ABSTRACT
We studied the capacity of adrenal medullary transplant to restore the deficits of GABAergic and dopaminergic neurons in mice injected with quinolinic acid (QA), using an open field test as well as pharmacological and immunohistochemical techniques. We analysed behavioural traits-total locomotor activity, peripheral and central activities, grooming, leaning and rearing in the QA-lesioned mice and mice that had undergone adrenal medulla (AM) transplantation. We found that the adrenal transplant recovered a loss of GABAergic neurons. It reduced QA-induced hyperactivity in locomotion and improved emotional indices. In addition, immunohistochemical studies of catecholaminergic markers-tyrosine hydroxylase (TH), dopamine (DA) and neuronal vesicular monoamine transporter type 2- and a single post-trial injection of tetrabenazine (TBZ; 5 mg/kg) indicated that catecholamines-synthesising chromaffin cells in the AM grafts were also involved in the beneficial effects. A likely interpretation of this behavioural pattern of results is that adrenal medullary transplants set into play an interaction between GABAergic and DAergic factors. Our results may contribute to the clarification of the beneficial effects of AM transplants in striatal function.
Subject(s)
Adrenal Medulla/transplantation , Dopamine/metabolism , Locomotion/physiology , Membrane Transport Proteins , Neurons/transplantation , Neuropeptides , gamma-Aminobutyric Acid/metabolism , Adrenal Medulla/physiology , Adrenergic Uptake Inhibitors/pharmacology , Animals , Corpus Striatum/drug effects , Corpus Striatum/injuries , Corpus Striatum/pathology , Immunohistochemistry , Locomotion/drug effects , Male , Membrane Glycoproteins/metabolism , Mice , Motor Activity/drug effects , Motor Activity/physiology , Neurons/metabolism , Neurons/physiology , Neurotoxins/toxicity , Quinolinic Acid/toxicity , Tetrabenazine/pharmacology , Tyrosine 3-Monooxygenase/metabolism , Vesicular Biogenic Amine Transport Proteins , Vesicular Monoamine Transport ProteinsABSTRACT
A task requiring dynamic postural stabilisation during locomotion in a conflicting visual vestibular environment (rotating beam), has been devised to assess anxiety-related balance impairments and postural changes in mice. The model, already validated with acutely administered diazepam, was used to assess the action of two chronically administered selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine. On three behavioural measures (imbalance, elevation of trunk and angle of tail), observed in anxious BALB/cByJ mice, both compounds had the same diazepam-like effects: reduction in number of imbalances, higher elevation of trunk and increase in tail angle. These data suggest, for the first time, that SSRIs should be useful in the treatment of anxiety-induced balance impairments.
Subject(s)
Anxiety/complications , Mice, Inbred BALB C/genetics , Mice, Inbred C57BL/genetics , Postural Balance/drug effects , Posture/physiology , Selective Serotonin Reuptake Inhibitors/pharmacology , Vestibular Diseases/drug therapy , Animals , Anxiety/drug therapy , Anxiety/physiopathology , Central Nervous System/drug effects , Central Nervous System/physiopathology , Dose-Response Relationship, Drug , Female , Fluoxetine/pharmacology , Male , Mice , Paroxetine/pharmacology , Postural Balance/physiology , Sex Characteristics , Vestibular Diseases/etiology , Vestibular Diseases/physiopathologyABSTRACT
Immunohistochemical and behavioral techniques were used to study the effects of adrenal medulla grafts, implanted in striatum after bilateral kainic acid (KA) lesions of this structure, on the open field behavior of mice. KA-induced behavioral changes in leaning, grooming and locomotor activity of the open field test were significantly improved after grafting of the adrenal medulla, and in some respects, fully restored. Immunohistochemical identification showed that grafts contained neuron-like cells with a tyrosine hydroxylase (TH), phenylethanolamine N-methyltransferase, gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), and enkephalin-like immunostainings. A likely interpretation of this complex pattern of results is that adrenal medullary grafts may restore the deficits of GABAergic neurons which in turn reverse the abnormalities in emotionality and locomotion. Neurobiologically, these behavioral improvements probably involve GABAergic and catecholaminergic factors of adrenal medulla grafts, although other neuroactive substances, such as acetylcholine and enkephalins, cannot be excluded.
Subject(s)
Adrenal Medulla/transplantation , Arousal/physiology , Corpus Striatum/physiology , Grooming/physiology , Motor Activity/physiology , Social Environment , Animals , Brain Mapping , Catecholamines/physiology , Choline O-Acetyltransferase/physiology , Male , Mice , Nerve Regeneration/physiology , Neurons/physiology , Phenethylamines , Phenylethanolamine N-Methyltransferase/physiology , Tyrosine 3-Monooxygenase/physiology , gamma-Aminobutyric Acid/physiologyABSTRACT
A relation between anxiety disorders and balance control dysfunctions has been observed in many studies in humans. A mismatch in the integration of sensory inputs could trigger these disturbances. Very few experimental animal procedures have been designed to study the functional link between anxiety and balance control. A task was therefore developed, challenging the visual, vestibular and somesthesic sensory systems in mice. The test, called the 'rotating beam', gave an accurate assessment of balance control and the posture, using sensitive measures (number of falls and imbalances, position of tail and trunk). Striking differences were observed between the two inbred strains of mice known to have radically different anxiety-related behaviour. The highly anxious strain, BALB/cByJ, performed poorly compared to the non anxious strain, C57BL/6J. Balance control and postural abilities of anxious mice were improved by acute anxiolytic diazepam treatment. Lower behavioural performance level was registered in non anxious mice given anxiogenic beta-CCM treatment. The findings account for a strong relationship between anxiety and balance control in mice. Finally, the highly sensitive procedure proved to be well suited to the study of functional links between anxiety and sensorimotor processes.
Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety , Carbolines/pharmacology , Diazepam/pharmacology , Postural Balance/drug effects , Receptors, GABA-A/drug effects , Animals , Anxiety/chemically induced , Anxiety/genetics , Behavior, Animal/drug effects , Disease Models, Animal , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Posture , Psychomotor Performance/drug effects , Receptors, GABA-A/metabolismABSTRACT
Methyl beta-carboline-3-carboxylate (beta-CCM) is a ligand for the benzodiazepine (BZD) binding site of the GABA-A receptors with convulsive properties. We provided evidence for the involvement of a fragment of mouse chromosomes 4 and 13 in beta-CCM-induced seizures in a previous paper. Here, we analyzed, through [3H]-flumazenil binding, whether central BZD binding sites could be involved in the physiological processes underlying these differences of genetic sensitivities. In the JE/Le strain, where the effects of the chromosome 4 fragment can be analyzed, we found associations between [3H]-flumazenil binding and the convulsive action of beta-CCM. On the contrary, this no longer holds true in C3XtEso strain, where the effects of the chromosome 13 fragment were observed.
Subject(s)
Brain/metabolism , Carbolines/pharmacology , Chromosome Mapping , Convulsants/pharmacology , Receptors, GABA-A/physiology , Seizures/genetics , Animals , Brain/drug effects , Flumazenil/pharmacokinetics , Mice , Mice, Inbred Strains , Mice, Mutant Strains , Radioligand Assay , Receptors, GABA-A/drug effects , Seizures/chemically induced , Seizures/physiopathology , Species Specificity , TritiumABSTRACT
PURPOSE: A low dose of the benzodiazepine receptor inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM) (1 mg/kg) was used to assess [3H]-flumazenil binding in a subkindling situation in Swiss mice. METHODS: The brains were removed, and benzodiazepine receptor binding was studied every second day over 14 days of administration. RESULTS: With each successive trial, Bmax values showed a steady and significant decrease, whereas Kd values showed a steady and significant increase. Behavioral data showed that at this low dose, actual kindling (seizuring) was not reached at the behavioral level. CONCLUSIONS: The findings suggest that decreased gamma-aminobutyric acid (GABA) inhibition may occur even if behavioral effects of kindling are not observed.
Subject(s)
Carbolines/pharmacology , Convulsants/pharmacology , Flumazenil/metabolism , GABA Antagonists , Kindling, Neurologic/drug effects , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Seizures/chemically induced , Animals , Disease Models, Animal , Epilepsy/chemically induced , Epilepsy/metabolism , Male , Mice , Seizures/metabolism , TritiumABSTRACT
Two mouse lines were selectively bred according to their sensitivity (BS line) or resistance (BR line) to seizures induced by a single i.p. injection of methyl beta-carboline-3-carboxylate (beta-CCM), an inverse agonist of the GABA(A) receptor benzodiazepine site. Our aim was to characterize both lines' sensitivities to various physiological effects of other ligands of the GABA(A) receptor. We measured diazepam-induced anxiolysis with the elevated plus-maze test, diazepam-induced sedation by recording the vigilance states, and picrotoxin- and pentylenetetrazol-induced seizures after i.p. injections. Results presented here show that the differential sensitivities of BS and BR lines to beta-CCM can be extended to diazepam, picrotoxin, and pentylenetetrazol, suggesting a genetic selection of a general sensitivity and resistance to several ligands of the GABA(A) receptor.
Subject(s)
Carbolines/pharmacology , Convulsants/pharmacology , GABA Agonists/pharmacology , Receptors, GABA-A/genetics , Seizures/genetics , Selection, Genetic , Animals , Brain/drug effects , Female , Male , Mice , Mice, Inbred Strains , Receptors, GABA-A/drug effects , Seizures/chemically inducedABSTRACT
Spontaneous behavior patterns were assessed in eight different behavioral situations in two lines of mice, BR and BS, previously selected for their sensitivity to an anxiogenic benzodiazepine (BZ) receptor inverse agonist, Methyl beta-carboline-3-carboxylate (beta-CCM). BR is highly resistant, and BS, highly sensitive to beta-CCM-induced seizures. Tests used included an assessment of general locomotor activity, several situations classically used for measuring fear-motivated behaviors (open field, thigmotaxis, elevated plus-maze, light-dark discrimination, staircase), a test for measuring exploration (holeboard), and a test for measuring nociception (hot-plate). In the absence of beta-CCM, the results provide evidence of reduced motor activity and higher levels of anxiety in the BR line as compared to the BS line.
Subject(s)
Anxiety/genetics , Behavior, Animal/drug effects , Convulsants/pharmacology , Animals , Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Carbolines/pharmacology , Discrimination, Psychological/drug effects , Exploratory Behavior/drug effects , Mice , Mice, Inbred Strains , Motor Activity/genetics , Pain Measurement/drug effects , Postural Balance/drug effects , Reaction Time/drug effectsABSTRACT
Rat recombinant alpha1beta2gamma2 gamma-aminobutyric acid type A (GABAA) receptors were functionally expressed in Xenopus laevis oocytes and analyzed for the action of EDPC (Ethyl 3-(1,3-dithian-2-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate) using electrophysiological techniques. EDPC inhibited GABA currents at low concentrations (IC50 approximately/= 2 nM). The inhibition by 100 nM EDPC could be reversed by 1 microM of the benzodiazepine antagonistflumazenil (Ro 15-1788), indicating a negative allosteric modulation via the benzodiazepine binding site. In line with this conclusion are radioactive ligand binding studies. EDPC inhibited the binding of 2 nM [3H]flunitrazepam to membranes from the cerebellum or the cortex with IC50 values of about 8 and 25 nM, respectively.
Subject(s)
GABA Modulators/pharmacology , Pyridines/pharmacology , Receptors, GABA-A/metabolism , Allosteric Regulation/drug effects , Allosteric Regulation/physiology , Animals , Binding Sites , Cerebellum/physiology , Flumazenil/pharmacology , In Vitro Techniques , Ligands , Male , Mice , Oocytes , Prosencephalon/physiology , Radioligand Assay , Rats , Receptors, GABA-A/drug effects , Receptors, GABA-A/physiology , Recombinant Proteins/metabolism , Seizures/chemically induced , Xenopus laevisABSTRACT
Mice were selectively bred according to their sensitivity or their resistance to the convulsive effects of a 4-mg/kg dose of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine (BZ) receptor inverse agonist. The selection proved to be easy, with a clear separation of the two lines, convulsing with short latencies or resistant, already at the first generation of selection. Selection of a third line of animals convulsing with long latencies did not succeed. 3H-Ro 15-1788 binding analysis provided evidence for a strong decrease in Bmax in the resistant line.
Subject(s)
Carbolines/pharmacology , Convulsants/pharmacology , GABA Agents/pharmacology , Selection, Genetic , Animals , Female , Flumazenil/metabolism , Male , Mice , Mice, Inbred Strains , Radioligand Assay , Species SpecificityABSTRACT
A study of the effect of Ginkgo biloba extract (EGb 761) has shown enhancing effects on training in adult and aged Swiss mice. An analysis of inbred mice has confirmed this sensitivity to EGb 761, but depending on the strains, with different effects at different ages. The most interesting results are related to improvements in performances observed with aged mice of the DBA/2J strain. The results obtained with inbred strains in the study of the mossy fibers of the hippocampus make it possible to suggest a link between the improvements in training and the histological structure of the hippocampus. This possibility, which can be confirmed by further studies, is presented here.
Subject(s)
Aging/physiology , Maze Learning/drug effects , Memory/drug effects , Plant Extracts/pharmacology , Animals , Female , Ginkgo biloba , Hippocampus/drug effects , Hippocampus/physiology , Hippocampus/ultrastructure , Maze Learning/physiology , Memory/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Nerve Fibers/drug effects , Nerve Fibers/physiology , Species SpecificityABSTRACT
Analysis of beta-CCM induced seizures in three inbred strains of mice, ABP/Le, C57BL/6J and C57BL/6ByJ, and their F1s and F2s progeny, allowed identification of a putative seizure susceptibility controlling locus on chromosome 9 near the short-ear locus. The involvement of a gene in the medial segment of this chromosome in both seizure activity and GABA-controlled behaviour is discussed.
Subject(s)
Chromosome Mapping , Seizures/genetics , Seizures/physiopathology , Animals , Carbolines , Convulsants , Crosses, Genetic , Disease Susceptibility , Female , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Seizures/chemically inducedABSTRACT
The convulsant properties of methyl beta-carboline-3-carboxylate (beta-CCM) were evaluated in the TaT-fm/GncTa+/+Tfm strain carrying the tabby coat color (Ta) and/or the testicular feminization (Tfm) gene. When injected intraperitoneally within a 5-60 mg/kg dose range, beta-CCM-induced convulsions in less than 25% of the mice, thus providing evidence for a high resistance of this strain, as compared to classical strains of mice. However, this strain responds normally to the convulsant pentylenetetrazol (PTZ), suggesting a specific resistance to beta-CCM. Both the Ta gene and the TaTfm/Gnc genetic background were involved in the high resistance to beta-CCM. In addition, concentrations of neurosteroids and benzodiazepine binding, both modulating GABAA receptor efficacy, have been measured in order to elucidate the biological mechanisms of drug resistance.
Subject(s)
Brain Chemistry/physiology , Pregnanolone/analysis , Pregnenolone/analysis , Receptors, GABA-A/analysis , Seizures/genetics , Animals , Carbolines , Convulsants , Drug Resistance/genetics , Evaluation Studies as Topic , Female , Male , Mice , Mice, Mutant Strains , Pentylenetetrazole , Radioligand Assay , Seizures/chemically inducedABSTRACT
Reactivity to a new environment was studied in mice, using an open-field procedure in two strains, C57BL/6By and ABP/Le, the F1 populations and the intercrosses F2 and backcross segregating populations. The analysis of the behavioral traits: peripheral and central activities, leaning, rearing and defecation in the parental strains made it possible to show that the ABP/Le strain was more reactive than C57BL/6By. In addition, the study of segregating, for four phenotypic markers, in F2 and backcross populations strongly suggested that two autosomal regions were involved in the control of open-field behavior: one in chromosomal region comprising the b locus on chromosome 4 and one in chromosomal region comprising the p locus on chromosome 7.
Subject(s)
Behavior, Animal/physiology , Chromosomes/physiology , Analysis of Variance , Animals , Defecation/physiology , Exploratory Behavior/physiology , Female , Genetic Markers , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Motor Activity/physiology , PhenotypeABSTRACT
beta-Carbolines, such as methyl beta-carboline-3-carboxylate (beta-CCM), attach to the benzodiazepine receptors in the brain, but have effects completely opposite to those of benzodiazepines: beta-CCM is a convulsant at high doses, an anxiogenic at moderate doses, and enhances learning at low doses. The aim of this work was to detect some of the chromosomal segments involved in the regulation of beta-CCM-induced seizures. The method used was a derivation of the classical use of linkage-testing strains. We tested several strains and some of their intercrosses and back-crosses. For two of these strains, we obtained significant results showing that genes located on chromosomes 4 and 13, provisionally termed respectively Bis1 and Bis2, were involved in the regulation of beta-carboline-induced seizures. Testing of these two strains with two other convulsant agents (pentylenetetrazol, which acts at the picrotoxine site of the GABA receptor complex, and strychnine, which acts at the glycinergic receptor) provided evidence that the genes implicated are not involved in general seizure processes but specifically in beta-CCM-induced seizures.
Subject(s)
Carbolines/toxicity , Chromosome Mapping , Seizures/genetics , Animals , Crosses, Genetic , Mice , Mice, Inbred C3H , Seizures/chemically induced , Species SpecificityABSTRACT
Female mice of the inbred strains C57BL/6J, BALB/cJ and DBA/2J were used to determine the possible existence of a genetically-based differential susceptibility to the effects of treatment with an extract of Ginkgo biloba (EGb 761). Timm's silver-sulphide staining method was used to visualize and determine changes in the areas of the hippocampal structures of aged subjects, and more specifically on the projection fields of the mossy fibers which appear to decrease as a function of ageing. Experiments were begun when the animals were 15 months old. Treated animals received EGb 761 (50 mg/kg/day, p.o.) for 7 months in their drinking water. Inter-strain differences existed for the areas of the whole regio inferior, stratum pyramidale, stratum lacunosum moleculare and hilus (CA4) and for the projection field of intra- and infrapyramidal mossy fibers (iipMF) in the CA3 region of the hippocampus. Chronic treatment with EGb 761 significantly increased the projection field of iipMF and significantly reduced the area of the stratum radiatum, as compared with control mice. No differential sensitivity to EGb 761 existed among the mouse strains tested. Antioxydint properties of EGb 761 may explain its neuroprotective and neurotrophic actions on the hippocampus, and might explain certain improvements in memory and other cognitive functions in both humans and experimental animals.
Subject(s)
Hippocampus/drug effects , Plant Extracts/pharmacology , Aging , Animals , Female , Ginkgo biloba , Hippocampus/anatomy & histology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Synapses/drug effectsABSTRACT
The convulsant effects of a high (5 mg/kg intraperitoneally, i.p.) dose of benzodiazepine (BZD) receptor ligand methyl beta-carboline-3-carboxylate (beta-CCM), whether or not preceded by administration of two lower doses of beta-CCM (0.5 and 1 mg/kg i.p.) or of saline were studied in nine inbred mouse strains. In five of the strains (A/J, BALB/cBy, C3H/HeJ, CBA/H, and DBA/2J), neither saline nor preceding injections of beta-CCM had any effect on subsequent reactivity to the subsequent convulsant dose. In the other 4 strains, such injections induced either tolerance (CPB-K, NZB), or sensitization (C57BL/6J, XLII), whatever the compound subsequently administered (beta-CCM or saline). In these strains, the data rule out any tolerance or sensitization effect due to beta-CCM, but suggest that such effects could be due to injection itself.
Subject(s)
Carbolines , Convulsants , Mice, Inbred Strains/physiology , Seizures/chemically induced , Animals , Carbolines/administration & dosage , Carbolines/pharmacology , Convulsants/administration & dosage , Convulsants/pharmacology , Dose-Response Relationship, Drug , Drug Tolerance , Female , Injections, Intraperitoneal , Kindling, Neurologic/physiology , Male , Mice , Receptors, GABA-A/drug effects , Sodium Chloride/pharmacology , Species SpecificityABSTRACT
The copper-zinc superoxide dismutase (SOD-1) gene, located on chromosome 21 and triplicated in Down's syndrome (DS), is suspected to be involved in the neuropathology observed in Alzheimer's disease (AD), DS and physiological aging. In order to explore the effect of an overproduction of SOD-1 in the mouse hippocampus, we investigated the Timm-stained mossy fiber (MF) innervation in the hippocampus of transgenic mice for the human SOD-1 gene (hSOD-1 mice). The results showed a decrease of the MF projection area in the hSOD-1 mice overexpressing the SOD-1 protein. These findings suggest that free radicals could play a role in this particular synaptic loss.
Subject(s)
Hippocampus/enzymology , Nerve Fibers/enzymology , Superoxide Dismutase/biosynthesis , Animals , Axons/enzymology , Female , Free Radicals/metabolism , Hippocampus/anatomy & histology , Hippocampus/cytology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Superoxide Dismutase/geneticsABSTRACT
In a light-dark choice situation, the alpha-2 adrenoceptor antagonist idazoxan shows anxiogenic-like effects, which cannot be blocked by the alpha-2 adrenoceptor agonist clonidine, or by the benzodiazepine receptor antagonist Ro 15-1788. In a conditioned conflict situation, both idazoxan and the alpha-2-adrenoceptor yohimbine show anxiogenic-like effects; the effect of idazoxan could not be blocked by clonidine or Ro 15-1788. These data suggest that systems other than alpha-2 adrenoceptors or benzodiazepine receptors must be found to explain these anxiogenic-like properties.
