[Potentiation of Delta9-tetrahydrocannabinol (THC) effects by magnesium deficiency in the rat]. / Potentialisation des effets du Delta9-tétrahydrocannabinol (THC) par la carence magnésique chez le rat.

Aggressive behavior can be classified into three major categories: defense, social attack and predatory behavior. The predatory behavior of rats, which prompts them to prey on mice (muricidal behavior) may be induced by injection of high doses (11 mg/kg) of Delta9-tetrahydrocannabinol (THC) or by acute magnesium deficiency. We have studied the effect of a single injection of low doses of THC (2, 4 or 8 mg/kg) in rats with a severe (50 ppm magnesium diet) or moderate (150 ppm) magnesium deficiency. The combination of moderate magnesium deficiency with low doses of THC induced muricidal behavior in all the rats and an increase in aggressiveness at the doses of 4 or 8 mg/kg of THC. Hyperaggressiveness increased with magnesium deficiency severity. Serotonin is probably involved in aggressiveness induced by both moderate magnesium deficiency and low doses of THC, but implication of other neurotransmitters and magnesium deficiency-induced alterations of CB1-and/or CB2-receptor expression are not excluded.

Magnesium chloride or magnesium sulfate: a genuine question.

MgSO4 is routinely used in therapeutics despite its toxicity. The aim of the present review was to compare MgSO4 and MgCl2 effects in order to answer the question whether MgSO4 could be or not replaced by MgCl2. Considering that the two salts have both similar and proper effects, a clear-cut conclusion is not easy to draw. However, choosing MgCl2 seems advisable because of its more interesting clinical and pharmacological effects and its lower tissue toxicity as compared to MgSO4.

Magnesium depletion with hypo- or hyper- function of the biological clock may be involved in chronopathological forms of asthma.

Asthma is a chronic, inflammatory disorder of the airways leading to airflow limitation. Its worldwide rise, mainly in developed countries, is a matter of concern. Nocturnal asthma (NA) frequently occurs and concerns two thirds of asthmatics. But, it remains controversial whether NA is a distinct entity or is a manifestation of more severe asthma. Generally, it is considered as an exacerbation of the underlying pathology. The pathological mechanisms most likely involve endogenous circadian rhythms with pathological consequences on both respiratory inflammation and hyperresponsiveness. A decrease in blood and tissue magnesium levels is frequently reported in asthma and often testifies to a true magnesium depletion. The link with magnesium status and chronobiology are well established. The quality of magnesium status directly influences the Biological Clock (BC) function, represented by the suprachiasmatic nuclei and the pineal gland. Conversely, BC dysrythmias influence the magnesium status. Two types of magnesium deficits must be clearly distinguished: deficiency corresponding to an insufficient intake which can be corrected through mere nutritional Mg supplementation and depletion due to a dysregulation of the magnesium status which cannot be corrected through nutritional supplementation only, but requires the more or less specific correction of the dysregulation mechanisms. Both in clinical and in animal experiments, the dysregulation mechanisms of magnesium depletion associate a reduced magnesium intake with various types of stress including biological clock dysrhythmias. The differenciation between Mg depletion forms with hyperfunction of BC (HBC) and forms with hypofunction of BC (hBC) is seminal and the main biological marker is melatonin (MT) production alteration. We hypothesize that magnesium depletion with HBC or hBC may be involved in chronopathological forms of asthma. Nocturnal asthma would be linked to HBC, represented by an increase in MT levels. The corresponding clinical forms associate diverse expressions of nervous hypoexcitability such as depression, cluster headaches, dyssomnia, mainly advanced sleep phase syndrome, some clinical forms of chronic fatigue syndrome and of fibromyalgia. The main comorbidities are depression and/or asthenia. They take place during the night or the "bad" seasons (autumn and winter) when sunshine is at a minimum. The corresponding chronopathological therapy relies on bright light phototherapy sometimes with additional psychoanaleptics. Conversely, asthma forms linked to hBC are less frequently studied as a whole and present a decrease in MT levels. They associate various signs of nervous hyperexcitability such as anxiety, diurnal cephalalgia (mainly migraine), dyssomnia, mainly delayed sleep phase syndrome, and some clinical forms of chronic fatigue syndrome and of fibromyalgia. The treatment relies on diverse forms of "darkness therapy", possibly with the help of some psycholeptics. Finally, the treatment of asthma involves the maintenance of a standard dosing schedule of anti-asthma drugs, a balanced magnesium intake and the appropriate treatment of the chronopathological disorders.

Effect of Mg-deficiency on endothelial cell allogeneic activation in a model of isolated perfused mouse lung.

Following vascularized organ allotransplantation, an early intragraft inflammatory process is initiated by adhesion molecule-ligand interaction between recipient blood leukocytes and graft endothelial cells (EC). We have previously shown that chronic hypomagnesemia did not induce any inflammatory process in the lung, hence neither EC activation, nor lung remodelling. In the present study we have investigated the effects of allogeneic blood perfusion on lungs from magnesium-deficient mice in our experimental model of isolated mouse lung. After 3h of isogeneic or allogeneic perfusion, no inflammatory process was detected by histochemical examination of lung tissue; the mRNA levels of the adhesion molecules E-selectin, ICAM-1 and VCAM-1, and of the pro-inflammatory cytokines TNF-alpha and IL-2 in lung tissue, determined by reverse transcriptase-polymerase chain reaction (RT-PCR), were similar, and the expression of E-selectin and I-Ab antigen on EC by immunohistochemical staining was undetectable. All of these markers were shown to be dramatically increased after allogeneic perfusion of lung from magnesium-non deficient mice. Our results clearly show that allogeneic perfusion of lungs from magnesium-deficient mice cannot induce EC activation or lung inflammation, indicating that hypomagnesemia in donors does not constitute an additional risk for allograft outcome and might allow to lighten the recipient's immunosuppressive treatment.

Severe Mg-deficiency is not associated with endothelial cell activation in mouse lung.

Several experimental and clinical studies suggest that the lungs are a specific target of Mg-hypomagnesemia, which is a common side effect of cyclosporin A therapy. Due to the possible effect of hypomagnesemia on lung allograft function, the aim of this study was to evaluate endothelial cell (EC) activation and tissue remodelling (apoptosis) in the lungs from mice fed Mg-deficient diets. Immunocytochemical examinations did not reveal any inflammatory process in Mg-deficient mice, infiltration of leukocytes (CD45+ cells), expression of I-Ab class II molecules, E-selectin or ICAM-1 on ECs, and apoptotic cells. Quantification of mRNAs for E-selectin, ICAM-1 and VCAM-1, which are the most pertinent adhesins expressed by ECs, and for the cytokines TNFalpha and IL-2, demonstrated that severe Mg-deficiency does not result in EC activation. The balance between the up-regulation of G-CSF-R and CCL4 genes, and the down-regulation of the OPN gene shown by the cDNA microarray technique might be responsible for the absence of development of an inflammatory response, lung EC activation, and lung remodelling. However, we can hypothesize that severe Mg deficiency results in a latent inflammatory status of the lungs, which might be expressed following immune stresses, like transplantation conditions.

A new actimetry-based test of photic sensitization in a murine photosensitive magnesium depletion model.

Photic hypersensitivity may induce various signs of nervous hypersensitivity, including diurnal cephalalgias, anxiety, dyssomnia, seizures, fatigue and/or myalgias. The patients usually present both dishabituation and generalization in response to repetitive light stimuli instead of habituation as in normal subjects. These clinical manifestations appear when light intensity is maximum (daytime; spring and summer) in magnesium-depleted patients with hypofunction of the biological clock. The best photic hypersensitivity management involves darkness therapy, either darkness per se or darkness-mimicking agents. To detect efficiently the best drugs that may be used in the treatment of disorders due to photosensitive magnesium depletion, we are proposing a simple and reproducible actimetry-based test in a murine photosensitive magnesium depletion model. Photostimulation using a stroboscope (100 J, 50 Hz) was performed on magnesium-deficient and control mice. It led to habituation with a decreased activity in response to intermittent light stimulation in control mice, whereas it induced in magnesium-deficient mice both sensitization (or potentiation), with nervous hyperexcitability, and generalization, involving sound hypersensitivity, after visual stimulation. In preclinical evaluation, this test provides a valuable animal model to study the neuroprotective effect of drugs in photosensitive syndromes, which often associate sensitization and generalization to various stimuli.

Importance of magnesium depletion with hypofunction of the biological clock in the pathophysiology of headhaches with photophobia, sudden infant death and some clinical forms of multiple sclerosis.

Mg depletion is a type of Mg deficit due to a dysregulation of the Mg status. It cannot be corrected through nutritional supplementation only, but requires the most specific correction of the dysregulating mechanism. Among those, Biological Clock (BC) dysrhythmias are to be considered. The aim of this study is to analyze the clinical forms of Mg depletion with hypofunction of the Biological Clock (hBC). hBC may be due to either Primary disorders of BC [Suprachiasmatic Nuclei (SCN) and pineal gland (PG)] or Secondary with homeostatic response [reactive Photophobia (Pphi] to light neurostimulating effects [Nervous Hyper Excitability (NHE)]. The symptomatology is mainly diurnal and observed during fair weather (Spring,Summer). The elective marker of hBC is represented by a decrease in melatonin and in its metabolites in various fluids. The clinical forms of NHE due to Mg depletion with hBC are central and peripheral. The central forms associate anxiety, headaches and dyssomnia. The peripheral manifestations are neuromuscular: photosensitive epilepsia mainly. Three chronopathological forms of Mg depletion with hBC have been highlighted: 1. Headaches with Pphi: mainly migraine; 2. Sudden Infant Death Syndrome (SIDS); 3. Multiple Sclerosis (MS).- Headaches with Pphi, migraine particularly. These cephalalgias are diurnal with Pphi and are aggravated during the fair seasons (particularly during midnight sun-summer). Migraine is their typical form with its dishabituation to visual stimuli and its occipital cortex hyperexcitability. Comorbidity with anxiety is frequent. In 2/3 of the cases, it appears first.- SIDS might be linked to an impaired maturation of both photoendocrine system and brown adipose tissue. MS may be associated with primary disorders of BC Clinical forms of Mg depletion with hBC in MS present diurnal exacerbations and relapses during fair seasons. They have been underestimated because they disagree with the dogma of the << latitude gradient >>, presently questioned. Comorbidities with anxiety and migraine are frequent.hBC may be treated by using darkness therapy with a balanced Mg status. Absolute light deprivation should only be used only in acute indications and is time-limited. Partial substitutive therapy and chromatotherapy have not been validated yet and are still uncertain.

Magnesium deficiency reveals the neurotoxicity of delta-9-tetrahydrocannabinol (THC) low doses in rats.

In the present study, muricide behaviour (MB) was studied in Long Evans rats in various situations. The MB pattern of each experimental group was compared, in 6 successive assays 1 hr-delayed to that of natural killer rats (NK). The percentage of NK rats was 11% in the strain used. In the 11 mg THC/kg b.w. treated naive rats, a significant additional percentage of rats (59%) became muricidal. The durations of the 3 MB phases were significantly increased as a result of an increased aggressiveness in the 1st assay but returned progressively to NK values on the 6th assay, in parallel with the physiological elimination of THC. This result indicates a true killing training in those non killer rats that became muricidal under THC. A severe magnesium deficiency induced by a 50 ppm magnesium-deficient diet induced 100% MB whereas a 150 ppm magnesium deficiency did not induce additional MB. In the severe deficiency, the MB pattern was rather similar to that of NK with the exception of the attack on the living mouse which was doubled probably because of magnesium-induced hyperexcitability responsible for a lower attack efficiency. In both 50 but also 150 ppm magnesium-deficient rats, a single injection of THC at low doses (2, 4 or 8 mg THC/kg b.w.) which is without aggressive effect in control rats, induced a 100% MB, the pattern of which was all the more severe as the magnesium deficiency was important or the THC dose higher. The pattern showed an important decrease in the two first phases and a dramatic increase in the attack on the dead mouse, suggesting that the combination of both treatments provoked severe central damage with a compulsive killing behavior. Consequently, it appears that a magnesium deficiency, even a moderate one, may aggravate the neurotoxicity of THC at low doses and, reciprocally, that low doses of THC may reveal the potential neurotoxicity of a moderate magnesium deficiency.

Comparison of a short irradiation (50 sec) by different wavelengths on audiogenic seizures in magnesium-deficient mice: evidence for a preventive neuroprotective effect of yellow.

Audiogenic seizures triggered by an acoustic stimulus of determined frequency and amplitude have been described in many laboratory animals in many circumstances including magnesium deficiency. This model, recently validated, was used, in DBA/2 mice, to study the preventive neuroprotective effect of 6 wavelengths of the visible spectrum used in Chromatotherapia* (lambda(max) 440, 484, 528, 572, 616 and 660 nm) at low irradiance. Each short illumination lasted 50 seconds and was followed by 20 minutes of darkness. It appeared that yellow fully protected 16 out of 17 mice from seizure occurrence. Green allowed the survival of 69% of mice but did not protect them from seizure occurrence. On the contrary, the other four colors (orange, red, purple and blue) failed to protect the mice and showed a tendency to accelerate their death. White color was not protective but allowed the difficult survival of 30% of mice. Darkness had no protective effect. These results even though surprising open a great field of investigation.

Structural alterations of the vascular wall in magnesium-deficient mice. A possible role of gelatinases A (MMP-2) and B (MMP-9).

Vascular alterations during magnesium deficiency have long been known but the implicated mechanisms have so far been poorly documented. In this preliminary assay, we compared the thoracic aortic histology in Swiss OF1 mice fed a severe magnesium-deficient diet (50 +/- 5 ppm) for 42 days to that of controls fed a standard diet (1700 +/- 100 ppm magnesium). It appeared (eosin-haematoxylin coloration) that, in magnesium-deficient mice, the aortic wall was thinner than in controls. Specific colorations of the two of main fibers vascular tissue (collagens and elastin) showed severe structural alterations of both components. These changes were consecutive to the expression of matrix metalloproteinases (MMP) -2 and -9 which were present as zymogens (inactive forms) in controls and supposed to be present in their active and inactive forms in magnesium-deficient mice (zymography). These changes which have not been reported so far would explain, at least in part, the sensitivity of magnesium-deficient mice to various stress or xenobiotics.

Marfan syndrome, magnesium status and medical prevention of cardiovascular complications by hemodynamic treatments and antisense gene therapy.

The medical management of Marfan Syndrome (MFS) mainly relies on early prevention of the aortic complications. Hemodynamic treatments try to diminish the forcefulness of cardiac contractions and to reduce blood pressure: for example long term administration of propranolol may significantly reduce the rate of increase in aortic ratio (aortic diameter/expected aortic diameter). Retardation of aortic dilatation may be most often observed by early treatment started when the baseline end-diastolic aortic root diameter is < 40 mm. It seems better to use beta-blockers without intrinsic sympathomimetic activity. Successful acceptance of beta-blockers may be limited by side-effects, but the efficiency of alternative hypotensive agents (calcium channel inhibitors, ACE inhibitors) is not yet validated. Gene therapy might constitute an etiologic specific treatment of MFS. FBN1-RZ1 hammerhead antisense ribozyme is able to suppress expression of the mutant FBN1 allele. The use of ribozymes as systemic therapeutic agents will depend on efficient delivery to its target, but the various proposed vectors raise yet unsolved problems. A hydrogel angioplasty balloon might be a possible vector for delivering an antisense ribozyme in the aortic wall specifically. Ribozymes--as deoxyribonucleotides--may be taken up by tissue upon local application. Further research should study ex vivo local application of antisense ribozyme on human aortic wall, before assessing in vivo efficiency and tolerance of this aortic local vectorisation. It is always necessary to maintain a balanced magnesium intake in patients with MFS. Firstly to prevent the multiple noxious effects of magnesium deficiency on cardiovascular targets. Secondly to ensure the best efficiency and the least toxicity of the hemodynamic drugs used as long term prophylactic treatment for cardiovascular complications and of the etiologic antisense magnesium-dependent gene therapy, in the future.

Importance of the ratio between ionized and total Mg in serum or plasma: new data on the regulation of Mg status and practical importance of total Mg concentration in the investigation of Mg imbalance.

There is an inverse relationship between Mg balance and the ratio ionized Mg/total Mg in serum or plasma: in Mg excess, the ratio is decreased and in Mg deficiency the ratio is increased. It works as if a subtle homeostasic compensatory reaction modified the proportion of the most biologically active fraction of blood Mg in order to reduce the effects of Mg imbalance. Easy, available and unexpensive, the evaluation of total Mg in plasma or serum appears as a better marker than ionized Mg in Mg imbalance: it should be priviledged as the initial investigation in clinical practice.

Chronopathological forms of magnesium depletion with hypofunction or with hyperfunction of the biological clock.

The main mechanisms of the chronopathological forms of magnesium depletion associate a low Mg intake with various dysregulating biorhythms. The differentiation between forms with hyperfunction and forms with hypofunction of the biological clock is seminal and the main marker is the production of melatonin (MT). The clinical forms of the various patterns of the chronopathological forms of Mg depletion may be central or peripheral. The clinical forms with hyperfunction of the biological clock (marker: increase in MT) may associate diverse expressions of nervous hypoexcitability: depression (i.e. Seasonal affective disease); cephalalgias nocturnal, without photophobia (i.e. cluster headaches); dyssomnia LASPS (advanced sleep phase syndrome) particularly]; asthenia and myalgias (i.e. fibromyalgia, chronic fatigue syndrome). The main comorbidity is found with depressive states. The therapy relies on classical bright light phototherapy, sometimes associated with psychoanaleptics. The clinical forms with hypofunction of biological clock (marker: decrease in MT) may associate various signs of nervous hyperexcitability (HEN): anxiety (from generalized anxiety to panic attacks); cephalalgias diurnal with photophobia (mainly migraine); dyssomnia [DSPS (delayed sleep phase syndrome) particularly, jet lag, night work disorders, age related insomnia, sometimes with inappropriate behaviour; photogenic epilepsia, generalized or focal; some clinical forms of chronic fatigue syndrome and fibromyalgia. The main comorbidity is between migraine and epilepsia. The treatment relies on the diverse forms of darkness therapy, possibly with the help of some psycholeptics: anxiolytics and anticonvulsants. The indications of chromatotherapy remain to be validated.

A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.

FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.

Physiopathology of symptomatic and latent forms of central nervous hyperexcitability due to magnesium deficiency: a current general scheme.

Symptomatic forms of central nervous hyperexcitability (NHE) due to magnesium deficiency results from the sum of direct cellular effects and of local and systemic mediated effects inducing depolarization and NHE. Direct effects associate decreased energy and cationic gradient with disturbances in Ca distribution, decreased second messenger nucleotidic ratio and increased susceptibility to peroxidation. Local mediated effects associate increased activity of excitatory neuromediators: acetylcholine, catecholamines and ionotropic - (NMDA and non-NMDA) - receptors of excitatory aminoacids (EAA), with decreased activity of inhibitory neuromediators: GABA, taurine, glutaurine, adenosine and K receptors of opioids. Systemic mediated effects associate increased production of inflammatory mediators: neuropeptides, prostanoids, cytokines Th 1, aldehydes with decreased activity of oxidant and antialdehyde defences. Compensatory factors instrumental in the latency of NHE due to magnesium deficiency may also be direct or mediated. Increased intracellular pH, modifications of Ca and Mg binding proteins, increase in 'magnesium-like' polyamines, stimulation of cellular antioxidant system; decreased activity of EAA metabotropic receptors and of opioid mu (and delta) receptors, increased activity of inhibitory neuromediators, increased production of anti-inflammatory mediator such as cytokines Th 2, stimulation of systemic antioxidant and antialdehyde defences. A lot of diverse compounds are able to palliate symptomatic NHE due to magnesium deficiency either by pharmacodynamic effects or through physiopathological intervention. The efficiency of these treatments can be evaluated on multiple disparate parameters. The pattern of NHE due to magnesium deficiency differs according to species, strains, gender, age and intensity of magnesium deficiency. For example: hot plate test showed a hypoalgesia 'morphine-like' pattern induced by magnesium deficiency cured by magnesium acetyltaurinate in mice whilst paw pressure test showed a hyperalgic pattern caused by magnesium deficiency cured by dizolcipine in rats. Now it seems difficult to rank hierarchically the various physiopathological mechanisms of NHE due to magnesium deficiency. But the proposed general scheme of the factors controlling this NHE provides a possible explanation of both diffuse symptomatic and latent forms and stresses the complexity of the physiopathological mechanisms of central NHE due to magnesium deficiency.

Synthesis and anticonvulsant and neurotoxic properties of substituted N-phenyl derivatives of the phthalimide pharmacophore.

A series of compounds including 4-amino (1), 3-amino (2), 4-nitro (3), 2-methyl-3-amino (4), 2-methyl-3-nitro (5), 2-methyl-4-amino (6), 2-methyl-4-nitro (7), 2-methyl-5-amino (8), 2-methyl-5-nitro (9), 2-methyl-6-amino (10), 2-methyl-6-nitro (11), 2,6-dimethyl (12), 2-methyl-3-carboxy (13), 2-methoxycarbonyl (14), 2-methyl-4-methoxy (15), 2,4-dimethoxy (16), 2-chloro-4-amino (17), and 2-chloro-4-nitro (18) N-phenyl substituents of phthalimide were evaluated along with N-[3-methyl-(2-pyridinyl)]phthalimide (19), N-(3-amino-2-methylphenyl)succinimide (20), and phenytoin for anticonvulsant and neurotoxic properties. Initial screening in the intraperitoneal (ip) maximal electroshock-induced seizure (MES) test and the subcutaneous pentylenetetrazol-induced seizure (scPtz) test in mice led to the selection of 1, 2, 4, 10, 12, 17, and 19 for oral MES evaluation in rats. The resultant ED(50) values for 4, 10, 17, and phenytoin were 8.0, 28.3, 5.7 and 29.8 mg/kg, respectively. In the batrachotoxin affinity assay, IC(50) values for 17 and phenytoin were 0.15 and 0.93 microM, respectively, and in the recently validated magnesium deficiency-dependent audiogenic seizure test, ED(50) values of 5.2 and 23 mg/kg were obtained for 17 and phenytoin, respectively. Electrophysiology studies on compound 17 point out its ability to (i) potentiate GABA-evoked current responses with a failure to directly activate the GABAA receptor and (ii) to affect, at 100 microM excitatory non NMDA, but not NMDA, receptors with a 25% block of kainate-evoked response. Electrophysiology measurements on voltage-gated sodium channels in N1E-115 neuroblastoma cells confirm voltage-dependent block of these channels by compound 17. In view of its interaction with multiple ion channels, one would predict that compound 17 might be active in a wide range of seizure models.

Cardiovasoprotective foods and nutrients: possible importance of magnesium intake.

Various highly efficient cardiovasoprotective diets associate reduced intake of total and saturated fats, reasonable supply of monounsaturated fat and omega-3 fatty acids, moderate consumption of alcohol, increased intake of cereals, fruits, vegetables, fish and low fat dairy products. Among several protective nutrients magnesium should be given particular consideration because of the very frequent occurrence of chronic primary magnesium deficiency which appears to act as a cardiovascular risk factor and also reversely, because of the noticeable high level of the magnesium content in cardiovasoprotective diets.

Protective effect of Crassostrea gigas extract on audiogenic seizures in magnesium deficient mice.

Audiogenic seizures associated with loss of weight, prostration, piloerection, palpebral ptosis and motor deficiency were induced after sound stimulation of determined frequency and amplitude in magnesium-deficient DBA/2 mice. These symptoms were maintained when standard diet conditions (1700 ppm Mg2+) were restored. In contrast, mice were protected from audiogenic seizure in a dose related manner when Crassostrea gigas extract (JCOE) were added to the diet for 10 consecutive days. Although a rational explanation for this protective effect has not yet been determined, it is assumed that it might be due to a chelating complex formed between Mg2+ and taurine, which enhance the uptake of Mg2+.

Measurement of the three phases of muricidal behavior induced by delta9-tetrahydrocannabinol in isolated, fasting rats.

Delta9-Tetrahydrocannabinol (THC) has long been recognized as inducing mouse-killing behavior (muricidal behavior) in starving, isolated rats after a single injection. We showed that when the killing tendency was increased by THC, a preliminary contact with a mouse decreased the probability of muricidal behavior. By quantifying the three phases of the muricidal behavior in either nonkiller or naive THC-treated rats, we showed that the duration of each step was notably increased as compared to untreated natural killer rats, mainly the attack on the dead mouse, indicating increased aggressiveness. Finally, no significant changes were observed in the duration of the three phases in natural killer rats when the muricide assays were repeated every hour. In contrast, in THC-treated rats--either naive or nonkiller--all three phases decreased with the assay repetition to levels comparable to those of natural killer rats, suggesting that the killer behavior was progressively acquired for the six assays. These changes could be a useful model to study the central effects of THC and either its agonists or antagonists.

Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties.

A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test.