Amino acid neurotransmitter interactions in 'area tempestas': an epileptogenic trigger zone in the deep prepiriform cortex.
Explore the source record for details and available documents.
2-Amino-5-phosphonovalerate↗
Biomedical subjects
K Gale
Publications and source records attributed to K Gale.
Subcortical structures and pathways involved in convulsive seizure generation.
Convulsive seizures in animal models usually involve one or more of the following components: (1) limbic motor seizures, (2) explosive running-bouncing clonic seizures, and (3) tonic extensor seizures. Each of these components depends on specific and experimentally separable anatomic substrates. Limbic motor seizures depend on forebrain structures for their initiation and propagation, with the prepiriform, piriform, and entorhinal cortices playing a prominent role in conjunction with hippocampus, amygdala, substantia innominata, and mediodorsal thalamus. In contrast, seizures involving running-bouncing clonus or tonic extension depend on neural substrates in the brainstem and do not appear to require the integrity of the forebrain for their development or expression. The inferior colliculus is a region from which running-bouncing seizures can be elicited by chemical or electrical stimulation. Tonic extensor seizures depend on the integrity of the nucleus reticularis pontis oralis, but a specific locus responsible for triggering these seizures has yet to be identified. Under conditions of chronic or repeated seizure activity over prolonged time periods, seizures evoked from the hindbrain can recruit forebrain circuits; conversely, repeated stimulation of forebrain limbic circuits (e.g., kindling) can modify susceptibility to brainstem convulsions. These long-term alterations may result from changes in the activity of seizure "gating" pathways, which are circuits that influence seizure susceptibility by modulating the threshold for the initiation and/or propagation of the seizures. In general, these pathways are not part of any core seizure propagation pathway per se. In many cases, the gating substrates are relatively nonselective as to the type of seizure they can influence. In this category, the substantia nigra and its related circuits within the basal ganglia serve a prominent role. In addition, ascending noradrenergic projections have been implicated in the regulation of seizure threshold. Other gating mechanisms involve thalamic circuitry and pathways originating in cerebellum.
Animals↗
Regional changes in immediate early gene expression following focally-evoked limbic motor seizures.
Explore the source record for details and available documents.
Animals↗
GABA and epilepsy: basic concepts from preclinical research.
The role of gamma-aminobutyric acid (GABA) transmission in the control of convulsive epileptic seizures is considered from the perspective of the actions of drugs that augment GABA transmission in the brain. In particular, the effects of a directly acting GABAA receptor agonist, muscimol, is compared with the effects of a GABA-elevating agent, gamma-vinyl GABA (GVG, vigabatrin), in animal models of convulsive seizures. Evidence indicates that there are certain regions of the brain where enhanced GABA transmission is anticonvulsant; in other regions, blockade of GABA transmission exerts anticonvulsant actions. In addition, there are brain areas in which the effects of muscimol and GVG are distinct from one another, owing to a relatively low level of endogenous GABA transmission in those areas. The direct stimulation of postsynaptic GABA receptors (by direct receptor agonists) bypasses normal mechanisms of synaptic transmission and can evoke abnormal neurological symptoms, whereas the enhancement of presynaptic availability of GABA avoids these complications. GVG acts to boost presynaptic GABA stores, which can then be utilized physiologically; this may account for the relatively low incidence of CNS-related side effects with anticonvulsant doses of GVG. It is suggested that greater attention be focused on ways of enhancing endogenous GABA availability in future drug development for the control of seizure disorders.
Aminocaproates↗
Cocaine-induced turning behavior in rats with 6-hydroxydopamine lesions: effect of transplants of fetal substantia nigra.
Rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway were examined for cocaine-induced rotational behavior 1 month after receiving transplants of fetal substantia nigra grafted over the dopamine (DA)-deafferented striatum. The ipsiversive rotational behavior induced by cocaine was significantly reduced as compared with the pre-transplantation baseline, and occurred only during the first 2 min after injection. In all rats with transplants, cocaine induced strong contraversive rotation starting after 2-3 min and lasting for 10-15 min. This contraversive rotation, which was never observed in response to cocaine in rats prior to transplantation or in rats with sham transplants, was reproduced using nomifensine and GBR 12909, but not imipramine and fluoxetine. These results indicate that the transplant-reinnervated striatum responds selectively and in an exaggerated fashion to the actions of DA uptake inhibitors.
Amphetamine↗
Lack of proconvulsant action of GABA depletion in substantia nigra in several seizure models.
The effect of intranigral application of a gamma-aminobutyric acid (GABA) synthesis inhibitor, was examined in 3 different rat seizure models. Bilateral intranigral infusion of isoniazid (150 micrograms) did not potentiate the effect of subcutaneous administration of a threshold dose (1.5 mg/kg) of the GABA antagonist bicuculline. Similarly, following pretreatment with intranigral isoniazid, neither severity nor latency to onset of seizures elicited by systemic injection of kainic acid (9 mg/kg) were modified. In addition, convulsive seizures evoked by the focal injection of bicuculline methiodide (40 ng) in an epileptogenic site within the deep prepiriform cortex (area tempestas) were not potentiated by intranigral isoniazid. These results were in sharp contrast to the marked potentiating effect of intranigral isoniazid (150 or 85 micrograms) on seizures induced by systemic administration of a subconvulsant dose of pilocarpine (150 mg/kg). In addition, we attempted to evoke a proconvulsant action from striatum. The striatum, origin of GABAergic projections to substantia nigra, is a region in which application of GABA antagonists have been found to be anticonvulsant in several seizure models. We therefore examined the effect of bilateral intrastriatal infusion of the GABA agonist, muscimol (5 ng) on the convulsant effect of threshold doses of systemically administered bicuculline (1.5 mg/kg). As was true with intranigral isoniazid, no proconvulsant effect was found using intrastriatal muscimol. Our data demonstrate that whereas striatonigral GABA circuitry can be activated by exogenous treatments so as to produce anticonvulsant actions in most seizure models, suppression of this circuitry does not potentiate convulsant activity in many of the same models.
Animals↗
Transplants of fetal substantia nigra regulate glutamic acid decarboxylase gene expression in host striatal neurons.
Lesions of the dopaminergic innervation to the striatum result in increased activity of glutamic acid decarboxylase (GAD) and increased GAD mRNA in striatal GABAergic neurons. Here we show that solid transplants of dopamine-containing fetal mesencephalic tissue placed adjacent to the striatum can completely reverse the elevation of GAD mRNA in the striatum of adult rats with complete lesions of the nigrostriatal dopamine projections. The ability of the fetal transplants to re-establish control over gene expression in host target neurons indicates that there is a significant transneuronal influence of the transplanted neurons. Furthermore, striatal GAD mRNA levels appear to be a good marker of the functional impact of dopamine-producing transplants.
Animals↗
Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study.
The value of a short course of intensive immunosuppression with cyclophosphamide in stabilising chronic progressive multiple sclerosis (MS) was examined in a randomised single-blinded, placebo-controlled clinical trial. Forty two patients, from the Kaiser Permanente Medical Care Program, Northern California, were studied. Twenty two patients received a short course of cyclophosphamide in an outpatient neurology clinic until their leucocyte counts fell below 4000/mm3, and 20 patients received folic acid. Level of disability, impairment of functional systems, and performance of social roles were assessed before randomisation and reassessed 12, 18, and 24 months after therapy. In both the cyclophosphamide and folic acid groups, the mean level of disability increased from the baseline examination to the 12 month follow up examination (the primary endpoint) by 0.5 on Kurtzke's Expanded Disability Status Scale, indicating similar disease progression in the two groups. Although immunosuppression therapy can be safely administered to MS patients in an outpatient clinic, evidence of substantial benefits was not found.
Adult↗
Parallel increases in striatal glutamic acid decarboxylase activity and mRNA levels in rats with lesions of the nigrostriatal pathway.
Adult male rats were lesioned with 6-hydroxydopamine in order to destroy the nigrostriatal dopaminergic projections. In rats with such a lesion, we found a parallel increase in glutamic acid decarboxylase (GAD) activity and GAD mRNA in the striatum ipsilateral to the lesion at 4 weeks and 4 months after the lesion. These observations support the proposal that nigral dopaminergic neurons exert a tonic inhibitory control over the striatal GABAergic neurons. Our observations also suggest that the dopaminergic neurons can inhibit gene expression in striatal GABAergic neurons and that the enhanced striatal GAD activity following lesions of the dopaminergic projections is due to 'de novo' synthesis of the enzyme.
Animals↗
Evidence for a role of glycine in area tempestas for triggering convulsive seizures.
An epileptogenic region of the deep prepiriform cortex, area tempestas (AT), triggers convulsive seizures in response to the focal application of GABA antagonists, muscarinic agonists and excitatory amino acid agonists. In all cases, activation of N-methyl-D-aspartate (NMDA)-sensitive receptors in AT is required for triggering convulsions from this site. To determine whether glycine is involved in the activation of NMDA-sensitive receptors in AT, we evaluated the effects of 7-chlorokynurenic acid (7-CLKYN); kynurenic acid (KYN) and 3-amino-1-hydroxy-2-pyrrolidone (HA-966) on convulsions evoked by focal application of bicuculline methiodide (118 pmol) into AT. Significant anticonvulsant effects were obtained with 1.25 nmol of 7-CLKYN, 6.25 nmol of KYN and 60 nmol of HA-966 in AT. 7-CLKYN in AT also blocked the convulsant effects of carbachol (273 pmol) and kainic acid (117 pmol) injected into AT. When injected into the lateral ventricle, high doses (50-100 nmol) of 7-CLKYN were required in order to attenuate AT-evoked convulsions and these doses produced marked ataxia. In contrast, no ataxia was observed following 7-CLKYN application into AT at anticonvulsant doses. Our results implicate glycine antagonism as a mechanism for preventing convulsions triggered via NMDA receptor activation in AT and demonstrate that a different anatomical site of action is responsible for the motor impairment produced by glycine antagonism.
Animals↗
Selective stimulation of kainate but not quisqualate or NMDA receptors in substantia nigra evokes limbic motor seizures.
Bilateral microinjection of kainic acid (30-117 pmol) into the substantia nigra induced convulsive seizures resembling those elicited from limbic system structures. The convulsive seizures, which consisted of facial and forelimb clonus with rearing and falling, developed after a latency of more than 30 min and were preceded by wet dog shakes and non-convulsive seizure activity registered electroencephalographically. The convulsant effect of intranigral kainic acid was strictly dose-dependent (ED50 = 60 pmol) and anatomically site-specific. Stimulation of nigral neurons by focal application of agonists for NMDA or quisqualate receptors, or by focal application of the GABA antagonist, bicuculline, was without convulsant effects. The convulsant action of intranigral kainic acid was prevented by the focal application of kynurenic acid (100 nmol) but not by 2-amino-7-phosphonoheptanoic acid (AP-7) (25 nmol) or 7-chlorokynurenic acid (20 nmol), suggesting that the convulsant effect of kainic acid in the substantia nigra does not depend upon activation of NMDA receptors in this region.
Animals↗
Differential regulation of dopamine metabolism in solid fetal substantia nigra transplants and their terminals in the host striatum.
Explore the source record for details and available documents.
3,4-Dihydroxyphenylacetic Acid↗
Pharmacological evidence for feedback regulation of dopamine metabolism in solid fetal substantia nigra transplants.
Solid grafts of fetal ventral mesencephalic tissue transplanted into a cavity overlying a dopamine (DA)-deafferented striatum are known to survive, send terminals into the host striatum and release DA. Using this preparation, we have examined receptor-mediated feedback modulation of DA metabolism in the graft and, separately, in its terminals in the host striatum. For this purpose we administered the DA receptor antagonist, haloperidol, and the DA receptor agonist, apomorphine (APO), systemically, and calculated the dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios as an index of DA turnover in the graft itself as well as in the adjacent host striatum. A marked increase in dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios was seen after haloperidol treatment. This increase was found 1) within the solid transplant tissue itself as well as 2) within the transplant reinnervated regions of the host striatum. The net elevation in DA metabolites associated with the transplant terminals was less than that obtained in the intact striatum. APO significantly decreased the dihydroxyphenylacetic acid/DA and homovanillic acid/DA ratios in the transplant-innervated regions of the host striatum; this effect of APO was of a greater magnitude than that seen in intact controls. Within the solid transplant itself, APO caused slight but not significant decreases in DA metabolism. Our findings demonstrate that the transplanted DA neurons are subject to negative feedback regulation mediated via DA receptors and that transplant DA utilization is subject to both increases and decreases in response to drug-induced manipulations of DA receptors.
Amphetamine↗
The ribosomal genes of the mosquito, Aedes aegypti.
The characterisation of the ribosomal genes of the mosquito, Aedes aegypti, is described. Preliminary experiments using a cloned Drosophila ribosomal DNA (rDNA) repeat to probe Southern transfers of Ae. aegypti genomic DNA has indicated that the rDNA repeat of Ae. aegypti is 9.0 kb in length and that individual rDNA repeats exhibit a high degree of homogeneity with respect to length and the position of restriction enzyme recognition sites within the rDNA. The preliminary mapping data together with partial digestion experiments demonstrate that, as in all other higher eukaryotes, the rDNA repeats are arranged in a head-to-tail, tandemly repeating manner. The restriction mapping of cloned rDNA repeats confirmed the largely uniform length of the Ae. aegypti rDNA repeat and provided a more detailed physical map of the DNA. A restriction site polymorphism was detected in one clone (Aar9) which contains an extra HincII site, which is not present in three other clones studied (Aar1, Aar3, or Aar7). Transcription mapping has allowed the allocation of identities to the various restriction fragments and the approximate positioning of the transcription unit. The estimate of rDNA repeat copy number in Ae. aegypti (approximately 500 copies per haploid genome) is similar to the estimate reported for the closely related species, Aedes albopictus, of 430 copies per haploid genome. Ribosomal DNA thus comprises approximately 0.6% of the total Ae. aegypti genome. Analysis of the variation of the rDNA repeat unit both within individual mosquitoes and between strains of Ae. aegypti, has severed to confirm the remarkable homogeneity of the rDNA repeat unit in this insect.
Aedes↗
Effect of dopaminergic denervation and transplant-derived reinnervation on a marker of striatal GABAergic function.
Solid grafts of dopamine-containing fetal mesencephalon were placed adjacent to the striatum of rats with 6-hydroxydopamine lesions of ascending dopaminergic projections. These grafts resulted in a significant, although partial, reversal of the lesion-induced increase in striatal glutamic acid decarboxylase (GAD) when measured 3-4 months after the lesion. These results suggest that the grafted neurons can partly restore inhibitory control over striatal GABA neurons. In the same rats, the grafts partially reversed apomorphine-induced turning although amphetamine-induced turning was nearly abolished. It is likely that both apomorphine-induced behavior and striatal GAD activity reflect the sustained chronic influence of the graft on target neurons in striatum.
Amphetamine↗
Anticonvulsant action of GABA receptor blockade in the nigrotectal target region.
Anticonvulsant activity in a wide variety of experimental seizure models can be obtained by enhancing gamma-aminobutyric acid (GABA) transmission within the pars reticulata of substantia nigra. Recent evidence indicates that the nigrotectal projection may mediate some of the nigra-evoked anticonvulsant effects. The action of GABA within substantia nigra would, by inhibiting the GABAergic nigrotectal projections, cause disinhibition of target neurons in the superior colliculus. This hypothesis predicts that administration of GABA antagonists into the region of the superior colliculus that receives nigrotectal terminals should also have anticonvulsant actions. We therefore examined the effects of injections of bicuculline methiodide aimed at rostrolateral superior colliculus upon maximal electroshock convulsions. The incidence and duration of tonic hindlimb extension was substantially reduced by these injections, a result consistent with the hypothesis that the nigrotectal GABAergic pathway may mediate the anticonvulsant actions of GABA transmission in the substantia nigra.
Animals↗
Seizures evoked from area tempestas are subject to control by GABA and glutamate receptors in substantia nigra.
The functional relationship between the substantia nigra (SN) and the area tempestas (AT), an epileptogenic site in the deep prepiriform cortex, was investigated. Stimulation of GABA receptors in SN with muscimol, or blockade of nigral excitatory amino acid receptors with 2-aminophosphonoheptanoic acid (AP7), protected against convulsions evoked by the unilateral focal injection of bicuculline in the AT. The protective effects were obtained only with bilateral nigral injections; unilateral manipulations were without anticonvulsant effect. Bilateral intranigral morphine did not exert an anticonvulsant effect against convulsions evoked from the AT, although this treatment induced stereotyped sniffing and gnawing behavior similar to that evoked by intranigral muscimol and AP7. The data indicate that seizures evoked from the AT of one hemisphere are susceptible to suppression by inhibition in the SN, but only when the inhibition occurs in the SN of both hemispheres. This suggests that the seizure suppressant action evoked from the SN is exerted during the course of the propagation of the seizure, once it has spread bilaterally.
2-Amino-5-phosphonovalerate↗
GABA in epilepsy: the pharmacologic basis.
GABA transmission plays a key role in controlling seizure activity. The precise nature of its effect depends on the particular location in the brain and the pathway involved. Animal studies have helped to define specific brain regions such as the substantia nigra and area tempestas that are critical in controlling seizure activity. Antiepileptic drugs such as vigabatrin [gamma vinyl GABA (GVG)], a drug rationally developed to treat resistant epilepsy, can enhance GABA transmission in these regions and may thereby afford seizure protection.
Aminocaproates↗