Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 16 de 16
Filter
1.
J Neurogenet ; 25(4): 152-66, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22091727

ABSTRACT

There is growing evidence suggesting that antagonists of group II metabotropic glutamate receptors (mGluR2/3) exhibit antidepressant-like properties in several preclinical models of depression. However, all those studies have been performed using competitive group II non-selective orthosteric antagonists. In this study we extensively characterized a group II selective negative allosteric modulator (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one, namely RO4491533, Woltering et al., 2010) in several in vitro biochemical assays and in vivo models of depression. In vitro, RO4491533 completely blocked the glutamate-induced Ca(2+) mobilization and the glutamate-induced accumulation in [(35)S]GTP(γS) binding in cells expressing recombinant human or rat mGluR2 and in native tissues. Results from Schild plot experiments and reversibility test at the target on both cellular and membrane-based assays confirmed the negative allosteric modulator properties of the compound. RO4491533 was equipotent on mGluR2 and mGluR3 receptors but not active on any other mGluRs. RO4491533 has acceptable PK properties in mice and rats, is bioavailable following oral gavage (F = 30%) and brain-penetrant (CSF conc/total plasma conc ratio = 0.8%). RO4491533 appeared to engage the central mGluR2 and mGluR3 receptors since the compound reversed the hypolocomotor effect of an mGluR2/3 orthosteric agonist LY379268 in a target-specific manner, as did the group II orthosteric mGluR2/3 antagonist LY341495. RO4491533 and LY341495 dose-dependently reduced immobility time of C57Bl6/J mice in the forced swim test. Also, RO4491533 and LY341495 were active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. These data suggest that mGluR2/3 receptors are viable targets for development of novel pharmacotherapies for depression.


Subject(s)
Antidepressive Agents/pharmacology , Benzodiazepines/pharmacology , Benzodiazepinones/pharmacology , Depressive Disorder/drug therapy , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Allosteric Regulation/drug effects , Allosteric Regulation/genetics , Animals , Antidepressive Agents/therapeutic use , Benzodiazepines/therapeutic use , Benzodiazepinones/therapeutic use , Depressive Disorder/genetics , Depressive Disorder/metabolism , Disease Models, Animal , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acid Antagonists/therapeutic use , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism
2.
Article in English | AIM (Africa) | ID: biblio-1267861

ABSTRACT

We report a case of Total Hip Arthroplasty using cemented Charnley prothesis. This was done in an old tuberculous hip without using antituberculous chemoprophylaxis. The patient developed periprosthetic bacterial infection not related to tuberculous site reactivation. We report our experience with this case and review of relevant literatures


Subject(s)
Arthroplasty , Tuberculosis
3.
Ann Pharm Fr ; 62(5): 332-42, 2004 Sep.
Article in French | MEDLINE | ID: mdl-15314581

ABSTRACT

Depression is a multifactorial illness and genetic factors play a role in its etiology. The understanding of its pathophysiology relies on the availability of experimental models potentially mimicking the disease. Here is presented a model built up by selective breeding of mice with strikingly different responses in the tail suspension test, a stress paradigm aimed at screening potential antidepressants. Indeed, "helpless" mice are essentially immobile in the tail suspension test, as well as the Porsolt forced-swim test, and they show reduced consumption of a palatable 2% sucrose solution. In addition, helpless mice exhibit sleep-wakefulness alterations resembling those classically observed in depressed patients, notably a lighter and more fragmented sleep, with an increase pressure of rapid eye movement sleep. Compared with "nonhelpless" mice, they display higher basal serum corticosterone levels and lower serotonin metabolism index in the hippocampus. Remarkably, serotonin1A autoreceptor stimulation induced greatest hypothermia and inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis in helpless than in nonhelpless mice. Thus, helpless mice exhibit a decrease in serotoninergic tone, which evokes that associated with endogenous depression in humans. Finally, both the behavioral impairments and the serotoninergic dysfunction can be improved by chronic treatment with the antidepressant fluoxetine. The helpless line of mice may provide an opportunity to approach genes influencing susceptibility to depression and to investigate neurophysiological and neurochemical substrates underlying antidepressant effects.


Subject(s)
Depressive Disorder/psychology , Animals , Brain Chemistry/physiology , Depressive Disorder/etiology , Disease Models, Animal , Female , Male , Mice , Receptor, Serotonin, 5-HT1A/physiology
4.
J Neuroendocrinol ; 15(12): 1171-7, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14636179

ABSTRACT

A2A receptor knockout (A2AR-/-) mice are more anxious and aggressive, and exhibit reduced exploratory activity than their wild-type littermates (A2AR+/+). Because alpha-melanocyte-stimulating hormone (alpha-MSH) influences anxiety, aggressiveness and motor activity, we investigated the effect of A2AR gene disruption on alpha-MSH content in discrete brain regions and pro-opiomelanocortin (POMC) expression in the hypothalamus and pituitary. No modification in alpha-MSH content was observed in the hypothalamus and medulla oblongata where POMC-expressing perikarya are located. In the arcuate nucleus of the hypothalamus, POMC mRNA levels were not affected by A2AR disruption. Conversely, in A2AR-/- mice, a significant increase in alpha-MSH content was observed in the amygdala and cerebral cortex, two regions that are innervated by POMC terminals. In the pars intermedia of the pituitary, A2AR disruption provoked a significant reduction of POMC mRNA expression associated with a decrease in alpha-MSH content. By contrast, in the anterior lobe of the pituitary, a substantial increase in POMC mRNA and adrenocorticotropin hormone concentrations was observed, and plasma corticosterone concentration was significantly higher in A2AR-/- mice, revealing hyperactivity of their pituitary-adrenocortical axis. Together, these results suggest that adenosine, acting through A2A receptors, may modulate the release of alpha-MSH in the cerebral cortex and amygdala. The data also indicate that A2A receptors are involved in the control of POMC gene expression and biosynthesis of POMC-derived peptides in pituitary melanotrophs and corticotrophs.


Subject(s)
Pituitary Gland, Anterior/physiology , Pro-Opiomelanocortin/metabolism , Receptor, Adenosine A2A/genetics , alpha-MSH/metabolism , Animals , Gene Expression , Hypothalamus/cytology , Hypothalamus/physiology , Male , Medulla Oblongata/cytology , Medulla Oblongata/physiology , Mice , Mice, Inbred Strains , Mice, Knockout , Pituitary Gland, Anterior/cytology , RNA, Messenger/analysis
5.
Neuropharmacology ; 45(7): 977-85, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14573390

ABSTRACT

The role of the adenosine A(2A) receptor in the hypnotic effects of ethanol was assessed in mice. The duration of the loss of righting reflex following acute ethanol administration was shorter for A(2A) receptor-deficient mice (A(2A)R KO) than for wild-type mice (A(2A)R WT), whereas the fall in body temperature was not different between the two phenotypes. In contrast, the duration of the loss of righting reflex was increased in A(2A)R KO mice versus controls after administration of pentobarbital. Dipyridamole, an inhibitor of adenosine uptake, increased the sleep time observed following administration of ethanol in CD1 mice and in A(2A)R WT but not in A(2A)R KO mice. SCH 58261, a selective A(2A) receptor antagonist, unlike DPCPX, a selective A(1) receptor antagonist, shortened the duration of the loss of righting reflex induced by ethanol, thus mimicking the lack of receptor in deficient mice. Finally, the non-selective adenosine receptor antagonist caffeine (25 mg/kg) reduced ethanol-induced hypnotic effects. These results indicate that the activation of A(2A) receptors that follows an increase in extracellular adenosine levels caused by the administration of high doses of ethanol plays a role in its hypnotic effects. Thus, A(2A) receptor antagonists may be useful therapeutic agents for alleviating ethylic coma.


Subject(s)
Adenosine A2 Receptor Antagonists , Caffeine/pharmacology , Central Nervous System Depressants/antagonists & inhibitors , Central Nervous System Stimulants/pharmacology , Ethanol/antagonists & inhibitors , Adenosine A1 Receptor Antagonists , Animals , Body Temperature/drug effects , Central Nervous System Depressants/poisoning , Dipyridamole/pharmacology , Drug Overdose/drug therapy , Ethanol/poisoning , Hypnotics and Sedatives/pharmacology , Male , Mice , Mice, Knockout , Neuroprotective Agents/pharmacology , Pentobarbital/pharmacology , Postural Balance/drug effects , Pyrimidines/pharmacology , Receptor, Adenosine A2A/genetics , Triazoles/pharmacology , Vasodilator Agents/pharmacology , Xanthines/pharmacology
6.
Chir Main ; 21(1): 51-5, 2002 Jan.
Article in French | MEDLINE | ID: mdl-11885390

ABSTRACT

A case of simultaneous proximal radio ulnar joint divergent dislocation combined with a bone avulsion of the coronoid apophysis of the same elbow in a 16 years-old girl is presented. After a closed reduction and two weeks of plaster immobilization, normal function of the elbow was recovered within three months. There are only ten cases reported of such a divergent elbow dislocation in modern literature.


Subject(s)
Elbow Injuries , Joint Dislocations/pathology , Orthopedic Procedures/methods , Adolescent , Elbow/pathology , Elbow/surgery , Female , Humans , Immobilization , Joint Dislocations/surgery , Radius/pathology , Ulna/pathology
7.
Eur J Neurosci ; 14(9): 1567-70, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11722618

ABSTRACT

The selective A2A receptor antagonist [3H]SCH 58261 was injected intravenously in mice and the radioactivity accumulating in various brain regions was determined by tissue sampling. Radioactivity levels in regions of interest such as the striatum were highest 15 min after injection and quickly declined thereafter (30 min and 1 h postinjection) in a time-dependent manner. The amount of labelling was ranked as follows: striatum (4.6 +/- 0.3 fmol/mg protein) >> cortex > hippocampus > pons = hypothalamus > cerebellum (0.5 +/- 0.05 fmol/mg protein). Specific labelling of the A2A receptor occurred in striatum and cortex because significantly less radioactivity accumulated in these areas from adenosine A2A receptor knockout mice as compared to wild-type littermates. In control outbred CD1 mice, a striatum-to-cerebellum ratio of 7.6 +/- 0.6 was found. At 30 min postinjection, the nonselective adenosine receptor antagonist caffeine reduced the radioactivity due to [3H]SCH 58261 in the striatum by 32% at 1 mg/kg i.p. and by 66% at the stimulant dose of 6.25 mg/kg i.p. Radioactivity in the striatum was lowered, respectively, by 66 and 86% 30 min after injection of 3 or 10 mg/kg i.p. doses of unlabelled SCH 58261. The present results indicate that [3H]SCH 58261 directly labels striatal A2A receptors in vivo. Thus [3H]SCH 58261 is an excellent tool for studying brain distribution and A2A receptor occupancy of various compounds ranging from xanthines, such as caffeine, to other A2A antagonists.


Subject(s)
Adenosine/metabolism , Brain/drug effects , Neurons/drug effects , Neuroprotective Agents/metabolism , Purinergic P1 Receptor Antagonists , Pyrimidines/metabolism , Triazoles/metabolism , Animals , Binding Sites/drug effects , Binding Sites/physiology , Binding, Competitive/drug effects , Binding, Competitive/physiology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/physiology , Brain/cytology , Brain/metabolism , Caffeine/pharmacology , Dose-Response Relationship, Drug , Drug Interactions/physiology , Male , Mice , Mice, Knockout , Neurons/metabolism , Phosphodiesterase Inhibitors/pharmacology , Radioligand Assay , Receptor, Adenosine A2A , Receptors, Purinergic P1/deficiency , Receptors, Purinergic P1/genetics , Tritium/metabolism
8.
Br J Pharmacol ; 134(1): 68-77, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11522598

ABSTRACT

1. Adenosine, an ubiquitous neuromodulator, and its analogues have been shown to produce 'depressant' effects in animal models believed to be relevant to depressive disorders, while adenosine receptor antagonists have been found to reverse adenosine-mediated 'depressant' effect. 2. We have designed studies to assess whether adenosine A2A receptor antagonists, or genetic inactivation of the receptor would be effective in established screening procedures, such as tail suspension and forced swim tests, which are predictive of clinical antidepressant activity. 3. Adenosine A2A receptor knockout mice were found to be less sensitive to 'depressant' challenges than their wildtype littermates. Consistently, the adenosine A2A receptor blockers SCH 58261 (1 - 10 mg kg(-1), i.p.) and KW 6002 (0.1 - 10 mg kg(-1), p.o.) reduced the total immobility time in the tail suspension test. 4. The efficacy of adenosine A2A receptor antagonists in reducing immobility time in the tail suspension test was confirmed and extended in two groups of mice. Specifically, SCH 58261 (1 - 10 mg kg(-1)) and ZM 241385 (15 - 60 mg kg(-1)) were effective in mice previously screened for having high immobility time, while SCH 58261 at 10 mg kg(-1) reduced immobility of mice that were selectively bred for their spontaneous 'helplessness' in this assay. 5. Additional experiments were carried out using the forced swim test. SCH 58261 at 10 mg kg(-1) reduced the immobility time by 61%, while KW 6002 decreased the total immobility time at the doses of 1 and 10 mg kg(-1) by 75 and 79%, respectively. 6. Administration of the dopamine D2 receptor antagonist haloperidol (50 - 200 microg kg(-1) i.p.) prevented the antidepressant-like effects elicited by SCH 58261 (10 mg kg(-1) i.p.) in forced swim test whereas it left unaltered its stimulant motor effects. 7. In conclusion, these data support the hypothesis that A2A receptor antagonists prolong escape-directed behaviour in two screening tests for antidepressants. Altogether the results support the hypothesis that blockade of the adenosine A2A receptor might be an interesting target for the development of effective antidepressant agents.


Subject(s)
Antidepressive Agents/pharmacology , Purinergic P1 Receptor Antagonists , Animals , Behavior, Animal/drug effects , Blepharoptosis/chemically induced , Blepharoptosis/prevention & control , Disease Models, Animal , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Dose-Response Relationship, Drug , Female , Haloperidol/pharmacology , Immobilization , Male , Mice , Mice, Knockout , Motor Activity/drug effects , Purines/pharmacology , Pyrimidines/pharmacology , Receptor, Adenosine A2A , Receptors, Dopamine D2/physiology , Receptors, Purinergic P1/genetics , Reserpine/administration & dosage , Swimming , Time Factors , Triazoles/pharmacology
9.
Rev Chir Orthop Reparatrice Appar Mot ; 87(4): 397-401, 2001 Jun.
Article in French | MEDLINE | ID: mdl-11431637

ABSTRACT

We report four cases of echinococcosis of the pelvic bone in 3 women and a man aged 30 to 55 years. Disease spread was wide, involving the entire hemipelvis in one case and the sacrum in another making surgical excision difficult. In two cases, computed tomography was highly contributive to diagnosis and assessment of local extension. We used surgical excision and hydrogen peroxide sterilization for the first two case. For the two last cases, we used albendazole in four 4-week cures at a 2-week interval before and after surgery. The clinical course was favorable to these two cases at 3 and 4 years. The albendazole-surgery combination appears to be the best therapeutic option.


Subject(s)
Bone Diseases, Infectious/diagnostic imaging , Bone Diseases, Infectious/therapy , Echinococcosis/diagnostic imaging , Echinococcosis/therapy , Pelvic Bones , Adult , Albendazole/therapeutic use , Anti-Infective Agents, Local/therapeutic use , Anticestodal Agents/therapeutic use , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Hydrogen Peroxide/therapeutic use , Male , Middle Aged , Osteotomy , Patient Selection , Perioperative Care , Tomography, X-Ray Computed , Treatment Outcome
10.
Neuroreport ; 12(5): 983-6, 2001 Apr 17.
Article in English | MEDLINE | ID: mdl-11303773

ABSTRACT

Catalepsy assessed using the bar test was measured in both adenosine A2A receptor knockout (A2AR KO) and wild-type (A2AR WT) mice submitted to acute administration of the dopamine D2 receptor antagonist haloperidol (0.5, 2, 4, 6 mg/kg i.p.), the dopamine D1 antagonist SCH 23390 (0.3-3 mg/kg, s.c.), the vesicular monoamine transporter blocker reserpine (3-5 mg/kg, s.c.) or the acetylcholine muscarinic receptor agonist pilocarpine (25-50 mg/kg, i.p.). Except for reserpine, catalepsy scores were significantly lower in A2AR KO mice than in A2AR WT mice following low doses of these cataleptogenic agents. These results suggest that adenosine A2A receptors influence not only dopamine D2 and D1 receptor-mediated neurotransmission but also acetylcholine muscarinic receptor-mediated neurotransmission.


Subject(s)
Catalepsy/chemically induced , Receptors, Purinergic P1/physiology , Animals , Benzazepines , Catalepsy/genetics , Dopamine Antagonists , Haloperidol , Male , Mice , Mice, Knockout , Muscarinic Agonists , Pilocarpine , Receptor, Adenosine A2A , Receptors, Purinergic P1/genetics , Reserpine , Sympatholytics
11.
Neuropharmacology ; 40(3): 424-32, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11166335

ABSTRACT

Considering the existing interactions between ethanol and adenosine, the influence of the genetic impairment of the adenosine A(2A) receptor has been examined upon the seizures occurring at the cessation of chronic ethanol intake or 'ethanol withdrawal' in male mice. Acute clearance of ethanol did not differ between adenosine A(2A) receptor knockout and wild-type mice. Mice were exposed for 10 days to a diet consisting of a milky chocolate drink that contained increasing concentrations (1.8, 3.6 and 6.3% v/v) of ethanol. Adenosine A(2A) receptor knockout mice ingested similar amounts of the fluid, either containing alcohol or not, as did the controls. The severity of handling-induced convulsions during withdrawal was significantly reduced in the adenosine A(2A) receptor knockout mice as compared with their wild-type controls. The selective adenosine A(2A) receptor antagonist ZM 241385 (20 mg/kg) also significantly attenuated the intensity of withdrawal-induced seizures occurring in wild-type male mice when intraperitoneally administered twice daily during the last 5 days of the forced alcohol intake. These results suggest that selective adenosine A(2A) receptor antagonists may be useful in the treatment of alcohol withdrawal.


Subject(s)
Alcohol Withdrawal Seizures/genetics , Purinergic P1 Receptor Antagonists , Receptors, Purinergic P1/deficiency , Administration, Oral , Alcohol Withdrawal Seizures/prevention & control , Animals , Beverages , Cacao , Disease Models, Animal , Drug Administration Schedule , Eating/drug effects , Ethanol/administration & dosage , Ethanol/blood , Female , Flavoring Agents , Injections, Intraperitoneal , Male , Mice , Mice, Knockout , Receptor, Adenosine A2A , Receptors, Purinergic P1/genetics , Triazines/administration & dosage , Triazoles/administration & dosage
12.
Eur J Pharmacol ; 401(1): 63-77, 2000 Jul 28.
Article in English | MEDLINE | ID: mdl-10915839

ABSTRACT

The acute motor effects elicited by drugs acting upon adenosine A(2A) receptors, namely the highly selective agonist CGS 21680 or the antagonists SCH 58261 and ZM 241385, were investigated in mice. CGS 21680 dose-dependently (0.1-2.5 mg/kg i.p.) decreased horizontal and vertical motor activities. The depressant effect of CGS 21680 (0. 5 mg/kg i.p.) was maintained in mice pretreated by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (10-30 mg/kg i.p. ), which poorly penetrates the blood-brain barrier, but was completely lost in adenosine A(2A) receptor knockout mice. Thus, the adenosine A(2A) receptor is critically involved in motor activity. SCH 58261 (1-10 mg/kg i.p.) increased locomotion and rearing with a quick onset, but for a shorter period in mice habituated to the environment than in mice unfamiliar to it. ZM 241385 (7.5-60 mg/kg i. p.) stimulated horizontal and vertical activities with a slow onset at the two highest tested doses, similarly in naive and in habituated mice. The increase in locomotion elicited by ZM 241385 (15-30 mg/kg i.p. and 10-20 nM i.c.v.) was retained in mice treated by CGS 21680 (0.5 mg/kg i.p.) but that elicited by SCH 58261 (1-3-10 mg/kg i.p. and 10-20 nM i.c.v.) partially subsided. In conclusion, both 'striatal-like'/'SCH 58261-sensitive' adenosine A(2A) receptors and 'ZM 241385-sensitive'/'atypical' CGS 21680 binding sites may mediate CGS 21680-induced motor effects. Moreover, our results suggest that 'atypical' CGS 21680 binding sites could be adenosine A(2A) receptors with a peculiar pharmacological profile.


Subject(s)
Adenosine/analogs & derivatives , Adenosine/pharmacology , Motor Activity/drug effects , Neuroprotective Agents/pharmacology , Phenethylamines/pharmacology , Pyrimidines/pharmacology , Triazines/pharmacology , Triazoles/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Interactions , Exploratory Behavior/drug effects , Injections, Intraventricular , Male , Maze Learning/drug effects , Mice , Mice, Knockout , Receptor, Adenosine A2A , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/genetics , Receptors, Purinergic P1/physiology , Time Factors
13.
Br J Pharmacol ; 129(7): 1465-73, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10742303

ABSTRACT

1. The locomotor stimulatory effects induced by caffeine (1,3, 7-trimethylxanthine) in rodents have been attributed to antagonism of adenosine A(1) and A(2A) receptors. Little is known about its locomotor depressant effects seen when acutely administered at high doses. The roles of adenosine A(1) and A(2A) receptors in these activities were investigated using a Digiscan actimeter in experiments carried out in mice. Besides caffeine, the A(2A) antagonist SCH 58261 (5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine), the A(1) antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), the A(1) agonist CPA (N(6)-cyclopentyladenosine) and A(2A) receptor knockout mice were used. 2. Caffeine had a biphasic effect on locomotion of wild-type mice not habituated to the open field, stimulating locomotion at 6.25 - 25 mg kg(-1) i.p. doses, while depressing it at 100 mg kg(-1). In sharp contrast, caffeine dose-dependently decreased locomotion in A(2A) receptor knockout mice over the whole range of tested doses. 3. The depressant effects induced by high doses of caffeine were lost in control CD1 mice habituated to the open field. 4. The A(1) agonist CPA depressed locomotion at 0.3 - 1 mg kg(-1) i.p. doses. 5. The A(1) antagonist DPCPX decreased locomotion of A(2A) receptor knockouts and CD1 mice at 5 mg kg(-1) i.p. and 25 mg kg(-1) i.p. respectively. 6. DPCPX (0.2 - 1 mg kg(-1) i.p.) left unaltered or even reduced the stimulant effect of SCH 58261 (1 - 3 mg kg(-1) i.p.) on CD1 mice. 7. These results suggest therefore that the stimulant effect of low doses of caffeine is mediated by A(2A) receptor blockade while the depressant effect seen at higher doses under some conditions is explained by A(1) receptor blockade.


Subject(s)
Behavior, Animal/drug effects , Caffeine/pharmacology , Central Nervous System Stimulants/pharmacology , Motor Activity/drug effects , Purinergic P1 Receptor Antagonists , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Habituation, Psychophysiologic , Male , Mice , Mice, Knockout , Pyrimidines/pharmacology , Receptor, Adenosine A2A , Receptors, Purinergic P1/genetics , Receptors, Purinergic P1/physiology , Triazoles/pharmacology , Xanthines/pharmacology
14.
Psychopharmacology (Berl) ; 148(2): 153-63, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10663430

ABSTRACT

RATIONALE: The elevated plus-maze and the light/dark box are two established anxiety tests in rodents, which are useful to screen putative anxiogenic effects of drugs. OBJECTIVE: Caffeine is well known to promote anxious behaviour in humans and animal models, but the precise site of action of the drug is still a matter of debate. The present study investigated whether the anxiogenic effects of caffeine observed in mice depend on the blockade of A(2A) receptor. First, the effects induced by the non-selective drug caffeine were compared with those elicited by two selective A(2A) receptor antagonists over a wide range of doses in the same experimental conditions. The effects of A(2A) or A(1 )adenosine receptor agonists and of a selective A(1) adenosine receptor antagonist were also investigated. Second, wild-type and A(2A) receptor knockout mice offered another approach to delineate the role played by A(2A) receptor in caffeine's anxiogenic effects. METHODS: Mice were exposed to the elevated plus-maze or to the light/dark box for 5 min after acute or chronic administration of tested drugs. RESULTS: Caffeine acutely administered (50 or 100 mg/kg IP) induced anxiety-like effects in both procedures. Its chronic administration (50 mg/kg IP twice daily) for 1 week or consumption in the drinking water (0.3 g/l) for 8 days or 2 months were also anxiogenic in the plus-maze test. The A(2A) receptor antagonists ZM241385 (up to 60 mg/kg IP) and SCH58261 (up to 10 mg/kg IP) were devoid of acute effects in both tests. One week administration of ZM241385 (30 mg/kg IP) or SCH58261 (3 mg/kg IP) had no effects in the plus-maze test. An antagonist (DPCPX) and an agonist (CPA) at A(1) receptors had no acute effects on anxiety-related indices, whereas an A(2A) receptor agonist (CGS 21680) displayed non-specific motor effects in the plus-maze test. Acute administration of caffeine (50 mg/kg IP) induced no clear-cut anxiety-like effects in the plus-maze test in A(2A) receptor knockout mice that exhibited higher basal anxiety levels than wild-type mice. Chronic administration (50 mg/kg IP twice daily) for 1 week elicited less anxiety-like behaviour in A(2A) receptor knockout than in wild-type mice. CONCLUSIONS: Adaptative mechanisms following mutation in A(2A) receptors or their long-term blockade after chronic ingestion of caffeine may be responsible for increase proneness to anxiety. However, the short-term anxiety-like effect of caffeine in mice might not be related solely to the blockade of adenosine A(2A) receptors, since it is not shared by A(2A) selective antagonists.


Subject(s)
Anxiety/chemically induced , Caffeine/administration & dosage , Purinergic P1 Receptor Antagonists , Adenosine/administration & dosage , Adenosine/analogs & derivatives , Administration, Oral , Animals , Anxiety/drug therapy , Behavior, Animal/drug effects , Darkness , Drug Administration Schedule , Injections, Intraperitoneal , Light , Male , Maze Learning/drug effects , Mice , Mice, Knockout , Neuroprotective Agents/administration & dosage , Phenethylamines/administration & dosage , Purinergic P1 Receptor Agonists , Pyrimidines/administration & dosage , Reaction Time/drug effects , Receptor, Adenosine A2A , Triazines/administration & dosage , Triazoles/administration & dosage , Xanthines/administration & dosage
15.
Nature ; 388(6643): 674-8, 1997 Aug 14.
Article in English | MEDLINE | ID: mdl-9262401

ABSTRACT

Adenosine is released from metabolically active cells by facilitated diffusion, and is generated extracellularly by degradation of released ATP. It is a potent biological mediator that modulates the activity of numerous cell types, including various neuronal populations, platelets, neutrophils and mast cells, and smooth muscle cells in bronchi and vasculature. Most of these effects help to protect cells and tissues during stress conditions such as ischaemia. Adenosine mediates its effects through four receptor subtypes: the A1, A2a, A2b and A3 receptors. The A2a receptor (A2aR) is abundant in basal ganglia, vasculature and platelets, and stimulates adenylyl cyclase. It is a major target of caffeine, the most widely used psychoactive drug. Here we investigate the role of the A2a receptor by disrupting the gene in mice. We found that A2aR-knockout (A2aR-/-) mice were viable and bred normally. Their exploratory activity was reduced, whereas caffeine, which normally stimulates exploratory behaviour, became a depressant of exploratory activity. Knockout animals scored higher in anxiety tests, and male mice were much more aggressive towards intruders. The response of A2aR-/- mice to acute pain stimuli was slower. Blood pressure and heart rate were increased, as well as platelet aggregation. The specific A2a agonist CGS 21680 lost its biological activity in all systems tested.


Subject(s)
Receptors, Purinergic P1/physiology , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine/physiology , Aggression/physiology , Animals , Blood Pressure/physiology , Brain/physiology , Caffeine/pharmacology , Cloning, Molecular , Heart Rate/physiology , Humans , Hypertension/etiology , Male , Mice , Mice, Knockout , Molecular Sequence Data , Pain , Phenethylamines/pharmacology , Platelet Aggregation/physiology , Purinergic P1 Receptor Antagonists , Receptors, Purinergic P1/deficiency , Receptors, Purinergic P1/genetics , Restriction Mapping , Sequence Homology, Amino Acid
16.
Article in French | MEDLINE | ID: mdl-7899633

ABSTRACT

One case of divergent dislocation of the elbow is reported. It was associated with other lesions of the upper limb due to the violence of the initial trauma. The authors found 6 other cases reported in the literature. They discuss the mechanism, diagnosis and treatment of such lesions.


Subject(s)
Elbow Injuries , Fracture Fixation, Internal/methods , Joint Dislocations , Adult , Elbow Joint/surgery , Fracture Fixation, Internal/adverse effects , Humans , Humeral Fractures/complications , Humeral Fractures/surgery , Joint Dislocations/complications , Joint Dislocations/diagnostic imaging , Joint Dislocations/therapy , Male , Manipulation, Orthopedic , Prognosis , Radiography , Ulna Fractures/complications , Ulna Fractures/surgery
SELECTION OF CITATIONS
SEARCH DETAIL
...