.8% or 3.6% saline). In isoosmotic conditions, ethanol induced an immediate and significant increase in taurine microdialysate content, confirming results of previous studies. However, the effects of ethanol on taurine concentrations were modulated by osmotic manipulations. Hypoosmotic conditions significantly potentiated ethanol-induced taurine release. In contrast, ethanol-induced increases in extracellular taurine levels were attenuated by 1.8% saline injection and totally prevented by 3.6% saline administration. These results strongly argue in favor of a primary role of osmoregulation in ethanol-induced taurine release. Ethanol-induced cell swelling probably activates volume-sensitive channels, and taurine passively diffuses outside the cells along its concentration gradient.

Animals↗

PubMed2003

Effects of acamprosate on excitatory amino acids during multiple ethanol withdrawal periods.

BACKGROUND: Our previous studies on the effects of acamprosate on enhanced locomotion during repeated withdrawals are now extended to the effects of acamprosate on excitatory amino acids in the hippocampus during repeated ethanol withdrawals. METHODS: In this study, Wistar rats were made ethanol dependent by 4 weeks of vapor inhalation. After this first cycle of chronic ethanol treatment, rats underwent repeated and alternate cycles of 24 hr withdrawals and 1 week of chronic ethanol treatment. The microdialysis technique was used together with high-performance liquid chromatography and electrochemical detection to quantify different amino acids such as aspartate and glutamate. RESULTS: An intraperitoneal administration of acamprosate (400 mg/kg) to naïve rats did not alter aspartate or glutamate levels compared with the saline groups. During the first cycle of ethanol withdrawal, the administration of acamprosate (400 mg/kg, intraperitoneally) 2 hr after the commencement of ethanol withdrawal decreased both aspartate and glutamate microdialysate levels when compared with their respective saline group. Acamprosate administration also significantly decreased glutamate levels during the third withdrawal compared with the saline group, whereas no changes were seen in aspartate levels. CONCLUSION: The results of this work demonstrate that acamprosate reduced the excitatory amino acid glutamate increase observed during repeated ethanol withdrawal. These effects of acamprosate may provide a protective mechanism against neurotoxicity by reducing excitatory amino acids, particularly glutamate.

Acamprosate↗

PubMed2002

Acamprosate reduces context-dependent ethanol effects.

RATIONALE: Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of environmental stimuli previously associated with ethanol administrations. This action is believed to contribute to the clinical benefits of acamprosate treatment in alcoholics. OBJECTIVES: In the present experiment, a classical drug-conditioning paradigm was used to test whether acamprosate modulates the effects of ethanol-paired environmental stimuli on spontaneous motor activity. METHODS: Wistar rats were divided into three groups: cued, uncued and control. The cued group daily received ethanol injections (2.0 g/kg, IP) in a specific testing environment. The uncued group daily received ethanol injections (2.0 g/kg, IP) in their home cage but never experienced ethanol in the testing environment. The control group was injected with saline and never experienced ethanol. After 8 conditioning days, the rats were IP injected with various ethanol doses (saline, 1.0, 1.5 or 2.0 g/kg) and their spontaneous motor activity in the testing environment was recorded to investigate their respective tolerance to ethanol inhibitory effects. In the second part of the study, the same procedure was repeated with chronically acamprosate-treated rats. The chronic acamprosate treatment (400 mg/kg per day) started 2 weeks before the conditioning procedure by diluting acamprosate in the drinking bottles and was maintained throughout the whole experiment. RESULTS: The cued rats showed a significant environment-dependent tolerance to ethanol inhibitory effects relative to the uncued and control rats. This higher ethanol tolerance of the cued rats was mainly due to a faster recovery from ethanol's inhibitory effects on spontaneous activity. Furthermore, the cued rats showed a higher level of activity in the testing environment after the saline injection. However, it is not clear whether this hyperactivity is a conditioned compensatory response or an increased exploratory behavior. Acamprosate totally abolished the environment-dependent tolerance to ethanol, whereas it did not alter the hyperactivity of the cued rats in the testing environment. CONCLUSIONS: The results of the present study suggest that acamprosate reduces ethanol-conditioned effects. Such an action may be of importance to explain the anti-relapse effects of acamprosate.

Acamprosate↗

PubMed2002

Potential neuroprotective effects of acamprosate.

This article represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizers were Barbara J. Mason and George F. Koob. Anita M. Goodman served as chair. The presentations were (1) Acamprosate inhibits alcohol withdrawal-induced neurotoxicity in organotypic hippocampal cultures, by John Littleton; (2) Acamprosate alteration of NMDA receptor-dependent synaptic transmission and synaptic plasticity, by George R. Siggins; (3) Acamprosate and glutamate during ethanol withdrawal, by Philippe De Witte; (4) Clinical evidence of protective CNS effects of acamprosate in alcohol-dependent individuals, by Barbara J. Mason.

Acamprosate↗

PubMedDate not supplied

Challenges to medications development in treating alcohol dependence: an international perspective.

Few medications for treating alcohol dependence exist. Greater partnership is needed between academia and the pharmaceutical industry to develop, licence and market efficacious medications for treating alcohol dependence. Methodologies that span the divide between preclinical and large-scale clinical studies need to be developed in order to provide sufficient information on safety, toleration, drug-interaction profile and efficacy, with which to guide development decisions. Due to the heterogeneous nature of alcohol dependence, the effort of developing an efficacious medication is likely to be enhanced by clearer choices about the characteristics of the population. Careful consideration of potential mechanism of action of the putative therapeutic medication should enable the appropriate choice of drinking endpoint. The pharmaceutical industry in collaboration with academia might need to develop new approaches to determining appropriate treatment endpoints with regulatory bodies. The investment risk to industry should be appraised not only in terms of the rather poor results of previous marketing efforts but with a view to the opportunity to penetrate a potentially enormous and largely untapped market.

Alcoholism↗