strychnine and Disease-Models--Animal

The strychnine-sensitive glycine receptor (GlyR) is a pentameric chloride channel protein that exists in several developmentally and regionally regulated isoforms in the CNS. These result from the differential expression of four genes encoding different variants (alpha 1-alpha 4) of the ligand-binding subunit of the GlyR. Their assembly with the structural beta subunit is governed by "assembly cassettes" within the extracellular domains of these proteins and creates chloride channels of distinct conductance properties. GlyR gating is potentiated by Zn2+, a metal ion co-released with different neurotransmitters. Site-directed mutagenesis has unraveled major determinants of agonist binding and Zn2+ potentiation. During development, glycine receptors mediate excitation that results in Ca2+ influx and neurotransmitter release. Ca2+ influx triggered by the activation of embryonic GlyRs is required for the synaptic localization of the GlyR and its anchoring protein gepyhrin. In the adult, mutations in GlyR-subunit genes result in motor disorders. The spastic and spasmodic phenotypes in mouse as well as human hereditary startle disease will be discussed.

Topics: Animals; Carrier Proteins; Chloride Channels; Disease Models, Animal; Genetic Linkage; Humans; Membrane Proteins; Mutation; Receptors, Glycine; Reflex, Startle; Strychnine; Synaptic Transmission; Zinc

Topics: Adrenocorticotropic Hormone; alpha-Methyltyrosine; Amnesia; Amphetamine; Animals; Anisomycin; Cycloheximide; Disease Models, Animal; Electroshock; Ether; Ethyl Ethers; Humans; Learning; Methyltyrosines; Phenoxybenzamine; Protein Biosynthesis; Puromycin; Reserpine; Strychnine; Tyrosine 3-Monooxygenase; Vasopressins

Herbal medicines have gained tremendous surge of interest in recent years. M. nigra leaves are a rich source of phenolics which are well-known for their antioxidant property. Morus nigra popularly known as black mulberry is considered to be the most significant species of genus Morus. This study was designed to evaluate its activity on seizure model in different doses. Five groups were made comprising of n=10 animals in each group respectively. Group I was on distilled water, Group II was administered with reference drug diazepam and Group III, IV and V were on 125mg/kg, 250mg/kg and 500mg/kg dose of Morus nigra for 15 days prior to experiment. On day 16th all animals were administered with strychnine after 30 minutes of respective treatments and three parameters were recorded i.e. duration, frequency and onset of seizures. M. nigra treatment showed significant seizure protection as noted by delayed latency of seizures (P<0.05), decrease in frequency and jerk's duration (P<0.05) in comparison to control and reference standard. Most significant (P<0.05) anticonvulsant effects were observed with 500mg/kg dose. Anticonvulsant activity of M. nigra could be due to potentiation of both Gabaergic and glycinergic activities. Antiepileptic potential of extract could also be amplified due to its antioxidant activity. This could serve as a non-pharmacological treatment for seizure management.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Fruit; Male; Mice; Morus; Plant Extracts; Seizures; Strychnine; Time Factors

The decoction from the stem bark of Psychotria camptopus (Rubiaceae) is used in the Cameroonian pharmacopoeia to treat neurological pathologies including epilepsy.. The present work was undertaken to study the anticonvulsant properties of the aqueous (AE) and methanol (ME) extracts from the stem bark of P. camptopus in acute models of epileptic seizures in Wistar rats.. AE and ME were obtained by decoction and maceration of the stem bark powder in water and methanol, respectively. They were tested orally at the doses of 40, 80 and 120 mg/kg, on the latency of onset and duration of epileptic seizures induced by pentylene tetrazole (PTZ, 70 mg/kg, i.p.). The kinetic effect of both extracts at 120 mg/kg was evaluated. Their effects on diazepam (50 mg/kg) induced sleep and strychnine (STR, 2.5 mg/kg, i.p.) induced seizures were determined. ME was further tested on picrotoxin (PIC, 7.5 mg/kg, i.p.) and thiosemicarbazide (TSC, 50 mg/kg, i.p.) induced seizure models. The phytochemical composition of ME was assessed using LC-MS method, as well as its acute toxicity.. AE and ME significantly (p < 0.001) reduced the duration of seizures in both PTZ and STR models. Their maximal effect was observed at 1 h after administration, though their effect at 120 mg/kg was maintained (p < 0.05) up to 24 h post-treatment. Both extracts significantly (p < 0.01) reduced sleep duration. ME significantly (p < 0.001) increased the latency of rat death on PIC-induced convulsions. In TSC rats, ME significantly (p < 0.001) delayed the latency to the first convulsion, and decreased the duration and frequency of convulsions. ME showed no acute toxicity while its phytochemical screening revealed the presence of two flavonoids (Rutin and Butin), two triterpenoid saponins (Psycotrianoside B and Bauerenone) and four alkaloids (10-Hydroxy-antirhine, 10-hydroxy-iso-deppeaninol, Emetine and Hodkinsine). In conclusion, AE and ME from the stem bark of P. camptopus have comparable anticonvulsant properties. The effect of ME is likely due to the presence of flavonoids and alkaloid and the activation of GABA pathway. These results further justify and support the use of P. camptopus in traditional medicine for the treatment of epilepsy.

Topics: Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Epilepsy; Methanol; Mice; Pentylenetetrazole; Phytochemicals; Picrotoxin; Plant Bark; Plant Extracts; Plant Stems; Psychotria; Rats, Wistar; Seizures; Semicarbazides; Sleep; Sleep Latency; Strychnine; Water

Myocardial infarction (MI) is the most extensive manifestations of cardiovascular disease (CVD), associated with prolonged supply and demand blood oxygen imbalance to the heart muscle. The treatment of MI includes several conventional medicines which are beta-blockers and calcium antagonists. Though, these were reported to be either not efficient or associated with life threatening adverse effects. Brucine, the main alkaloid bioactive compound from Strychnos nux-vomica seeds, offers unique compatibility advantages in inflammatory diseases associated clinical practices. Thus, the present investigation was projected to explore the activity of brucine towards MI provoked by isoprenaline hydrochloride (ISO) in rats. The cardioprotective properties of brucine were evaluated via detecting the infarct size, serum cardiac marker enzymes (CK, CK-MB, cTnT, and cTnI), endogenous antioxidants (CAT, SOD, GPx), and lipid peroxidation (TBARS and LOOH), inflammatory mediators (NF-κB, TNF-α and IL-6) and histopathological analysis. The results demonstrated, brucine effectively restored the infarct size by increasing the endogenous antioxidants and decreasing the status of TBARS and LOOH, marker enzymes and ameliorated the histopathological injuries. Brucine's cardioprotective effect might be associated with TNF-α, IL-6 signaling molecules activation, revealing its pharmacological actions.

Topics: Animals; Disease Models, Animal; Isoproterenol; Myocardium; Rats; Strychnine

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signalling in spinal cord, brain stem, and higher centres of the central nervous system. We examined the glycinergic activity of sarcophine (SN), a marine terpenoid known for its various biological activities, and its trans-diol derivative (7S, 8R)-dihydroxy-deepoxysarcophine (DSN). SN was isolated from the Red Sea soft coral Sacrophyton glaucum, DSN was semisynthesized by hydrolysis of the epoxide ring. In cytotoxicity tests against HEK293 cells, SN and DSN had LD

Topics: 4-Butyrolactone; Animals; Anthozoa; Binding Sites; Binding, Competitive; Brain; Disease Models, Animal; Excitatory Amino Acid Antagonists; HEK293 Cells; Humans; Male; Mice; Protein Binding; Receptors, Glycine; Seizures; Strychnine

An imbalance between inhibitory (GABA) and excitatory (Glutamate) neurotransmission contribute to the development of epilepsy. Earlier studies reported that dysregulation of GABA and glutamatergic activities resulted in status epilepticus (SE) and ultimately support the development of temporal lobe epilepsy (TLE), a type of resistant epilepsy. In the earlier work, 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine demonstrated anticonvulsant activity against pentylenetetrazole (PTZ)-induced seizures. Apart from the PTZ-induced TLE, the dysregulation muscaranic receptors and glycine receptors are also widely reported phenomena in the development of temporal lobe epilepsy. Keeping the role of these two receptors in epilepsy, the present work investigated the effect of 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine in pilocarpine-induced and strychnine-induced seizure models. Our results demonstrated that 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine significantly delayed the onset of seizure with maximum protection from SE in pilocarpine-induced seizure model. However, the test compound did not revealed any effect on strychnine-induced seizures in mice. Based on these observations, we suggest that 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine could be a potential candidate in reduction of SE and treatment of temporal lobe epilepsy (TLE) in future.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy; Male; Mice; Pentylenetetrazole; Pilocarpine; Seizures; Strychnine

The majority of the world population suffers from mental and behavioral disorder. It is the need of the time to find an alternate of presently available medicines in order to decrease the medical expense. Homeopathic remedies are available and prescribed by homeopaths for treatment of anxiety and depression. Unfortunately, no data are available that proves its potential to relieve mental illness. The current study is designed to assess neuro behavioral and antidepressant like effects of homeopathic remedies Staphysagria, Argentum nitricum and Ignatia amara in comparison with standard drug (escitalopram). Different neuro behavioral activities were analyzed. The animals were administered the doses of all homeopathic remedied (60 µl to the rats) and escitalopram (0.042 mg to rats) through the oral route. The activities were observed on day 30th and day 60th. Our result suggests that the swimming time in Staphysagria treated group were significantly improved (p<0.001) after day 60th and significance rise was observed (p<0.01) in Ignatia amara treated animals, whereas significant decline (p<0.05) in struggling time was observed in Argentum nitricum administered animals after the 60th day as compared to 30th day. The central square crossings were improved highly significantly (p<0.001) after the 30th day dosing, by all three remedies and peripheral squares crossing were found highly significantly increased (p<0.001) after chronic dosing in Staphysagria and Ignatia amara treated groups. It is concluded from the results that all three homeopathic remedies produce comparable effects like standard drug while among all three remedies Staphysagria possess a potent antidepressant activity. To the best of our knowledge the current study reports first time the anti-depressant potential of homeopathic remedies in rodents.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Delphinium; Depression; Disease Models, Animal; Female; Homeopathy; Locomotion; Male; Open Field Test; Plant Extracts; Rats; Silver Nitrate; Strychnos; Swimming; Time Factors

Licorice, one of the most widely used medicinal herbs in East Asia, has effects such as anti-inflammation, antioxidant, and detoxifying. This study aimed to evaluate the protective effect of licorice on brucine-induced nephrotoxicity. Sprague Dawley rats were administered with brucine intraperitoneally for 7 consecutive days with or without treatment with licorice. The content of blood urea nitrogen and creatinine in serum, the activities of superoxide dismutase and content of glutathione, malonaldehyde in kidney tissue were detected. Hematoxylin-eosin staining was employed to observe the histopathological changes of kidney. The expression and phosphorylation levels of protein were evaluated by Western blotting and immunohistochemical analysis. The results illustrated that treatment with licorice extracts (LE) significantly protected against the brucine-induced nephrotoxicity by reducing the content of blood urea nitrogen and serum creatinine, attenuating pathologic damage. The unbalance of oxidative stress was repaired by LE via increasing the level of glutathione, promoting the activities of superoxide dismutase and decreasing the content of malonaldehyde. In addition, LE overturned the influence of brucine on apoptosis-related protein and signal transducer and activator of transcription-3 (STAT3) activation. Taken together, these data demonstrate that licorice may attenuate brucine-induced nephrotoxicity via inactivation of oxidative stress and mitochondrial-mediated apoptosis pathway. More importantly, the renoprotective effects may be mediated, at least partly, by preventing the activation of STAT3 protein.

Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Gene Expression Regulation; Glutathione; Glycyrrhiza; Injections, Intraperitoneal; Male; Malondialdehyde; Mitochondria; Plant Extracts; Random Allocation; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Strychnine; Superoxide Dismutase

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA

Topics: Animals; Bicuculline; Disease Models, Animal; Glycine; Hyperalgesia; Imidazoles; Inhibitory Postsynaptic Potentials; Male; Mice, Inbred C57BL; Neurons; Neurotransmitter Agents; Peripheral Nerve Injuries; Phenanthrolines; Potassium Channels, Inwardly Rectifying; Receptors, GABA-A; Receptors, Glycine; Strychnine; Synaptic Transmission; Tissue Culture Techniques; Touch

The aim of the study was to evaluate the anticonvulsant and neuroprotective activity of Cocculus laurifolius D.C leaves in albino wistar rats against strychnine induced convulsions. Initially the extract was investigated for acute oral toxicity testing in order to examine any signs of toxicity and mortality. For anticonvulsant activity, the ethanolic extract was evaluated at doses 200 and 400 mg/kg, p.o. against strychnine induced convulsions model, at 1, 7, 15 and 30th day of treatment. Meanwhile, the neuroprotective effect of the extract was investigated via histopathological assessment. Cocculus laurifolius (200 and 400 mg/kg, p.o.) exhibited anticonvulsant activity as indicated by significant delay in the onset of convulsions and time to death after strychnine induced convulsions. Similarly, significant reduction in the duration of convulsions and percentage of mortality was observed by ethanolic extract (200 and 400 mg/kg p.o.) at 1, 7, 15 and 30th day of test sessions. Furthermore, Cocculus laurifolius leaves (200 and 400 mg/kg p.o.) also exhibited neuroprotective effect with considerable preserved neuronal structures and significant decrease in neuronal apoptosis, in comparison with control. The results obtained from the present study indicate that ethanolic extract of Cocculus laurifolius leaves possess potential anticonvulsant and neuroprotective effect against strychnine induced convulsions. Therefore, it can be concluded that Cocculus laurifolius leaves may be a valuable in management of epilepsy, however further studies are required on large number of animals to confirm these findings.

Topics: Animals; Anticonvulsants; Apoptosis; Brain; Cocculus; Disease Models, Animal; Female; Male; Neurons; Neuroprotective Agents; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Seizures; Strychnine

Some cannabinoids have been shown to suppress chronic pain by targeting glycine receptors (GlyRs). Although cannabinoid potentiation of α3 GlyRs is thought to contribute to cannabinoid-induced analgesia, the role of cannabinoid potentiation of α1 GlyRs in cannabinoid suppression of chronic pain remains unclear. Here we report that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, significantly suppresses chronic inflammatory pain caused by noxious heat stimulation. This effect may involve spinal α1 GlyRs since the expression level of α1 subunits in the spinal cord is positively correlated with CFA-induced inflammatory pain and the GlyRs antagonist strychnine blocks the DH-CBD-induced analgesia. A point-mutation of S296A in TM3 of α1 GlyRs significantly inhibits DH-CBD potentiation of glycine currents (I

Topics: Action Potentials; Analgesics; Animals; Animals, Genetically Modified; Cannabinoids; Cyclohexanones; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Gene Expression Regulation; Glycine Agents; HEK293 Cells; Humans; In Vitro Techniques; Inflammation; Male; Mice; Mice, Inbred C57BL; Mutation; Neurons; Pain; Pain Measurement; Patch-Clamp Techniques; Receptors, Glycine; Reflex, Startle; Rotarod Performance Test; Spinal Cord; Strychnine; Time Factors; Transfection

Novel non-imidazole histamine H3 receptor (H3R) antagonists (2-8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1-H4R. These novel H3R antagonists (2-8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i.p.). Contrary, all compounds 2-8 showed moderate protection in the strychnine (STR)-induced convulsion model following acute pretreatment (10 mg/kg, i.p.). Moreover, the acute systemic administration of H3R antagonist 6 (10 mg/kg, i.p.) significantly prolonged latency time for MES convulsions. Furthermore, the anticonvulsant effect observed with compound 6 in MES-model was entirely abrogated when rats were co-injected with the brain penetrant H1R antagonist pyrilamine (PYR) but not the brain penetrant H2R antagonist zolantidine (ZOL). However, PYR and ZOL failed to abolish the full protection provided by the H3R antagonist 6 in PTZ- and STR-models. No mutagenic or antiproliferative effects or potential metabolic interactions were shown for compound 6 when assessing its antiproliferative activities and metabolic profiling applying in-vitro methods. These findings demonstrate the potential of non-imidazole H3R antagonists as novel antiepileptic drugs (AEDs) either for single use or in addition to currently available epilepsy medications.

Topics: Animals; Anticonvulsants; Benzothiazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Histamine H3 Antagonists; Humans; Male; Phenoxypropanolamines; Piperidines; Pyrilamine; Rats; Rats, Wistar; Reaction Time; Seizures; Strychnine

Out of genetically determined epilepsy models a special interest draws the model of audiogenic seizures, which does not require whatever additional intervention (e.g. pharmacological or/and electric stimulation), because epileptic responses are elicited by specific sensory stimulation only. Notwithstanding the fact that different formations of the central nervous system are recruited in audiogenic seizure reactions, critical importance for the manifestation of this type epilepsy is attributed to the inferior colliculus and brainstem reticular nuclei. Significance of the diencephalic structures and the thalamic reticular nucleus, in particular for development and/or modulation of audiogenic seizures is ambiguous. Total of eight Krushinsky- Molodkina (KM) strain rats, weighting 250-300 g, served as the subjects of chronic experiments. The neocortex was bilaterally activated by way of administration of 1 µl strychnine (0.1% solutipon) with a microsyringe through a metal capillary prefixed on the cortical surface. Metal electrodes for recording electrical activity were implanted into the neocortex and brainstem reticular formation. Experiments have shown that against strychnine discharges in the neocortex there occurred an increase in the latency of wild runs and the pause between the first and second wild runs in response to a sound stimulus. Proceeding from the above-said, it can be assumed that activation of the neocortex must stipulate intensification of the thalamic reticular nucleus neuronal activity that, in turn, should have a modulating effect on the audiogenically induced seizure reactions.

Topics: Acoustic Stimulation; Animals; Convulsants; Disease Models, Animal; Epilepsy, Reflex; Excitatory Postsynaptic Potentials; Neocortex; Rats, Inbred Strains; Strychnine

The seeds of

Topics: Administration, Cutaneous; Analgesics; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Cell Line; Cell Proliferation; Cell Survival; Cells, Cultured; Dinoprostone; Disease Models, Animal; Drug Delivery Systems; Edema; Formaldehyde; Gels; Humans; Macrophages; Male; Mice; Pain; Phytotherapy; Rats, Wistar; Strychnine; Strychnos nux-vomica; Synoviocytes

The critical role of α1-glycine receptor (α1-GLYRs) in pathological conditions such as epilepsy is well known. In the present study, structure-activity relations for a series of phenylalanine derivatives carrying selected hydrogen bond acceptors were investigated on the functional properties of human α1-GLYR expressed in Xenopus oocytes. The results indicate that one particular substitution position appeared to be of special importance for control of ligand activity. Among tested ligands (1-8), the biphenyl derivative (2) provided the most promising antagonistic effect on α1-GLYRs, while its phenylbenzyl analogue (5) exhibited the highest potentiation effect. Moreover, ligand 5 with most promising potentiating effect showed in-vivo moderate protection when tested in strychnine (STR)-induced seizure model in male adult rats, whereas ligand 2 with highest antagonistic effect failed to provide appreciable anti(pro)convulsant effect. Furthermore, ligands 2 and 5 with the most promising effects on human α1-GLYRs were examined for their toxicity and potential neuroprotective effect against neurotoxin 6-hydroxydopamine (6-OHDA). The results show that ligands 2 and 5 possessed neither significant antiproliferative effects, nor necrotic and mitochondrial toxicity (up to concentration of 50μM). Moreover, ligand 2 showed weak neuroprotective effect at the 50μM against 100μM toxic dose of 6-OHDA. Our results indicate that modulatory effects of ligands 2 and 5 on human α1-GLYRs as well as on STR-induced convulsion can provide further insights for the design of therapeutic agents in treatment of epilepsy and other pathological conditions requiring enhanced activity of inhibitory glycine receptors.

Topics: Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Glycine; HEK293 Cells; Humans; Ligands; Male; Membrane Potentials; Microinjections; Neuroblastoma; Oocytes; Oxidopamine; Patch-Clamp Techniques; Phenylalanine; Rats; Rats, Wistar; Receptors, Glycine; Seizures; Strychnine; Transduction, Genetic; Xenopus laevis

The ketogenic diet (KD) is a cheap and effective alternative therapy for most epilepsy. There are paucity of experimental data in Nigeria on the usefulness of KD in epilepsy models. This is likely to be responsible for the poor clinical acceptability of the diet in the country. This study therefore aimed at providing experimental data on usefulness of KD on seizure models.  The study used 64 Wistar rats that were divided into two dietary groups [normal diet (ND) and ketogenic diet (KD)]. Animal in each group were fed for 35days. Medium chain triglyceride ketogenic diet (MCT-KD) was used and it consisted of 15% carbohydrate in normal rat chow long with 5ml sunflower oil (25% (v/w). The normal diet was the usual rat chow. Seizures were induced with one of Pentelyntetrazole (PTZ), 4-Aminopyridine (AP) and Strychnine (STR). Fasting glucose, ketosis level and serum chemistry were determined and seizure parameters recorded. Serum ketosis was significantly higher in MCT-KD-fed rats (12.7 ±2.6) than ND-fed (5.17±0.86) rats. Fasting blood glucose was higher in ND-fed rats (5.3±0.9mMol/l) than in MCT-KD fed rats (5.1±0.5mMol/l) with p=0.9. Seizure latency was significantly prolonged in ND-fed compared with MCT-KD fed rats after PTZ-induced seizures (61±9sec vs 570±34sec) and AP-induced seizures (49±11sec vs 483±41sec). The difference after Str-induced seizure (51±7 vs 62±8 sec) was not significan. The differences in seizure duration between ND-fed and MCT-KD fed rats with PTZ (4296±77sec vs 366±46sec) and with AP (5238±102sec vs 480±67sec) were significant (p<0.05), but not with STR (3841±94sec vs 3510±89sec) respectively. The mean serum Na+ was significantly higher in MCT-KD fed (141.7±2.1mMol/l) than ND-fed rats (137±2.3mMol/l). There was no significant difference in mean values of other serum electrolytes between the MCT-KD fed and ND-fed animals. MCT-KD caused increase resistance to PTZ-and AP-induced seizures, but has no effect on STR-induced seizures. This antiseizure property is probably mediated through GABAergic receptors (PTZ effect) and blockade of membrane bound KATP channels (AP effect) with some enhancement by serum ketosis.

Topics: 4-Aminopyridine; Animal Nutritional Physiological Phenomena; Animals; Biomarkers; Blood Glucose; Diet, Carbohydrate-Restricted; Diet, Ketogenic; Disease Models, Animal; Ketosis; Male; Pentylenetetrazole; Plant Oils; Rats, Wistar; Reaction Time; Seizures; Sodium; Strychnine; Sunflower Oil; Time Factors

Cochlear neuropathy, i.e. the loss of auditory nerve fibers (ANFs) without loss of hair cells, may cause hearing deficits without affecting threshold sensitivity, particularly if the subset of ANFs with high thresholds and low spontaneous rates (SRs) is preferentially lost, as appears to be the case in both aging and noise-damaged cochleas. Because low-SR fibers may also be important drivers of the medial olivocochlear reflex (MOCR) and middle-ear muscle reflex (MEMR), these reflexes might be sensitive metrics of cochlear neuropathy. To test this hypothesis, we measured reflex strength and reflex threshold in mice with noise-induced neuropathy, as documented by confocal analysis of immunostained cochlear whole-mounts. To assay the MOCR, we measured contra-noise modulation of ipsilateral distortion-product otoacoustic emissions (DPOAEs) before and after the administration of curare to block the MEMR or curare + strychnine to also block the MOCR. The modulation of DPOAEs was 1) dominated by the MEMR in anesthetized mice, with a smaller contribution from the MOCR, and 2) significantly attenuated in neuropathic mice, but only when the MEMR was intact. We then measured MEMR growth functions by monitoring contra-noise induced changes in the wideband reflectance of chirps presented to the ipsilateral ear. We found 1) that the changes in wideband reflectance were mediated by the MEMR alone, and 2) that MEMR threshold was elevated and its maximum amplitude was attenuated in neuropathic mice. These data suggest that the MEMR may be valuable in the early detection of cochlear neuropathy.

Topics: Acoustic Stimulation; Animals; Audiometry; Auditory Fatigue; Auditory Threshold; Cochlear Nerve; Curare; Disease Models, Animal; Ear, Middle; Early Diagnosis; Hearing Loss, Noise-Induced; Male; Mice, Inbred CBA; Muscle, Skeletal; Neuromuscular Nondepolarizing Agents; Noise; Otoacoustic Emissions, Spontaneous; Predictive Value of Tests; Reflex; Strychnine; Synaptic Transmission; Vestibulocochlear Nerve Diseases

Neuroimaging studies of patients with chronic pain have shown that neurotransmitter abnormalities, including increases in glutamate and decreases in GABA, could be responsible for the cortical hyperactivity and hyperalgesia/allodynia observed in some pain conditions. These finding are particularly evident in the insula, a brain region known to play a role in both the sensory-discriminative and the affective-motivational aspects of pain processing. However, clinical studies are not entirely able to determine the directionality of these findings, nor whether they are causal or epiphenomenon. Thus, a set of animal studies was performed to determine whether alterations in glutamate and GABA are the result of injury, the cause of augmented pain processing, or both. Compared with controls, the excitatory neurotransmitters glutamate and aspartate are significantly higher in the rat insula after chronic constriction injury of the sciatic nerve (CCI). The CCI also produced significant increases in allodynia (mechanical and cold), thermal hyperalgesia, and nociceptive aversiveness. Unilateral microinjection of ionotropic glutamate receptor antagonists restored these nociceptive behaviors to preinjury values. Increasing endogenous levels of GABA or enhancing signaling at inhibitory glycinergic receptors had similar effects as the glutamate receptor antagonists. In naive rats, increasing endogenous levels of glutamate, decreasing endogenous levels of GABA, or blocking strychnine-sensitive glycine receptors in the insula significantly increased thermal hyperalgesia and mechanical allodynia. These data support the hypothesis that an altered balance of excitatory and inhibitory neurotransmitters in brain regions such as the insula occurs in chronic pain states and leads to augmented central pain processing and increased pain sensitivity.

Topics: Analysis of Variance; Animals; Avoidance Learning; Cerebral Cortex; Disease Models, Animal; Excitatory Amino Acid Agents; GABA Agents; gamma-Aminobutyric Acid; Glutamates; Glycine; Glycine Agents; Hyperalgesia; Male; Microdialysis; Microinjections; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Sciatica; Strychnine

After spinal cord injury, central neuropathic pain develops in the majority of spinal cord injury patients. Spinal hemisection in rats, which has been developed as an animal model of spinal cord injury in humans, results in hyperexcitation of spinal dorsal horn neurons soon after the hemisection and thereafter. The hyperexcitation is likely caused by permanent elimination of the descending pain systems. We examined the change in synaptic transmission of substantia gelatinosa neurons following acute spinal hemisection by using an in vivo whole-cell patch-clamp technique.. An increased spontaneous action potential firings of substantia gelatinosa neurons was detected in hemisected rats compared with that in control animals. The frequencies and amplitudes of spontaneous excitatory postsynaptic currents and of evoked excitatory postsynaptic currentss in response to non-noxious and noxious stimuli were not different between hemisected and control animals. On the contrary, the amplitude and frequency of spontaneous inhibitory postsynaptic currents of substantia gelatinosa neurons in hemisected animals were significantly smaller and lower, respectively, than those in control animals (P < 0.01). Large amplitude and high-frequency spontaneous inhibitory postsynaptic currents, which could not be elicited by mechanical stimuli, were seen in 44% of substantia gelatinosa neurons in control animals but only in 17% of substantia gelatinosa neurons in hemisected animals. In control animals, such large amplitude spontaneous inhibitory postsynaptic currents were suppressed by spinal application of tetrodotoxin (1 µM). Cervical application of lidocaine (2%, 10 µl) also inhibited such large amplitude of inhibitory postsynaptic currents. The proportion of multi-receptive substantia gelatinosa neurons, which exhibit action potential firing in response to non-noxious and noxious stimuli, was much larger in hemisected animals than in control animals.. These suggest that substantia gelatinosa neurons receive tonic inhibition by spinal inhibitory interneurons which generate persistent action potentials. Spinal hemisection results in hyperexcitation of substantia gelatinosa neurons at least in part by eliminating the tonic descending control of spinal inhibitory interneurons from supraspinal levels.

Topics: Anesthetics, Intravenous; Animals; Bicuculline; Disease Models, Animal; Electric Stimulation; Functional Laterality; Hyperalgesia; Male; Neurons; Neurotransmitter Agents; Patch-Clamp Techniques; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Strychnine; Substantia Gelatinosa; Synaptic Transmission; Tetrodotoxin; Urethane

Various morphological parts of pomegranate (Punica granatum L.) have extensively been used in the folk medicine to treat an array of human ailments. The aim of the present study is to demonstrate the anticonvulsant potential of the ethanolic extract of P. granatum L. seed in chemoconvulsant-induced seizures in mice.. The anticonvulsant activity of the ethanolic extract was investigated in strychnine (STR)-induced and pentylenetetrazole (PTZ)-induced seizure models in mice. Diazepam was used as reference anticonvulsant drug. Ethanolic extract (150, 300, and 600 mg/kg per os, p.o.), diazepam (1 mg/kg intraperitoneally, i.p.), and distilled water (10 ml/kg, i.p.) were administered before induction of seizures by PTZ (60 mg/kg, i.p.) or STR (2.5 mg/kg, i.p.). The latent time before the onset of convulsions, the duration of convulsions, the percentage of seizure protection, and mortality rate were recorded.. The seed ethanolic extract did not show any toxicity and did not protect the animals against seizures but demonstrated a significant increase in seizure latency at 300 and 600 mg/kg in both STR and PTZ seizure models (P < 0.001). It also showed a significant reduction in seizure duration at 300 mg/kg (P < 0.05) and 600 mg/kg (P < 0.001) in the STR seizure model and 600 mg/kg (P < 0.01) in the PTZ seizure model compared with the control group.. Ethanol extract has dose-dependent anticonvulsant activity against STR- and PTZ-induced seizures. This activity might be due to its saponins, flavonoids, triterpenes, and alkaloids ingredients.

Topics: Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Lythraceae; Male; Mice; Pentylenetetrazole; Phytotherapy; Plant Extracts; Random Allocation; Seeds; Seizures; Strychnine; Treatment Outcome

Glycinergic transmission has an important role in regulating nociception in the spinal cord. The glycine transporter-2 (GlyT2) is localized at presynaptic terminals of glycinergic neurons and eliminates glycine from the synaptic cleft to terminate glycinergic transmission. Systemic and intrathecal administration of GlyT2 inhibitors alleviate various types of pain. Although the GlyT2s and glycine receptors are widely distributed in the central nervous system, little is known about the role of glycinergic transmission in pain perception at supraspinal regions. The present study examined the antinociceptive effect of intracerebroventricular (i.c.v.) administration of the selective GlyT2 inhibitor ALX1393 on inflammatory and neuropathic pain in experimental models. For i.c.v. administration, a guide cannula was implanted into the right lateral ventricle of male Sprague-Dawley rats. Normal rats were used to assess inflammatory nociception using the formalin test and motor function using the rotarod test. Chronic constriction injury (CCI) to the sciatic nerve was induced in the rats. The CCI rats were then used to assess mechanical, cold, and thermal hyperalgesia using the electronic von Frey test, cold plate test, and the plantar test, respectively. ALX1393 (25, 50, and 100 μg) was administered i.c.v. to examine its effects on supraspinal antinociception. Supraspinal ALX1393 in normal rats suppressed the late-phase response in the formalin test but did not affect motor performance. In the CCI rats, ALX1393 inhibited mechanical and cold hyperalgesia in a dose-dependent manner. The antihyperalgesic effects of ALX1393 (100 μg) were reversed completely by i.c.v. pretreatment with a glycine receptor antagonist strychnine (10 μg). These results suggest that GlyT2 contributes to nociceptive transmission at supraspinal level and that the selective GlyT2 inhibitor is a promising candidate for the treatment of inflammatory and neuropathic pain without causing motor dysfunction.

Topics: Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Glycine Plasma Membrane Transport Proteins; Hyperalgesia; Inflammation; Infusions, Intraventricular; Male; Neuralgia; Pain; Pain Measurement; Rats; Rotarod Performance Test; Serine; Strychnine

The spinal cord contains the circuitry to control posture and locomotion after complete paralysis, and this circuitry can be enabled with epidural stimulation [electrical enabling motor control (eEmc)] and/or administration of pharmacological agents [pharmacological enabling motor control (fEmc)] when combined with motor training. We hypothesized that the characteristics of the spinally evoked potentials after chronic administration of both strychnine and quipazine under the influence of eEmc during standing and stepping can be used as biomarkers to predict successful motor performance. To test this hypothesis we trained rats to step bipedally for 7 wk after paralysis and characterized the motor potentials evoked in the soleus and tibialis anterior (TA) muscles with the rats in a non-weight-bearing position, standing and stepping. The middle responses (MRs) to spinally evoked stimuli were suppressed with either or both drugs when the rat was suspended, whereas the addition of either or both drugs resulted in an overall activation of the extensor muscles during stepping and/or standing and reduced the drag duration and cocontraction between the TA and soleus muscles during stepping. The administration of quipazine and strychnine in concert with eEmc and step training after injury resulted in larger-amplitude evoked potentials [MRs and late responses (LRs)] in flexors and extensors, with the LRs consisting of a more normal bursting pattern, i.e., randomly generated action potentials within the bursts. This pattern was linked to more successful standing and stepping. Thus it appears that selected features of the patterns of potentials evoked in specific muscles with stimulation can serve as effective biomarkers and predictors of motor performance.

Topics: Animals; Biomechanical Phenomena; Disease Models, Animal; Electric Stimulation Therapy; Electromyography; Evoked Potentials, Motor; Female; Glycine Agents; Hindlimb; Muscle, Skeletal; Quipazine; Rats; Rats, Sprague-Dawley; Recovery of Function; Serotonin Receptor Agonists; Spinal Cord Injuries; Strychnine; Time Factors

This study was designed to evaluate the neuroprotective effect of l-serine and the underlying mechanisms in mice after traumatic brain injury (TBI) induced using a weight drop model. The mice were intraperitoneally injected with l-serine 3 h after TBI and then injected twice each day for 7 days or until the end of the experiment. The neurological severity score, brain water content, lesion volume, and neurone loss were determined. The levels of TNF-α, IL-1β, IL-6, and IL-10 and the number of GFAP- and Iba-1-positive cells and activated caspase-3-positive neurones in the brain tissue ipsilateral to TBI were also measured. Simultaneously, the influences of l-serine on these variables were observed. In addition, the expression of glycine receptors and l-serine-induced currents were measured. We found l-serine treatment: 1) decreased the neurological deficit score, brain water content, lesion volume, and neurone loss; 2) inhibited activated caspase-3; and 3) reduced the levels of TNF-α, IL-1β and IL-6 and the number of GFAP- and Iba-1-positive cells. The effects of l-serine were antagonised by the administration of strychnine, an antagonist of glycine receptors. In addition, we found that glycine receptors were expressed mainly in the cortical neurones but less in the astrocytes or microglial cells, and l-serine activated these receptors and induced strychnine-sensitive currents in these neurones. In conclusion, l-serine induces the activation of glycine receptors, which alleviates neuronal excitotoxicity, a secondary brain injury process, thereby reduces the activation of astrocytes and microglial cells and secretion of proinflammatory cytokines and inhibits neuronal apoptosis. Thus, l-serine treatment leads to neuroprotection of brain tissue through reducing inflammatory responses and improves recovery of the neurological functions in mice after traumatic brain injury.

Topics: Animals; Apoptosis; Astrocytes; Brain; Brain Edema; Brain Injuries; Cytokines; Disease Models, Animal; Glycine Agents; Mice, Inbred ICR; Microglia; Neuroimmunomodulation; Neurons; Neuroprotection; Neuroprotective Agents; Random Allocation; Receptors, Glycine; Serine; Strychnine

This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2) in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain.

Topics: Analgesics; Animals; Benzamides; Disease Models, Animal; Glycine Plasma Membrane Transport Proteins; HEK293 Cells; Humans; Ligation; Male; Mice, Inbred ICR; Neuralgia; Phenoxybenzamine; Piperidines; Sciatic Nerve; Spinal Cord; Strychnine

Hearing loss among the elderly correlates with diminished social, mental, and physical health. Age-related cochlear cell death does occur, but growing anatomical evidence suggests that synaptic rearrangements on sensory hair cells also contribute to auditory functional decline. Here we present voltage-clamp recordings from inner hair cells of the C57BL/6J mouse model of age-related hearing loss, which reveal that cholinergic synaptic inputs re-emerge during aging. These efferents are functionally inhibitory, using the same ionic mechanisms as do efferent contacts present transiently before the developmental onset of hearing. The strength of efferent inhibition of inner hair cells increases with hearing threshold elevation. These data indicate that the aged cochlea regains features of the developing cochlea and that efferent inhibition of the primary receptors of the auditory system re-emerges with hearing impairment.. Synaptic changes in the auditory periphery are increasingly recognized as important factors in hearing loss. To date, anatomical work has described the loss of afferent contacts from cochlear hair cells. However, relatively little is known about the efferent innervation of the cochlea during hearing loss. We performed intracellular recordings from mouse inner hair cells across the lifespan and show that efferent innervation of inner hair cells arises in parallel with the loss of afferent contacts and elevated hearing threshold during aging. These efferent neurons inhibit inner hair cells, raising the possibility that they play a role in the progression of age-related hearing loss.

Topics: Acetylcholine; Age Factors; Alcohol Oxidoreductases; Animals; Animals, Newborn; Apamin; Calcium Channel Blockers; Co-Repressor Proteins; Cochlea; Conotoxins; Curare; Disease Models, Animal; DNA-Binding Proteins; Evoked Potentials, Auditory, Brain Stem; Female; Glycine Agents; Hair Cells, Auditory, Inner; Hearing Loss; Mice; Mice, Inbred C57BL; Neural Inhibition; Neuromuscular Nondepolarizing Agents; Phosphoproteins; Strychnine

Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes.. This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain.

Topics: Action Potentials; Analgesics, Opioid; Animals; Conditioning, Operant; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Excitatory Amino Acid Antagonists; Glycine Agents; Heroin; Hyperalgesia; Inflammation; Inhibitory Postsynaptic Potentials; Male; Neurons; Pain; Pain Threshold; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Strychnine; Sucrose; Ventral Tegmental Area

Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine (2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures induced. Compound 13 turned out to be the most active candidate within the strychnine model, having an average survival time of 6 min close to that of the positive control phenytoin, while compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Drug Design; Male; Mice; Molecular Structure; Pentylenetetrazole; Phenobarbital; Piperazines; Seizures; Structure-Activity Relationship; Strychnine

Intractable neuropathic dynamic allodynia remains one of the major symptoms of human trigeminal neuropathy and is commonly accepted to be the most excruciatingly painful condition known to humankind. At present, a validated animal model of this disorder is necessary for efficient and effective development of novel drug treatments. Intracisternal strychnine in rats has been shown to result in localized trigeminal dynamic allodynia, thus representing a possible model of trigeminal neuralgia. The purpose of this study was to validate a mouse model of trigeminal glycinergic inhibitory dysfunction using established positive (carbamazepine epoxide) and negative (morphine) controls.. The actions of conventional first-line treatment (carbamazepine epoxide [CBZe]) and clinically ineffective morphine were tested for trigeminal dynamic mechanical allodynia produced by intracisternal strychnine. In mice under halothane anesthesia, we injected either strychnine (0.3 μg), strychnine with CBZe (4 ng), or artificial cerebrospinal fluid (aCSF) intracisternally (i.c.). In a separate set of experiments, subcutaneous morphine (3 mg·kg(-1) sc) was injected with intracisternal strychnine. Dynamic mechanical allodynia was induced by stroking the fur with polyethylene (PE-10) tubing. The response of each mouse was rated to determine its allodynia score, and scores of each group were compared. In addition, in a separate dichotomous disequilibrium study, pairs of mice were injected with strychnine/saline, strychnine/strychnine-CBZe, or strychnine/strychnine-morphine. A blinded observer recorded which mouse of each pair had the greater global pain behaviour.. Strychnine (i.c.) produced higher quantitative allodynia scores in the trigeminal distribution (mean 81.5%; 95% confidence interval [CI] 76.4 to 86.6) vs the aCSF group (mean 11.3%; 95% CI 8.1 to 14.4) (P < 0.0001). Carbamazepine epoxide (i.c.) completely abolished allodynia when co-injected with strychnine (mean 83.2%; 95% CI 78.1 to 88.4) vs strychnine alone (mean 3.2%; 95% CI -0.9 to 7.2) (P < 0.0001). Morphine co-injected with strychnine did not result in reduced allodynia (mean 65.7%; 95% CI 42.0 to 89.4) compared with strychnine alone (mean 87.6%; 95% CI 77.6 to 97.6) (P = 0.16). In a further global allodynia assessment, strychnine (i.c.) produced greater allodynia than both aCSF and strychnine administered with CBZe (P = 0.03). Morphine (ip) administered with strychnine did not result in reduced global allodynia compared with strychnine administered alone (P = 1.0).. In this study, we have developed and validated a novel murine model of trigeminal dynamic allodynia induced by intracisternal strychnine. The use of mice to study trigeminal allodynia has many benefits, including access to a vast repository of transgenic mouse variants, ease of handling, low cost, and minimal variance of results. The present model may have utility in screening drug treatments for dynamic mechanical allodynia resulting from trigeminal neuropathies.

Topics: Analgesics, Non-Narcotic; Animals; Carbamazepine; Cerebrospinal Fluid; Cisterna Magna; Disease Models, Animal; Female; Glycine; Glycine Agents; Injections; Injections, Subcutaneous; Mice; Morphine; Narcotics; Pain Measurement; Random Allocation; Single-Blind Method; Strychnine; Trigeminal Neuralgia

Here we report that indazole is characterized as a potential anticonvulsant, inhibiting pentylenetetrazole-, electroshock- and strychnine-induced convulsions in mice (ED50's: 39.9, 43.2 and 82.4 mg/kg, respectively) but not bicuculline- and picrotoxin-induced convulsions. The median toxic dose (TD(50)) of indazole was 52.3 mg/kg by the minimal motor impairment test. Therefore, nontoxic doses produced anticonvulsant activity against pentylenetetrazole- and electroshock-induced seizures. Indazole (50 mg/kg) had no effect on spontaneous activity but induced hypothermia. It also inhibited the metabolism of dopamine and 5-hydroxytryptamine in the brain in vivo and the activities of monoamine oxidase A and B in vitro, with IC(50) values of 20.6 μM and 16.3 μM, respectively. However, these inhibitory effects do not account for the anticonvulsant activity because treatment with typical monoamine oxidase inhibitors such as pargyline or tranylcypromine did not completely reproduce the anticonvulsant activity of indazole. In the animal seizure models tested, the anticonvulsant profile of indazole most resembled that of gabapentin and somewhat resembled those of the AMPA/kainate antagonist NBQX and the sodium channel inhibitor phenytoin, but differed from that of benzodiazepine. The isobolographic analyses showed that the interactive mode of indazole with gabapentin, NBQX or phenytoin is additive. These results suggest that indazole has anticonvulsant activity and multiple mechanisms.

Topics: Animals; Anticonvulsants; Bicuculline; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Indazoles; Male; Mice; Pentylenetetrazole; Phenytoin; Seizures; Strychnine

The caudal division of the trigeminal spinal nucleus (Sp5C) is an important brainstem relay station of orofacial pain transmission. The aim of the present study was to examine the effect of cortical electrical stimulation on nociceptive responses in Sp5C neurons. Extracellular recordings were performed in the Sp5C nucleus by tungsten microelectrodes in urethane-anesthetized Sprague-Dawley rats. Nociceptive stimulation was produced by application of capsaicin cream on the whisker pad or by constriction of the infraorbital nerve. Capsaicin application evoked a long-lasting increase in the spontaneous firing rate from 1.4±0.2 to 3.4±0.6 spikes/s. Non-noxious tactile responses from stimuli delivered to the receptive field (RF) center decreased 5 min. after capsaicin application (from 2.3±0.1 to 1.6±0.1 spikes/stimulus) while responses from the whisker located at the RF periphery increased (from 1.3±0.2 to 2.0±0.1 spikes/stimulus under capsaicin). Electrical train stimulation of the primary (S1) or secondary (S2) somatosensory cortical areas reduced the increase in the firing rate evoked by capsaicin. Also, S1, but not S2, cortical stimulation reduced the increase in non-noxious tactile responses from the RF periphery. Inhibitory cortical effects were mediated by the activation of GABAergic and glycinergic neurons because they were blocked by bicuculline or strychnine. The S1 and S2 cortical stimulation also inhibited Sp5C neurons in animals with constriction of the infraorbital nerve. Consequently, the corticofugal projection from S1 and S2 cortical areas modulates nociceptive responses of Sp5C neurons and may control the transmission of nociceptive sensory stimulus.

Topics: Action Potentials; Afferent Pathways; Animals; Bicuculline; Biophysics; Capsaicin; Constriction; Disease Models, Animal; Electric Stimulation; Female; GABA-A Receptor Antagonists; Glutamic Acid; Glycine Agents; Hyperalgesia; Iontophoresis; Male; Neural Inhibition; Neuralgia; Nociceptors; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Somatosensory Cortex; Strychnine; Time Factors; Trigeminal Nucleus, Spinal

To study the effects of brucine on vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in a nude mouse model of bone metastasis due to breast cancer, and to assess the possible antitumor mechanism of brucine.. A syringe needle was used to directly inject 0.2 mL monoplast suspension (with 2×10(5) human breast cancer cells contained) into the bony femoral cortex of the right hind leg for modeling. Twenty-five nude mice were randomized into five groups and administered with an intraperitoneal injection of saline or drug for 8 consecutive days: model group (0.2 mL normal saline), low-dose brucine group (1.73 mg·kg(-1)), medium-dose brucine group (3.45 mg·kg(-1)), high-dose brucine group (6.90 mg·kg(-1)), and thalidomide group (200 mg·kg(-1)). Diet and activity were recorded, and the tumors were harvested 5 weeks later. The percentage of VEGF-positive cells was determined with hematoxylin and eosin staining and immunohistochemical staining, and MVD expression was determined by optical microscopy.. The VEGF expressions in brucine- or thalidomide-treated mice were significantly reduced as compared with mice in the model group (P <0.01). There were no significant difference between the high-dose brucine group and the thalidomide group (P >0.05). Significant difference was between the high- and low-dose brucine group P<0.05). Further, VEGF expression was significantly increased in the low- and medium-dose brucine groups compared with the thalidomide group (P <0.05). The MVD values in the three brucine and thalidomide groups were significantly lower than that in the model group (P <0.01). The MVD values in the medium- and high-dose brucine groups were not significantly different from those in the thalidomide group (P >0.05), while the MVD value showed a significant increase in the low-dose group compared with the thalidomide group (P <0.05).. Brucine could inhibit the growth of breast cancer to bone metastases, possibly by inhibiting tumor angiogenesis.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Microvessels; Strychnine; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Ignatia amara (Ignatia), a remedy made from the Strychnos ignatii seeds, is used for anxiety-related symptoms, but consistent evidence of its activity in reproducible experimental models is lacking. An investigation was performed in order to assess on mice, by means of emotional response models, the activity of homeopathic Ignatia dilutions/dynamizations.. Groups of 8 mice of the CD1 albino strain were treated intraperitoneally for 9 days with 0.3ml of five centesimal (C) dilutions/dynamizations of Ignatia (4C, 5C, 7C, 9C and 30C). Control mice were treated with the same hydroalcoholic (0.3%) solution used to dilute the medicines. Diazepam (1mg/kg) was the positive reference drug. Validated test models for locomotion and emotional response, the Open-Field (OF) and the Light-Dark (LD) tests, were employed. Five replications of the same protocol were carried out, in a randomised way using coded drugs/controls.. In the OF the general locomotion of mice was slightly decreased by Ignatia 4C, but not by Ignatia 5C, 7C, 9C and 30C, indicating the absence of unspecific motor impairment or sedation by these dilutions/dynamizations. Ignatia and diazepam seemed to decrease the number of urine spots released in the OF during 10min, with borderline significance (P=0.083). In the LD the tested medicine showed anxiolytic-like activity (increase of time spent and distance travelled in the lit area), though to a lesser extent than diazepam. The highest and most significant difference with untreated controls (P<0.01) was observed with the 9C dilution/dynamization. Among the 5 replication experiments, the best drug effects were obtained where the baseline anxiety of mice was higher.. Homeopathic Ignatia dilutions/dynamizations (peak at 9C) modify some emotion-related symptoms in laboratory mice without affecting locomotion.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Disease Models, Animal; Exploratory Behavior; Homeopathy; Male; Mice; Mice, Inbred Strains; Phytotherapy; Plant Extracts; Seeds; Strychnos

Glycine inhibitory dysfunction provides a useful experimental model for studying the mechanism of dynamic mechanical allodynia, a widespread and intractable symptom of neuropathic pain. In this model, allodynia expression relies on N-methyl-d-aspartate receptors (NMDARs), and it has been shown that astrocytes can regulate their activation through the release of the NMDAR coagonist d-serine. Recent studies also suggest that astrocytes potentially contribute to neuropathic pain. However, the involvement of astrocytes in dynamic mechanical allodynia remains unknown. Here, we show that after blockade of glycine inhibition, orofacial tactile stimuli activated medullary dorsal horn (MDH) astrocytes, but not microglia. Accordingly, the glia inhibitor fluorocitrate, but not the microglia inhibitor minocycline, prevented allodynia. Fluorocitrate also impeded activation of astrocytes and blocked activation of the superficial MDH neural circuit underlying allodynia, as revealed by study of Fos expression. MDH astrocytes are thus required for allodynia. They may also produce d-serine because astrocytic processes were selectively immunolabeled for serine racemase, the d-serine synthesizing enzyme. Accordingly, selective degradation of d-serine with d-amino acid oxidase applied in vivo prevented allodynia and activation of the underlying neural circuit. Conversely, allodynia blockade by fluorocitrate was reversed by exogenous d-serine. These results suggest the following scenario: removal of glycine inhibition makes tactile stimuli able to activate astrocytes; activated astrocytes may provide d-serine to enable NMDAR activation and thus allodynia. Such a contribution of astrocytes to pathological pain fuels the emerging concept that astrocytes are critical players in pain signaling. Glycine disinhibition makes tactile stimuli able to activate astrocytes, which may provide d-serine to enable NMDA receptor activation and thus allodynia.

Topics: Analysis of Variance; Animals; Astrocytes; CD11b Antigen; Citrates; Disease Models, Animal; Enzyme Inhibitors; Glial Fibrillary Acidic Protein; Glycine; Hyperalgesia; Male; Oncogene Proteins v-fos; Pain Measurement; Rats; Rats, Sprague-Dawley; Serine; Spinal Nerve Roots; Strychnine; Time Factors

Retinal prosthetic devices are being developed to bypass degenerated retinal photoreceptors by directly activating retinal neurons with electrical stimulation. However, the retinal circuitry that is activated by epiretinal stimulation is not well characterized. Whole-cell patch clamp recordings were obtained from ganglion cells in normal and rd mice using flat-mount and retinal slice preparations. A stimulating electrode was positioned along the ganglion cell side of the preparation at different distances from the stimulated tissue. Pulses of cathodic current evoked action potentials in ganglion cells and less frequently evoked sustained inward currents that appeared synaptic in origin. Sustained currents reversed around E(Cl) and were inhibited by blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-proprionate (AMPA)-type glutamate receptors with 2,3-dihydroxy-6-nitro-sulfamoyl-benzo(f)-quinoxaline-2,3-dione (NBQX), γ aminobutyric acid a/c (GABA(a/c)) receptors with picrotoxinin, or glycine receptors with strychnine. This suggests that epiretinal stimulation activates glutamate release from bipolar cell terminals, which in turn evokes release of GABA and glycine from amacrine cells. Synaptic current thresholds were lower in ON ganglion cells than OFF cells, but the modest difference did not attain statistical significance. Synaptic currents were rarely observed in rd mice lacking photoreceptors compared to normal retina. In addition, confocal calcium imaging experiments in normal mice retina slices revealed that epiretinal stimulation evoked calcium increases in the outer plexiform layer. These results imply a contribution from photoreceptor inputs to the synaptic currents observed in ganglion cells. The paucity of synaptic responses in rd mice retina slices suggests that it is better to target retinal ganglion cells directly rather than to attempt to engage the inner retinal circuitry.

Topics: Animals; Biophysics; Calcium; Disease Models, Animal; Electric Stimulation; Evoked Potentials; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA-A Receptor Antagonists; Glycine Agents; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Confocal; Patch-Clamp Techniques; Picrotoxin; Quinoxalines; Retina; Retinal Degeneration; Retinal Ganglion Cells; Sesterterpenes; Strychnine; Visual Pathways

To investigate the anticonvulsant activity of the leaf extract of Justicia extensa T. Anders used traditionally in the treatment of convulsion.. The anticonvulsant activity of the methanolic extract of Justicia extensa (50, 100 and 200 mg/kg, p.o.) was assessed in strychnine-induced (STR) and picrotoxin-induced (PCT) convulsion models in mice. Diazepam (1 mg/kg) and phenobarbitone (2 mg/kg) were used as reference drugs respectively.. The extract showed no toxicity and significantly prolonged (p<0.01-0.05) the onset and reduced the duration of the seizures induced by picrotoxin (5 mg/kg, i.p.) in a dose dependent manner. Phenobarbitone completely inhibited the seizures in this model. Similarly, in the seizures induced by strychnine (1 mg/kg, i.p.), the extract also prolonged the onset and reduced the duration of the seizures though not in a dose dependent manner. Diazepam failed to inhibit the strychnine-induced seizures. The plant extract however showed a significantly higher anticonvulsant activity at 100 and 200 mg/kg in comparison with diazepam.. The results obtained from this work suggest that Justicia extensa has anticonvulsant activity and this supports the use of the plant traditionally in the treatment of convulsion.

Topics: Acanthaceae; Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Female; Male; Medicine, African Traditional; Methanol; Mice; Nigeria; Phenobarbital; Phytotherapy; Picrotoxin; Plant Extracts; Plant Leaves; Seizures; Solvents; Strychnine

The objective of this study is to investigate the anticonvulsant, anxiolytic and sedative activities of the aqueous root extract of Securidaca longepedunculata.. The anticonvulsant effect of the aqueous root extract (100, 200 and 400 mg/kg) was evaluated in mice using the strychnine- and picrotoxin-induced seizure models. Its anxiolytic activity was evaluated using the elevated plus maze (EPM) and the Y maze (YM) methods (Hogg, 1996; Yemitan and Adeyemi, 2003) while the hexobarbitone induced sleep and the hole board models were used to evaluate the sedative and exploratory activities in mice respectively. The acute toxicity studies and phytochemical analysis of the extract were also carried out.. The extract (100-400 mg/kg) produced a significant (P<0.01) dose dependent increase in onset of convulsion compared to the control for strychnine- and picrotoxin-induced seizures. It also produced a significant (P<0.01) dose dependent prolongation of the cumulative time spent in the open arms of the elevated plus maze and Y maze compared with the control. The extract (100-400 mg/kg) produced significant (P<0.01) reduction in the time of onset of sleep induced by hexobarbitone. The prolongation of hexobarbitone sleeping time by the extract (200 mg/kg) was comparable to that produced by diazepam (3 mg/kg). At doses of 100-400 mg/kg, the extract produced a dose dependent decrease in exploratory activity of the mice. The reduction in exploratory activity produced by the extract (400 mg/kg) was greater than that of chlorpromazine (1 mg/kg). The results obtained from the experiments indicate that the extract has central nervous system depressant and anxiolytic activities. The LD(50) obtained for the acute toxicity studies using both oral and intraperitoneal routes of administration were 1.74 g/kg and 19.95 mg/kg respectively.. These findings justify the use of Securidaca longepedunculata in traditional medicine for the management of convulsion and psychosis.

Topics: Administration, Oral; Animals; Anti-Anxiety Agents; Anticonvulsants; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Female; Hexobarbital; Hypnotics and Sedatives; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Picrotoxin; Plant Extracts; Plant Roots; Securidaca; Seizures; Sleep; Strychnine; Time Factors

Chronic neuropathic pain remains an unmet clinical problem because it is often resistant to conventional analgesics. Metabotropic glutamate receptors (mGluRs) are involved in nociceptive processing at the spinal level, but their functions in neuropathic pain are not fully known. In this study, we investigated the role of group III mGluRs in the control of spinal excitatory and inhibitory synaptic transmission in a rat model of neuropathic pain induced by L5/L6 spinal nerve ligation. Whole-cell recording of lamina II neurons was performed in spinal cord slices from control and nerve-ligated rats. The baseline amplitude of glutamatergic EPSCs evoked from primary afferents was significantly larger in nerve-injured rats than in control rats. However, the baseline frequency of GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) was much lower in nerve-injured rats than in control rats. The group III mGluR agonist l(+)-2-amino-4-phosphonbutyric acid (l-AP4) produced a greater inhibition of the amplitude of monosynaptic and polysynaptic evoked EPSCs in nerve-injured rats than in control rats. l-AP4 inhibited the frequency of miniature EPSCs in 66.7% of neurons in control rats but its inhibitory effect was observed in all neurons tested in nerve-injured rats. Furthermore, l-AP4 similarly inhibited the frequency of GABAergic and glycinergic IPSCs in control and nerve-injured rats. Our study suggests that spinal nerve injury augments glutamatergic input from primary afferents but decreases GABAergic and glycinergic input to spinal dorsal horn neurons. Activation of group III mGluRs attenuates glutamatergic input from primary afferents in nerve-injured rats, which could explain the antinociceptive effect of group III mGluR agonists on neuropathic pain.

Topics: Aminobutyrates; Animals; Biophysical Phenomena; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Glycine Agents; Hyperalgesia; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Neuralgia; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Spinal Nerves; Strychnine; Synaptic Transmission

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. We recently provided a novel perspective on the mechanisms of this symptom by showing that a simple switch in trigeminal glycine synaptic inhibition can turn touch into pain by unmasking innocuous input to superficial dorsal horn nociceptive specific neurons through a local excitatory, NMDA-dependent neural circuit involving neurons expressing the gamma isoform of protein kinase C. Here, we further investigated the clinical relevance and processing of glycine disinhibition. First, we showed that glycine disinhibition with strychnine selectively induced dynamic but not static mechanical allodynia. The induced allodynia was resistant to morphine. Second, morphine did not prevent the activation of the neural circuit underlying allodynia as shown by study of Fos expression and extracellular-signal regulated kinase phosphorylation in dorsal horn neurons. Third, in contrast to intradermal capsaicin injections, light, dynamic mechanical stimuli applied under disinhibition did not produce neurokinin 1 (NK1) receptor internalization in dorsal horn neurons. Finally, light, dynamic mechanical stimuli applied under disinhibition induced Fos expression only in neurons that did not express NK1 receptor. To summarize, the selectivity and morphine resistance of the glycine-disinhibition paradigm adequately reflect the clinical characteristics of dynamic mechanical allodynia. The present findings thus reveal the involvement of a selective dorsal horn circuit in dynamic mechanical allodynia, which operates through superficial lamina nociceptive-specific neurons that do not bear NK1 receptor and provide an explanation for the differences in the pharmacological sensitivity of neuropathic pain symptoms.

Topics: Analgesics, Opioid; Animals; Bicuculline; Blood Pressure; Capsaicin; Disease Models, Animal; Drug Resistance; Extracellular Signal-Regulated MAP Kinases; GABA Antagonists; Glycine; Hyperalgesia; Male; Morphine; Nonlinear Dynamics; Oncogene Proteins v-fos; Pain Measurement; Pain Threshold; Physical Stimulation; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Strychnine

A new series of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one were synthesized to study the effect of cyclization of the semicarbazone moiety of aryl semicarbazones on the anticonvulsant activity. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity in four animal models of seizures, viz. maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. The compounds were also evaluated for neurotoxicity. Compounds 4, 9, 14-19 exhibited anticonvulsant activity in all the four animal models of seizure.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroshock; Male; Mice; Pentylenetetrazole; Picrotoxin; Rats; Rats, Sprague-Dawley; Seizures; Semicarbazones; Structure-Activity Relationship; Strychnine; Toxicity Tests

Possible central nervous system effects of the gymnosperm lectin from Araucaria angustifolia seeds were studied in seizure and open field tests. Male Swiss mice were administered saline (control), lectin (0.1, 1, and 10 mg/kg), flumazenil (1 mg/kg), or diazepam (1 mg/kg) intraperitoneally. Lectin at the highest dose increased time to death in the pentylenetetrazole- and strychnine-induced seizure models as compared with control, but not in the pilocarpine model. In the open field test, lectin reduced locomotor activity at all doses tested, as did diazepam, when compared with control. These locomotor effects were reversed by flumazenil pretreatment. In conclusion, A. angustifolia lectin had a protective effect in the pentylenetetrazole- and strychnine-induced seizure models, suggestive of activity in the GABAergic and glycinergic systems, respectively, and also caused a reduction in animal movements, which was reversed by flumazenil, pointing to a depressant action mediated by a GABAergic mechanism.

Topics: Analysis of Variance; Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Flumazenil; Lectins; Locomotion; Male; Mice; Pentylenetetrazole; Phytotherapy; Plant Extracts; Reaction Time; Seeds; Seizures; Strychnine

Acute ethanol depresses respiration, but little is known about chronic ethanol exposure during gestation and breathing, while the deleterious effects of ethanol on CNS development have been clearly described. In a recent study we demonstrated that pre- and postnatal ethanol exposure induced low minute ventilation in juvenile rats. The present study analysed in juvenile rats the respiratory response to hypoxia in vivo by plethysmography and the phrenic (Phr) nerve response to ischaemia in situ. Glycinergic neurotransmission was assessed in situ with strychnine application and [(3)H]strychnine binding experiments performed in the medulla. After chronic ethanol exposure, hyperventilation during hypoxia was blunted in vivo. In situ Phr nerve response to ischaemia was also impaired, while gasping activity occurred earlier and recovery was delayed. Strychnine applications in situ (0.05-0.5 microM) demonstrated a higher sensitivity of expiratory duration in ethanol-exposed animals compared to control animals. Moreover, [(3)H]strychnine binding density was increased after ethanol and was associated with higher affinity. Furthermore, 0.2 microM strychnine in ethanol-exposed animals restored the low basal Phr nerve frequency, but also the Phr nerve response to ischaemia and the time to recovery, while gasping activity appeared even earlier with a higher frequency. Polycythaemia was present after ethanol exposure whereas lung and heart weights were not altered. We conclude that chronic ethanol exposure during rat brain development (i) induced polycythaemia to compensate for low minute ventilation at rest; (ii) impaired the respiratory network adaptive response to low oxygen because of an increase in central glycinergic tonic inhibitions, and (iii) did not affect gasping mechanisms. We suggest that ethanol exposure during early life can be a risk factor for the newborn respiratory adaptive mechanisms to a low oxygen environment.

Topics: Animals; Animals, Newborn; Central Nervous System Depressants; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Female; Male; Oxygen; Poisons; Polycythemia; Potassium; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Strychnine

Some new substituted coumarinylthiazolines, coumarinylthiazolidin-4-ones, and substituted chromenothiazoles were synthesized and evaluated for anticonvulsant activity. Some selected compounds were assayed against seizures induced by pentylenetetrazole (PTZ) and strychnine in mice. Compounds 3b, 6b, and 7b were the most active of the series against PTZ induced seizures. Compound 7b provided anticonvulsant activity (PD(50)=95mg/kg, ip) at a dose 200mg/kg compared to phenobarbital (PD(50)=16mg/kg, ip) at a dose 30mg/kg (90% protection). No clear correlation was observed between the antiepileptic activity and molecular lipophilicity descriptors of the tested compounds.

Topics: Animals; Anticonvulsants; Coumarins; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Molecular Structure; Pentylenetetrazole; Seizures; Stereoisomerism; Structure-Activity Relationship; Strychnine

Amyotrophic lateral sclerosis is a lethal, adult-onset disease characterized by progressive degeneration of motoneurons. Recent data have suggested that the disease could be linked to abnormal development of the motor nervous system. Therefore, we investigated the electrical properties of lumbar motoneurons in an in-vitro neonatal spinal cord preparation isolated from SOD1(G85R) mice, which is a transgenic model of amyotrophic lateral sclerosis. The study was performed on young animals at the beginning of their second week, between postnatal days 6 and 10. Measurements of resting membrane potential and action potential characteristics of motoneurons were similar in wild-type and SOD1(G85R) mice. However, the input resistance of motoneurons from transgenic mice was significantly lower than that of wild-type animals, whereas their membrane capacitance was increased, strongly suggesting larger SOD1(G85R) motoneurons. Furthermore, the slope of the frequency-intensity curve was steeper in motoneurons from wild-type pups. Interestingly, the input resistance as well as the slope of the frequency-intensity curves of other spinal neurons did not show such differences. Finally, the amplitude of dorsal root-evoked potentials following high-intensity stimulation was significantly smaller in SOD1(G85R) motoneurons. The superoxide dismutase 1 mutation thus induces specific alterations of the functional properties of motoneurons early in development.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Dose-Response Relationship, Radiation; Electric Stimulation; Glycine Agents; Lumbosacral Region; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons; Patch-Clamp Techniques; Spinal Cord; Strychnine; Superoxide Dismutase; Superoxide Dismutase-1

Bilateral alternation of muscle contractions requires reciprocal inhibition between the two sides of the hindbrain and spinal cord, and disruption of this inhibition should lead to simultaneous activation of bilateral muscles. At 1 day after fertilization, wild-type zebrafish respond to mechanosensory stimulation with multiple fast alternating trunk contractions, whereas bandoneon (beo) mutants contract trunk muscles on both sides simultaneously. Similar simultaneous contractions are observed in wild-type embryos treated with strychnine, a blocker of the inhibitory glycine receptor (GlyR). This result suggests that glycinergic synaptic transmission is defective in beo mutants. Muscle voltage recordings confirmed that muscles on both sides of the trunk in beo are likely to receive simultaneous synaptic input from the CNS. Recordings from motor neurons revealed that glycinergic synaptic transmission was missing in beo mutants. Furthermore, immunostaining with an antibody against GlyR showed clusters in wild-type neurons but not in beo neurons. These data suggest that the failure of GlyRs to aggregate at synaptic sites causes impairment of glycinergic transmission and abnormal behavior in beo mutants. Indeed, mutations in the GlyR beta-subunit, which are thought to be required for proper localization of GlyRs, were identified as the basis for the beo mutation. These data demonstrate that GlyRbeta is essential for physiologically relevant clustering of GlyRs in vivo. Because GlyR mutations in humans lead to hyperekplexia, a motor disorder characterized by startle responses, the zebrafish beo mutant should be a useful animal model for this condition.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation, Developmental; Molecular Sequence Data; Muscles; Mutation; Protein Subunits; Receptors, Glycine; Rhombencephalon; Spinal Cord; Strychnine; Synaptic Transmission; Touch; Zebrafish; Zebrafish Proteins

We sought to modify normal laryngeal constrictor (LC) motoneuron activity to induce a pattern of aberrant LC muscle function that may serve as a model of congenital bilateral vocal cord paralysis.. Single unit extracellular recordings of functionally identified LC motoneurons were made in anesthetized Sprague-Dawley rats, and the response to both intravenous and iontophoretic application of the glycine antagonist strychnine was studied.. The postinspiratory firing pattern of LC motoneurons became inspiratory after intravenous injection of strychnine (4 of 5 rats), but no change was recorded in response to strychnine iontophoresis (7 of 8 rats).. Blockade of glycinergic inhibitory neurotransmission by strychnine, acting above the level of the LC motoneuron, causes LC motoneurons to fire during inspiration rather than after inspiration. This observation suggests that impaired glycine neurotransmission may be an underlying mechanism that explains the clinical manifestations of congenital bilateral vocal cord paralysis.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Glycine Agents; Injections, Intravenous; Iontophoresis; Laryngeal Muscles; Motor Neurons; Phrenic Nerve; Rats; Rats, Sprague-Dawley; Strychnine; Vocal Cord Paralysis

The present study was carried out to determine possible panicogenic effects of strychnine administered in subconvulsive doses to rats. Two experiments were conducted to assess two major features of panic in animal models: panic-related flight (through the observation of wild running [WR]) and defensive fights. In the first one, 20 adult male Wistar rats were injected with six different doses of strychnine ranging from 0.5 to 4.0 mg/kg. After 15 min of free observation, the animals were submitted to high-intensity acoustic stimulation and the incidence of WR was recorded. Higher doses of strychnine (above 2.5 mg/kg) easily evoked seizures, but lower doses raised the incidence of WR in a dose-dependent manner. The most effective dose for WR (1.5 mg/kg) was used in the second experiment, in which we investigated the effects of strychnine on sleep-deprivation-induced fights (SDIFs) that have defensive characteristics. For this purpose, 40 subjects were submitted to 5 days of REM-sleep deprivation by the single-platform method and were then assigned into two groups, i.e., strychnine vs. control. After the injections, the animals were observed in social groupings for SDIF recordings over a period of 60 min. The strychnine-treated groups had more SDIF than the control groups (P<.05, Mann-Whitney U test). We conclude that the high level of neural excitability promoted by partial blockade of the glycinergic system can contribute to the manifestation of panic reactions.

Topics: Acoustic Stimulation; Aggression; Animals; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Panic; Random Allocation; Rats; Rats, Wistar; Seizures; Sleep Deprivation; Strychnine

We examined the influence of lumbosacral glycinergic neurons on the spinobulbospinal and spinal micturition reflexes. Female rats were divided into intact rats, rats with acute injury to the lower thoracic spinal cord (SCI), and rats with chronic SCI. Under urethane anesthesia, isovolumetric cystometry was performed in each group before and after intrathecal (IT) injection of glycine or strychnine into the lumbosacral cord level. The glutamate and glycine levels of the lumbosacral cord were measured after injection of glycine or strychnine in intact and chronic SCI rats. Expression of strychnine-sensitive glycine receptor alpha-1 (GlyR alpha1) mRNA in the lumbosacral cord was also assessed in both rats. In chronic SCI rats, the interval and amplitude of bladder contractions were shorter and smaller when compared with intact rats. IT glycine (0.1-100 microg) prolonged the interval and decreased the amplitude of bladder contractions in both intact rats and chronic SCI rats. IT strychnine (0.01-10 microg) elevated the baseline pressure in intact rats and induced bladder contraction in acute SCI rats. On amino acid analysis, IT glycine (0.01-100 microg) decreased the glutamate level of the lumbosacral cord in intact rats, but not in chronic SCI rats. The glycine level of the lumbosacral cord was 54% lower in chronic SCI rats when compared with intact rats, while the GlyR alpha1 mRNA level did not change after SCI. These results suggest that glycinergic neurons may have an important inhibitory effect on the spinobulbospinal and spinal micturition reflexes at the level of the lumbosacral cord.

Topics: Acute Disease; Animals; Chronic Disease; Disease Models, Animal; Female; Glutamic Acid; Glycine; Glycine Agents; Injections, Spinal; Lumbosacral Region; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Reflex; RNA, Messenger; Spinal Cord; Spinal Cord Injuries; Strychnine; Urinary Bladder; Urination

To further understand the purpose of the traditional processing method of the seeds of Strychnos nux-vomica L. (Loganiaceae) as well as analgesic and anti-inflammatory activities of brucine and brucine N-oxide extracted from this medicinal plant, various pain and inflammatory models were employed in the present study to investigate their pharmacological profiles. Both brucine and brucine N-oxide revealed significant protective effects against thermic and chemical stimuli in hot-plate test and writhing test. However, on different phases they exerted analgesic activities in formalin test. Brucine N-oxide showed stronger inhibitory effect than brucine in carrageenan-induced rat paw edema, both of them significantly inhibited the release of prostaglandin E2 in inflammatory tissue, reduced acetic acid-induced vascular permeability and the content of 6-keto-PGF1a in Freund's complete adjuvant (FCA) induced arthritis rat's blood plasma. In addition, brucine and brucine N-oxide were shown to reduce the content of 5-hydroxytryptamine (5-HT) in FCA-induced arthritis rat's blood plasma, while increase the content of 5-hydroxytryindole-3-acetic acid (5-HIAA) accordingly. These results suggest that central and peripheral mechanism are involved in the pain modulation and anti-inflammation effects of brucine and brucine N-oxide, biochemical mechanisms of brucine and brucine N-oxide are different even though they are similar in chemical structure.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Capillary Permeability; Cyclic N-Oxides; Disease Models, Animal; Edema; Female; Male; Mice; Mice, Inbred ICR; Pain; Plant Extracts; Rats; Rats, Sprague-Dawley; Seeds; Serotonin; Strychnine; Strychnos nux-vomica

The glycine transporter subtype 1 (GlyT1) is widely expressed in astroglial cells throughout the mammalian central nervous system and has been implicated in the regulation of N-methyl-D-aspartate (NMDA) receptor activity. Newborn mice deficient in GlyT1 are anatomically normal but show severe motor and respiratory deficits and die during the first postnatal day. In brainstem slices from GlyT1-deficient mice, in vitro respiratory activity is strikingly reduced but normalized by the glycine receptor (GlyR) antagonist strychnine. Conversely, glycine or the GlyT1 inhibitor sarcosine suppress respiratory activity in slices from wild-type mice. Thus, during early postnatal life, GlyT1 is essential for regulating glycine concentrations at inhibitory GlyRs, and GlyT1 deletion generates symptoms found in human glycine encephalopathy.

Topics: Amino Acid Transport Systems, Neutral; Animals; Animals, Newborn; Brain; Disease Models, Animal; Genes, Lethal; Glycine; Glycine Plasma Membrane Transport Proteins; Homozygote; Mice; Mice, Knockout; Nerve Tissue Proteins; Neural Inhibition; Neuroglia; Phenotype; Respiration; Sarcosine; Strychnine; Synaptic Transmission

The present study was designed to evaluate the anticonvulsant effects of a high-fat ketogenic diet (KD) in rats. Animals were maintained on one of four experimental diets: (1) calorie-restricted ketogenic (KCR); (2) calorie-restricted normal (NCR); (3) ad libitum ketogenic (KAL); or (4) ad libitum normal (NAL). The calorie-restricted diets were fed in quantities such that they were calorically equivalent. All animals began diet treatment at age P37 and each was subjected to one of five chemically-induced seizure tests: bicuculline (BIC; s.c.), picrotoxin (PIC; s.c.), kainate (KA, i.p. or s.c.) and gamma-butyrolactone (GBL, i.p.), strychnine (s.c.). Bipolar epidural electrodes were implanted under ketamine/xylazine anesthesia to permit recording the spike and wave discharges (SWD) characteristic of electroencephalograms during absence seizures. Ketonemia was assayed by measuring blood levels of beta-hydroxybutyrate (BHB) spectrophotometrically prior to induction of seizures in each experiment. Animals fed ketogenic diets (i.e. either calorie restricted or ad libitum) exhibited greater blood levels of BHB compared to control groups. Seizure results show that treatment with a KD: (1) reduced the incidence of bicuculline-induced convulsions; (2) diminished the number of picrotoxin-induced seizures (KCR group only); (3) increased latency to GBL-induced SWD and reduced both the number and duration of SWD; but (4) conferred no protection from strychnine-induced seizures; and (5) made KA-induced seizures more severe. Together these results indicate a spectrum of anticonvulsant action for the KD in rats that includes threshold seizures induced via GABA receptors (BIC, PIC, GBL) but not those induced at glycine (strychnine) or the KA-subclass of glutamate receptors. Uniquely, the KD is the only treatment described that protects against both convulsive and non-convulsive (absence) seizures in rats.

Topics: 3-Hydroxybutyric Acid; Animals; Anticonvulsants; Bicuculline; Convulsants; Dietary Fats; Disease Models, Animal; Electroencephalography; Male; Picrotoxin; Rats; Rats, Sprague-Dawley; Seizures; Strychnine; Survival Rate; Time Factors

To see whether Strychnos nux-vomica extract (mother tincture [MT]), its potency Nux 30c, and its principal alkaloid, strychnine, could reduce voluntary ethanol intake in rats. To analyze the solution structure of Nux MT, Nux 30c, 90% ethanol, and ethanol 30c by means of electronic (ES) and nuclear nuclear magnetic resonance (NMR) spectra.. Potentially alcoholic rats were first given 20% ethanol and then kept on a two-choice bottle, one with 20% ethanol and another with tap water. These rats were given the following oral treatments for 15 days: group 1, control; group 2, strychnine at 0.36 mg/kg per day; group 3, ethanolic extract of S. nux-vomica seeds (Nux MT) at 3.6 mg/kg per day; and group 4, Nux 30c at 0.05 mL/d per rat. Nux 30c was prepared by successive dilution of Nux MT and 90% ethanol (1:100) and sonication at 20 kHz for 30 seconds in 30 steps.. Both Nux MT and Nux 30c significantly reduced ethanol intake and increased water intake in rats. ES of two dilutions of Nux MT and Nux 30c showed intersections at more than one point suggesting existence of molecular complexes. ES of Nux MT in CCl4 showed a red shift when 90% ethanol was added indicating molecular complexation and charge transfer interaction between ethanol and Nux compounds. NMR spectra of Nux MT, 90% ethanol, ethanol 30c, and Nux 30c indicated a change in solution structure of the medium (90% ethanol) of Nux 30c.. Nux MT and Nux 30c could reduce ethanol intake in rats. The altered solution structure of Nux 30c is thought to mimic Nux MT and produce ethanol aversion in rats.

Topics: Alcohol Deterrents; Alcoholism; Animals; Disease Models, Animal; Ethanol; Feeding Behavior; Homeopathy; Plant Extracts; Plants, Medicinal; Rats; Strychnine

After the administration of intrathecal strychnine, allodynia is manifested as activation of supraspinal sites involved in pain processing and enhancement of cardiovascular responses evoked by normally innocuous stimuli. The objective of this study was to investigate the effect of strychnine-induced allodynia on adrenergic neuronal activity in the C1 area of the rostral ventrolateral medulla (RVLM), a major site involved in cardiovascular regulation. The effect of intrathecal strychnine (40 microg) or saline followed by repeated hair deflection to caudal lumbar dermatomes in the urethane-anesthetized rat was assessed by measuring voltammetric changes in the RVLM catechol oxidation current (CA x OC), mean arterial pressure (MAP), and heart rate (HR). After the administration of intrathecal strychnine, hair deflection evoked a significant and sustained increase in the RVLM CA x OC and MAP (peak 146.4%+/-5.6% and 159%+/-18.4% of baseline, respectively; P < 0.05). There was a nonsignificant increase in HR (peak 128%+/-8.2%). In the absence of hair deflection, there was no demonstrable change. Intrathecal saline-treated rats failed to demonstrate changes in RVLM CA x OC, MAP, or HR. In the present study, we demonstrated that, after the administration of intrathecal strychnine, innocuous hair deflection evokes temporally related neuronal activation in the rat RVLM and an increase in MAP. This suggests that the RVLM mediates, at least in part, the cardiovascular responses during strychnine allodynia.. Neural injury-associated pain, as manifested by allodynia, is resistant to conventional treatment. In a rat model of allodynia, we demonstrated activation of the brain region involved in sympathetic control. Innovative therapies that target this region may be successful in managing this debilitating condition.

Topics: Anesthesia; Animals; Blood Pressure; Catechols; Disease Models, Animal; Heart Rate; Male; Medulla Oblongata; Pain; Rats; Rats, Sprague-Dawley; Strychnine; Sympathetic Nervous System

Effects of graded support loads and stimulators of the central nervous system (ephedrine and strychnine) on growth of bones and the volume of spongy bone tissue in the proximal metaphyses of the shin bones were studied in the 14-day experiment with rats suspended by tail in the orthostatic position. It is indicated that the support loads in combination with ephedrine injection prevent the suspension-induced inhibition of bone growth and development of osteopenia of spongiosa of metaphyses. The preventive effect of support loads and ephedrine relates with their stimulating influence on the functional activity of the STH-cells of adenohypophysis producing the growth hormone.

Topics: Animals; Bone Diseases, Metabolic; Central Nervous System Stimulants; Convulsants; Disease Models, Animal; Ephedrine; Follow-Up Studies; Head-Down Tilt; Male; Rats; Restraint, Physical; Strychnine; Tibia; Weight-Bearing

Using quantitative autoradiography, the strychnine-sensitive glycine site and strychnine-insensitive glycine site of the N-methyl-D-aspartate receptor were analyzed in the cervical segment of the spinal cord of the wobbler mouse, which is a purported model of human motor neuron diseases. Significantly increased density of the strychnine-sensitive site was found in the lamina II-inner (+17%) and laminae III & IV (+17%) of wobbler mice. The strychnine-insensitive site was also increased in lamina I & II-outer (+15%), lamina II-inner (+15%), laminae III & IV (+48%), laminae V-VIII (+43%) and lamina X (+26%) of wobbler mice. However, no significant differences were observed for the both sites in the ventral horn where motor neurons are located. These findings suggest that both inhibitory and excitatory-associated glycinergic dysfunctions are involved in the wobbler mouse motor neuron disease.

Topics: Animals; Disease Models, Animal; Female; Glycine; Male; Mice; Mice, Neurologic Mutants; Motor Neurons; Nerve Degeneration; Receptors, Glycine; Spinal Cord; Strychnine

Mutations in inhibitory glycine receptor (GlyR) subunit genes are associated with neuromotor diseases in man and mouse. To use the potential of the mouse mutants as animal models of human disease, we altered GlyR levels in mutant mice and studied their phenotype. A transgene coding for the beta subunit of the rat GlyR was introduced into the genetic background of the spa mutation, which is characterized by low endogenous expression levels of the beta subunit and a dramatic neuromotor phenotype. The resulting transgenic mice expressed the beta subunit mRNA at intermediate levels, and their phenotype was rescued. This provides formal proof for the casual relationship between GlyR beta gene mutation and motor disease, and indicates that a low level of beta gene expression (25% of normal) is sufficient for proper functioning of glycinergic synapses.

Topics: Animals; Base Sequence; Brain; Brain Chemistry; Disease Models, Animal; Glycine Agents; In Situ Hybridization; Membranes; Mice; Mice, Transgenic; Molecular Sequence Data; Neuromuscular Diseases; Pedigree; Phenotype; Receptors, Glycine; RNA, Messenger; Spinal Cord; Strychnine

The effects of two non-competitive NMDA antagonists--MK-801 and ketamine--were studied in a model of generalized seizures elicited by s.c. injection of strychnine (2 or 3 mg/kg) in adult rats. The animals were observed in isolation for 30 min after strychnine administration. Pretreatment with MK-801 (0.5 or 2 mg/kg i.p.) suppressed the tonic, but not the clonic phase of generalized seizures following both doses of strychnine. A similar action of ketamine (20 or 40 mg/kg i.p.) was indicated but it did not attain statistical significance. Strychnine-induced lethality was not changed significantly. A comparison with antiepileptic drugs demonstrated that only phenobarbital (10-80 mg/kg i.p.) was clearly effective against strychnine-induced seizures; carbamazepine (25 or 50 mg/kg i.p.) and partly phenytoin (30 or 60 mg/kg i.p.) were able to suppress the incidence of the tonic phase. Primidone (40 or 80 mg/kg i.p.) as well as the benzodiazpines bretazenil (0.1 or 1 mg/kg i.p.) and midazolam (two lower doses of 0.5 and 1 mg/kg i.p.) were without significant effect. The 2 mg/kg dose of midazolam was partly effective. Only phenobarbital, carbamazepine and the highest dose of midazolam prevented strychnine-induced lethality.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dizocilpine Maleate; Ketamine; Male; Rats; Rats, Wistar; Seizures; Strychnine

In the anaesthetized rat, regions of the somatosensory cortex have been subpially isolated, leaving intact the cortical blood supply and the connectivity via the white matter. Application of penicillin or strychnine into layer IV of intact cortex resulted in enhancement of amplitude and prolongation of evoked potentials together with the appearance of spontaneous epileptiform discharges. Within a partially isolated region of cortex, spontaneous and evoked potentials occurred as in normal cortex, but application of convulsant drug resulted in no changes in evoked potentials and in no spontaneous spiking. With incisions for which the surface profile measured 0.9 x 0.9 mm, full-depth isolation resulted in interruption of the propensity for epilepsy, whereas half-depth incisions left epileptic manifestations unimpaired. With the surface profile measuring 0.5 x 0.5 mm, half-depth isolation was sufficient to prevent epileptic activity. Results from isolated regions of various geometries and sizes indicated that the ability of cortical neurones to generate epileptic activity depends on the amount of connectivity with surrounding cortex. The propensity of cortex to become epileptic is thus a mass action effect and the 'epileptic neuronal aggregate' is operationally different from anatomically based modular organizations such as thalamo-cortical or cortico-cortical columns. In the small barrel field of the somatosensory cortex, partial isolations that prevented the appearance of spontaneous epileptiform spiking contained many barrels, indicating that a single thalamo-cortical module contains insufficient inherent lateral connectivity to support epileptiform activity. Theoretical considerations indicated that the excitability of a neurone depends both on its monosynaptic connections with other neurones and on the connectivity of these latter with neurones further afield. The interruption of epileptiform activity by partial isolation could be mimicked by a computer model in which connectivity was mediated via short synaptic paths. The model exhibited self-sustaining synchronized neural activity that could be prevented by interruption solely of polysynaptic paths.

Topics: Animals; Computer Simulation; Disease Models, Animal; Electroencephalography; Epilepsies, Partial; Evoked Potentials, Somatosensory; Male; Microelectrodes; Neural Pathways; Penicillins; Rats; Rats, Sprague-Dawley; Somatosensory Cortex; Strychnine; Thalamus

Abnormal glycinergic neurotransmission has been implicated in the pathophysiology of DDT-induced myoclonus. To examine the role of glycine receptors in the DDT model, was measured [3H]strychnine receptor binding in brainstem and spinal cord in the rat after acute administration of DDT. The highest dose of DDT tested significantly increased both Bmax (20%) and Kd (57%) of glycine sites in spinal cord but not brainstem compared to vehicle-treated controls at 4 h. Lower DDT doses, which also induced myoclonus, had no significant effects on [3H]strychnine specific binding. In vitro, 10(-7) DDT did not displace [3H]strychnine binding in naive rat spinal cord, but higher doses could not be studied due to poor solubility of DDT under the assay conditions. These data suggest that only a maximal dose of DDT has significant though mixed effects on parameters of [3H]strychnine binding in spinal cord which are not correlated with the onset of myoclonus.

Topics: Animals; Brain Stem; DDT; Disease Models, Animal; Male; Myoclonus; Rats; Rats, Inbred Strains; Receptors, Glycine; Receptors, Neurotransmitter; Spinal Cord; Strychnine

In this paper we describe new data and review some studies on the mechanisms of alcohol-induced motor impairment in rats. Habituation to handling did not affect the naive behavioural differences between the alcohol sensitive and alcohol insensitive rat lines. Nor was there any effect on the differential sensitivities of the lines to the motor impairing and hypnotic effects of alcohol. Peripheral mechanisms may be involved in the differential behaviours of these lines, as the plasma corticosterone response was much weaker in the alcohol sensitive animals, suggesting a limited capacity to react to stress and alcohol. A similar blunted response to acute ethanol exposure was found in the uptake of the benzodiazepine antagonist [3H]Ro 15-1788 in vivo by the cerebellum of alcohol sensitive rats. The finding that these rat lines do not have any general differences in their brain inhibitory GABAergic receptors was extended to the spinal cord inhibitory glycinergic receptors, which showed only a modest line difference in their dissociation constant. The apparent localisation of the two main receptor differences (high-affinity [3H]muscimol binding and diazepam sensitivity of [3H]Ro 15-4513 binding) to the cerebellar granule layer suggests a genetic modification in the granule cells of alcohol-sensitive rats. In conclusion, our studies on acute intoxication by moderate alcohol doses show that several central nervous and peripheral factors may be involved in this behaviour. As many of these factors mitigate the effects of alcohol, alcohol antagonistic treatments should be aimed at activating and supporting multiple adaptive phenomena.

Topics: Adrenal Glands; Alcoholic Intoxication; Animals; Behavior, Animal; Benzodiazepinones; Brain; Convulsants; Cortisone; Disease Models, Animal; Drug Tolerance; Ethanol; Habituation, Psychophysiologic; Kidney; Male; Rats; Strychnine

Topics: Alcoholic Intoxication; Animals; Caffeine; Cats; Dextroamphetamine; Disease Models, Animal; Dogs; Ethanol; gamma-Aminobutyric Acid; Humans; Maleates; Naloxone; Pentylenetetrazole; Rabbits; Strychnine

Foci of increased excitability were created in acute experiments on rats by means of weak strychnine solutions working at independent regimens. The hyperactive excitability focus induced by means of concentrated strychnine solutions played the role of a determinant structure. The importance of the latter is in the fact that it determines the activity character of other epileptogenic foci, enhances their convulsive activity, unites them into a single functional complex and determines the behaviour of the complex as a whole. This complex can be destroyed by depression of the determinant focus activity. Switching off any dependent foci included into this complex fails to destroy that latter. Results of the investigations confirmed on the new model the general concept of the role played by the determinant structures in the brain activity.

Topics: Acute Disease; Animals; Cerebral Cortex; Disease Models, Animal; Electroencephalography; Epilepsies, Partial; Evoked Potentials; Rats; Seizures; Strychnine

Topics: Adolescent; Adult; Animals; Apnea; Bradycardia; Child; Disease Models, Animal; Electrocardiography; Female; Humans; Infant; Infant, Newborn; Magnesium; Magnesium Deficiency; Male; Pregnancy; Rats; Respiratory System; Strychnine; Sudden Infant Death

Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Brain Mapping; Cats; Caudate Nucleus; Cerebral Cortex; Disease Models, Animal; Electric Stimulation; Electroencephalography; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Hippocampus; Humans; Mesencephalon; Myoclonus; Neural Pathways; Pentylenetetrazole; Phenothiazines; Psychotic Disorders; Reticular Formation; Seizures; Spinal Cord; Strychnine

Topics: Animals; Anticonvulsants; Cats; Cerebral Cortex; Cobalt; Disease Models, Animal; Electroencephalography; Epilepsy; Estrogens, Conjugated (USP); Evaluation Studies as Topic; Penicillin G; Strychnine; Taurine

Topics: Action Potentials; Animals; Brain; Cats; Cell Membrane Permeability; Cold Temperature; Cortical Spreading Depression; Disease Models, Animal; Electric Stimulation; Electroencephalography; Electrophysiology; Epilepsy; Membrane Potentials; Metabolic Diseases; Models, Biological; Neurons; Neurons, Afferent; Neurophysiology; Ouabain; Penicillins; Pentylenetetrazole; Potassium; Receptors, Neurotransmitter; Sodium; Strychnine; Synaptic Membranes; Synaptic Vesicles