Effect of chronic protein malnutrition on experimentally induced seizures in the rat

Rats malnourished at various stages of development by feeding them a low protein diet were tested at adulthood for susceptibility to motor seizures induced by pentylenetetrazol (PTZ), electroconvulsive shock (ECS), or amygdaloid kindling. Compared to control animals, malnourished rats were more sensitive to ECS, less susceptible to kindled motor seizures, and did not differ in sensitivity to PTZ. We conclude that malnutrition during development does not exert a uniform effect on all classes of seizure phenomena.     

Substantia nigra and pentylenetetrazol threshold in rats: correlation with striatal dopamine metabolism.

The time course of the metrazol threshold in rats with electrolytic lesions of the substantia nigra presents variations inversely proportional to the changes in dopamine and its metabolites in the neostriatum. Thus initially dopamine is increased and the threshold lowered, then a progressive decrease in dopamine and its metabolite is accompanied by a progressive increase in metrazol threshold. This supports the hypothesis that changes in functional activity of the caudate nucleus are reflected in variations of the brain's susceptibility to generalized seizures. When cobalt chloride was injected into the substantia nigra there were biochemical changes in the neostriatum similar to those observed with electrolytic lesions, but the pentylenetetrazol threshold steadily decreased. This is probably due to the fact that cobalt induces a lesion which changes in extent with time to involve adjacent brain stem nuclei sensitive to its epileptogenic action.     

Effect of different convulsant drugs on some seizure parameters in morphine-dependent mice

An investigation was made of the effect of morphine dependence on the characteristics of seizures induced in mice by convulsant drugs with differing mechanisms of action. Morphine dependence was induced in 90-day-old mice (weighing 29 to 32 g) by a 6-day schedule of twice daily i.p. injections of increasing doses of morphine (5, 32.5, 58, 82.5, 100, and 135 mg kg-1). Thirty minutes after the last morphine administration, convulsant drugs (4-aminopyridine 8 mg kg-1, pentylenetetrazol 50 mg kg-1, bicuculline 2.5 mg kg-1, strychnine 2.0 mg kg-1, and beta-mercaptopropionic acid 50 mg kg-1) were injected. 4-Aminopyridine (4-AP) and pentylenetetrazol (PTZ) increased both the number of animals with convulsions and death and in the case of 4-AP the period of convulsion latency was also increased. Naloxone at 1.0 mg kg-1 blocked the 4-AP effects, indicating that this action was mediated through an opioid receptor. Strychnine and beta-mercaptopropionic acid had an effect opposite 4-AP and PTZ in the number of animals with convulsions and death. On the other hand bicuculline had an effect more like 4-AP and PTZ than other inhibitory synapse-blocking drugs. We conclude that chronic morphine treatment modified the response of convulsant drugs depending on their mechanisms of action.     

Cobalt injections into the substantia nigra of the rat: effects on behavior and dopamine metabolism in the striatum

Small amounts of cobalt unilaterally injected into the substantia nigra of rats caused a strong, spontaneous contralateral turning which was suppressed by haloperidol. One to 2 days after intranigral cobalt microinjection, d-amphetamine decreased the intensity of the contralateral turning; 5 days after cobalt application, d-amphetamine changed the direction of the turning to the ipsilateral side. Intranigral cobalt microinjection initially caused a significant increase in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the ipsilateral striatum. Thereafter, dopamine and its metabolites declined progressively to values significantly below control values. Similar biochemical changes in the striatum were also seen after partial electrolytic lesions of the substantia nigra. However, such lesions produced only mild contralateral turning. Frontal hemisection did not result in any increase of striatal metabolite values, and produced mild ipsilateral turning. Thus, there was no parallelism between the intensity and time course of the turning behavior induced by the different techniques and the changes in dopamine metabolism in the striatum. Within the cobalt-injected substantia nigra, γ-aminobutyric acid (GABA) and glutamic acid decarboxylase were decreased to less than 60% of the contralateral control values. The possibility is considered that the depression of a GABA-mediated inhibitory influence on the nigrostriatal or mesolimbic dopamine neurons may play a role in the cobalt-induced contralateral turning and altered striatal dopamine metabolism.     

Acute effects of pyridoxine hydrochloride on monomethylhydrazine seizure latency and amygdaloid kindled seizure thresholds in cats

A number of similarities between the acute systemic convulsant, monomethylhydrazine (MMH), and the chronic focal epilepsy model, kindling, were recently identified. Those findings suggested a common neurophysiologic basis for the two experimental epilepsy models, which the present experiment further explored. Pyridoxine, which can facilitate neurohumoral transmitters thought to be deficient in both models, has been shown to prevent MMH seizures, but its effect on kindling is unknown. This report documented the effects of this substance on generalized tonic-clonic convulsions with both models. Eight, fully kindled (basolateral amygdala) cats underwent and A₁B₁A₂ design in which kindled seizure thresholds and MMH seizure latencies were examined sequentially during an initial, untreated baseline condition (A₁), after 20 mg/kg injections of pyridoxine (B₁), and during a final, untreated baseline condition (A₂). The MMH latencies were calculated in minutes postinjection and kindling thresholds represented the minimum level of stimulation (μA) necessary to elicit stage 6 convulsions. Pyridoxine completely blocked convulsions in seven of eight animals exposed to MMH. In addition, this substance yielded modest but statistically significant elevations in kindled seizure thresholds compared with initial and final baselines. These findings extend previous evidence of pyridoxine's anticonvulsant effect on MMH to kindling. Differences in the potency of effects suggested that the precise mechanism involved in MMH-induced and kindled convulsions may not be the same. Nevertheless, the fact that pyridoxine afforded some protection against seizures with both procedures provides some support for the initial hypothesis that similar neurochemical abnormalities may underlie the two experimental models.     

无抽搐电休克治疗对抑郁症患者γ-氨基丁酸的影响

目的 探讨无抽搐电休克治疗（MECT）对抑郁症患者γ-氨基丁酸（GABA）的影响。方法 入组45例抑郁症患者,接受12次MECT治疗,采用汉密尔顿抑郁量表（HAMD）评估疗效;采用ET-脑超慢涨落分析仪测定MECT治疗前后患者的GABA的相对功率。结果 经过12次MECT治疗,患者HAMD评分由治疗前的（28．87±6．01）分降低为（11．64±4．04）分,GABA相对功率由（14．21±7．93）升高为（29．71±8．46）,差异均有统计学意义（t值分别为-23．540,14．601;P〈0．01）;GABA递质相对功率的变化与抑郁症患者临床症状的改善呈正相关（r=0．61,P〈0．01）;GABA递质相对功率的变化能预测抑郁症临床症状变化的35．3％。结论 MECT可以使抑郁症患者异常降低的GABA的递质相对功率增高,GABA可能参与了抑郁症的发病机制。     

Effects of noradrenaline and dopamine injected into the supraoptic nucleus on urine flow rate in hydrated rats.

Monoaminergic agents were microinjected directly into the supraoptic nucleus in hydrated rats and the effects on urine flow rate were examined. Noradrenaline, adrenaline, and 5-hydroxytryptamine, transmitters of afferent monoaminergic fibers from the brain stem, caused a biphasic response: initial brief diuresis and subsequent antidiuresis with a rapid fall in the rate of urine flow. Dopamine, which is contained in intrahypothalamic monoaminergic fibers ending in the supraoptic nucleus, elicited a gradual antidiuretic response, milder than that caused by noradrenaline. Phenoxybenzamine, an α-adrenergic blocker, administered to the supraoptic nucleus prior to the injection of noradrenaline inhibited the antidiuretic response to noradrenaline, but enhanced the diuretic response. Dichlorisoproterenol, a β-blocker, prevented the diuretic response to noradrenaline, but not the antidiuretic response. We discuss the possibilities that α-adrenergic receptors of supraoptic neurons mediate the release stimuli and β-adrenergic receptors mediate the inhibitory stimuli for vasopressin release.     

Effects of restraint on electroencephalographic variables and monomethylhydrazine-induced seizures in the cat

The toxic derivative of hydrazine, monomethylhydrazine, at a dosage of 10 mg/kg is a potent convulsant, producing tonic-clonic seizures in the cat. In this study the effects of enforced restraint on susceptibility to MMH-induced seizures was examined in naive animals and in cats prepared neurosurgically with indwelling polygraphic recording electrodes. Using a counterbalanced design, latency to seizure following the intraperitoneal administration of the drug (10 mg/kg) was measured twice in all animals, under restraint and in freely moving conditions. Susceptibility to seizures was significantly decreased under the condition of restraint. Additionally, polygraphic recordings showed that restraint was accompanied by an increased incidence of “synchronous” EEG patterns. These results were not explained by metabolic variables, duration of intertrial interval, or changes in weight. The relationship between observed polygraphic patterns and seizure response is discussed in terms of the physiological alterations attendant upon restraint.     

Effects of progesterone on glutamate transporter 2 and gamma-aminobutyric acid transporter 1 expression in the developing rat brain after recurrent seizures

Seizures were induced by flurothyl inhalation. Rats were intramuscularly treated with progesterone after each seizure. Results demonstrated that glutamate transporter 2 and γ-aminobutyric acid transporter 1 expression levels were significantly increased in the cerebral cortex and hippocampus of the developing rat brain following recurrent seizures. After progesterone treatment, glutamate transporter 2 protein expression was upregulated, but γ-aminobutyric acid transporter 1 levels decreased. These results suggest that glutamate transporter 2 and γ-aminobutyric acid transporter 1 are involved in the pathological processes of epilepsy. Progesterone can help maintain a balance between excitatory and inhibitory systems by modulating the amino acid transporter system, and protect the developing brain after recurrent seizures.     

Enhancement of basal and pentylenetetrazol (PTZ)-stimulated dopamine release in the brain of freely moving rats by PTZ-induced kindling

The effects of pentylenetetrazol (PTZ)-induced kindling on the activity of mesocortical, mesoaccumbens, and nigrostriatal dopaminergic neurons was investigated with the transversal microdialysis technique in freely moving rats. Four days after the last chronic administration of PTZ, the basal extracellular concentrations of dopamine in the prefrontal cortex, nucleus accumbens, and striatum of kindled rats were significantly increased (+76, +36, +49%, respectively) relative to those of animals chronically treated with saline. Moreover, dopamine output was markedly more sensitive to the effect of a challenge injection of PTZ (20 mg/kg ip) in the prefrontal cortex (+93 vs. +50%, relative to basal values), the nucleus accumbens (+36 vs. +4%), and the striatum (+50 vs. +35%) of kindled rats relative to that in the control animals. Because kindled rats and their controls are habituated to handling, the neurochemical mechanisms that underlie the effects of chemical kindling on the sensitivity of dopaminergic neurons to PTZ were investigated by comparing the effects of an acute administration of PTZ (20 mg/kg ip) between naive and handling-habituated animals. The sensitivity of dopamine output to PTZ in naive rats was markedly greater than that in handling-habituated animals for the prefrontal cortex (+83 vs. +50%) and nucleus accumbens (+35 vs. +4%), but not for the striatum (+35 vs. +32%). These results indicate that PTZ kindling enhances the basal activity and the sensitivity to PTZ of dopamine neurons in rat brain and suggest that mesocortical, mesoaccumbens, and nigrostriatal dopaminergic neurons contribute to the central alterations associated with experimental epilepsy. Synapse 26:351–358, 1997. © 1997 Wiley-Liss Inc.     

Interactions of antiepileptic drugs on adenylate cyclase and phosphodiesterases in rat and mouse cerebrum.

Five anticonvulsant agents were tested in broken cellular preparations of mouse and rat cerebral cortex for their ability to modify either adenylate cyclase or three forms of cyclic AMP-dependent phosphodiesterase. In both species only carbamazepine inhibited the stimulation of cortical adenylate cyclase by catecholamines (norepinephrine and/or dopamine). Two benzodiazepines, diazepam and clonazepam, enhanced basal and catecholamine-stimulated adenylate cyclase. The latter observations were expecially prominent when phosphodiesterase inhibitors were removed from the preparations. In all instances diazepam was more potent than clonazepam and additionally exerted a more pronounced blockade of high and low K_m phosphodiesterase (mouse cerebrum) and the Ca²⁺-dependent, heatstable, activated phosphodiesterase in the rat cortex. Of the other anticonvulsants evaluated (carbamazepine, phenytoin, and phenobarbital), only phenobarbital inhibited phosphodiesterase, i.e., the low K_m form.     

Decreased sensitivity of neurons in the basolateral amygdala to dopamine and noradrenaline iontophoresis after a kindling stimulus

The depressant effects of iontophoretically applied dopamine and noradrenaline on glutamate-induced neuronal firing in the amygdaloid complex of cats were significantly reduced 1 and 2 h after induction of a local epileptiform afterdischarge of the kind used in kindling. Neuronal excitation by glutamate and depression by GABA were not significantly changed. This suggests that kindling is associated with a reduction of the inhibitory effects of endogenous catecholamines.     

Effects of adenosine and related compounds on an inhibitory process in rat cerebral cortex

Inhibition of neurons in the rat cerebral cortex was evoked by local cortical stimulation. Adenosine, AMP, and ATP applied by microiontophoresis produced no change of this inhibition. Theophylline and aminophylline, administered intravenously or iontophoretically, blocked the depression of neuronal firing by adenosine, but did not themselves affect the duration of inhibition. Dipyridamole and hexobendine, at iontophoretic doses which potentiated responses to adenosine, produced some reduction of inhibitory duration. We conclude that endogenous purines do not normally contribute to local cortical inhibition, but that their accumulation can inhibit this phenomenon, possibly presynaptically.     

Interaction of norepinephrine with cerebrocortical activity evoked by stimulation of somatosensory afferent pathways in the rat

This study investigated the action of norepinephrine (NE) on transmission of information through somatosensory cortical neuronal circuits. In the forelimb region of rat somatosensory cortex (SI), single-unit responses to natural stimulation (foot tap) of afferent pathways were recorded before, during, and after microiontophoretic application of NE. Actions of NE were quantitatively assessed by computer-based analysis of poststimulus time histograms. Overall, NE was found to enhance both excitatory and inhibitory responses generated by the afferent synaptic input. In 78% of the cells tested, low doses of NE differentially suppressed background discharge more than stimulus-bound excitation such that the signal to noise ratio was enhanced approximately twofold. Evoked spiking in 12 cells was quantitatively increased above control values during NE administration. In 82% of the units examined, NE augmented stimulus-bound inhibition and postexcitatory suppression of activity. Potentiation of inhibition was observed in 5 cells at doses of NE which caused little or no depression of spontaneous activity. These observed effects on neuronal responsiveness to afferent synaptic input often persisted for several minutes after termination of NE iontophoresis. Such modulatory actions of NE were demonstrated for cells situated throughout the vertical extent of the cortex. These results suggest that low amounts of NE may facilitate transfer of afferent information within the cerebral cortical circuitry and are consistent with a modulatory role rather than a specific information transfer function for NE.     

Effect of contraceptive steroids on gamma-aminobutyric acid metabolism and pyridoxal kinase activity in rat brain

Adult female albino rats were administered oral contraceptive steroids daily for 3 months and γ-aminobutyric acid (GABA) content as well as the GABA metabolizing enzyme(s) activity were assayed. GABA content of the brain was found to be elevated in both estrogenic and progestogenic hormone-treated animals. However, no significant change was observed either in glutamic acid decarboxylase (EC 4.1.1.15) activity or in γ-aminobutyric acid transminase (EC 2.6.1.19) activity of brain tissue in hormone-treated animals. Interestingly, parallel to the increase of GABA content, a concomitant elevation of pyridoxal kinase (PL-kinase) (EC 2.7.1.35) activity was observed. It seems that the increase in the GABA concentration by the contraceptive steroids might have been mediated through an elevated pyridoxal kinase activity of the brain. The possible mechanism and interrelationship between the metabolic activities is discussed.     

A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an in vitro electrophysiological study

Increased neurotransmission within the mesolimbic dopamine system is considered an essential component for the rewarding and dependence producing properties of nicotine. Nicotinic acetylcholine receptors on dopamine containing neurons in the ventral tegmental area are thought to be a prime target for nicotine’s stimulatory effects. However, there is no evidence regarding the actions of nicotine on ventral tegmental GABAergic interneurons which play an important modulatory role in mesolimbic dopamine neuronal excitability. In the present study we sought to characterize the effects of nicotine on the activity of both dopamine and non-dopamine neurons in the juvenile rat ventral tegmentum. Extracellular recording techniques in rat brain slices and two methods of drug perfusion were used. Nicotine was found to markedly increase the firing rate of both groups, although the dopamine neuronal response pattern was considerably different and more vigorous than that in the non-dopamine neurons. The nicotine-induced excitations were also reversed by mecamylamine. Furthermore, desensitization to nicotine’s stimulatory effects occurred in both neuronal populations, although non-dopamine neurons appeared to desensitize to a greater degree. In fact, the desensitization accompanying sequential uninterrupted applications of nicotine appears to occur at concentrations below that described to produce receptor activation. The low nM concentrations of nicotine used in the present study are comparable to plasma levels of nicotine found after smoking a cigarette or even with passive inhalation of tobacco smoke. Thus, the present results not only confirm that nicotine stimulates the firing rate of ventral tegmental area dopamine neurons, but also that GABAergic neurons may be an important target for nicotine’s central nervous system effects. The less robust response in the non-dopamine presumptive GABAergic population and their more pronounced desensitization could lead to disinhibition of dopamine neurons thereby facilitating a more sustained increase in the response of mesolimbic dopamine neurons to nicotine.     

Effects of repeated minimal electroshock seizures on NGF,BDNF and FGF-2 protein in the rat brain during postnatal development

Repeated brief seizures, such as those induced by electroconvulsive therapy (ECT), markedly elevate neurotrophic factor levels in the adult rat brain, but it is not known whether a similar response to seizures occurs in immature animals. To address this question, we evoked brief seizures with electroconvulsive shock (ECS) in rat pups at different stages of postnatal development and examined basic fibroblast growth factor (FGF-2), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) proteins in selected brain regions in which these trophic factors are known to increase in the adult rat following ECS-induced seizures.     

Effects of pentylenetetrazol-induced seizures on dopamine and norepinephrine levels and on glucose utilization in various brain regions of the developing rat

Levels of dopamine and norepinephrine were measured in seven brain areas after 60 min of sustained seizure activity induced by intraperitoneal repetitive timed administrations of pentylenetetrazol in rats at 10, 14, 17 and 21 days of postnatal life. The tissue levels of norepinephrine were markedly reduced in the majority of brain structures, except for striatum at 10 and 14 days. Conversely, dopamine concentrations increased in many areas and at various ages, except in cerebral cortex at 10 and 14 days and in midbrain between 14 and 21 days. PTZ seizures induced marked increases over control levels in the rates of glucose utilization, measured by the quantitative autoradiographic [14C]2-deoxyglucose method, in all dopamine- and norepinephrine-innervated areas studied at 10 and 14 days, except in cerebellar cortex at both ages and in frontal cortex and anteroventral thalamus at 14 days. At 17 and 21 days, glucose utilization remained increased over control levels in some areas, mainly in catecholaminergic cell groupings such as substantia nigra, ventral tegmental area and locus coeruleus, but was significantly reduced in cortex, caudate nucleus and thalamus, and similar to control rates in other regions. The present results suggest that pentylenetetrazol-induced seizures lead to a simultaneous increase in functional activity of norepinephrine neurons and an inhibition of dopaminergic-mediated neurons. They also confirm the maturation of connections, of metabolic activity and of neurotransmitter interaction within the brain, occurring mainly during the third week of postnatal life, paralleled by an increased selective vulnerability of some regions to this kind of insult.     

Effect of single and repeated doses of acrylamide and bis-acrylamide on glutathione-S-transferase and dopamine receptors in rat brain

The effect of single and repeated doses of acrylamide (a neurotoxin) and N,N'-methylene-bis-acrylamide (a non-neurotoxic analogue of acrylamide) on glutathione (GSH), glutathione-S-transferase (GST) and dopamine receptors has been studied in rat brain. In vitro, both acrylamide and bis-acrylamide decreased brain GSH content in a concentration-dependent manner. At equimillimolar concentrations (2-10 mM) bis-acrylamide was more effective than acrylamide in lowering GSH levels. In vitro, GST activity was also inhibited as a function of acrylamide concentration. A single dose of either acrylamide or bis-acrylamide depleted GSH content of rat brain in a concentration-dependent manner without inhibiting GST activity. Repeated administration of either acrylamide or bis-acrylamide in rats (50 mg/kg X 10 days) decreased GSH content in the brain but GST activity was inhibited only by acrylamide and not by bis-acrylamide. Single or repeated injections of acrylamide but not of bis-acrylamide increased brain dopamine receptors ([3H]spiroperidol binding) in a concentration-dependent manner.     

Effects of dynorphin 1–13 on opiate binding and dopamine and GABA uptake in stroked cat brain

We previously reported that the opioid peptide dynorphin1-13 improves survival chances in stroked cats. Some evidence also suggests that changes in dopamine and gamma-aminobutyric acid (GABA) uptake may be associated with stroke. In the present study, therefore, we determined binding of the opiate [3H]ethylketocyclazocine (EKC), as well as dopamine and GABA uptake in various brain regions of control, stroked and dynorphin1-13-treated stroked cats. Cats were stroked by middle cerebral artery occlusion. In the EKC binding study, the Kd of the high-affinity site of the occluded cortex was significantly increased, relative to that of both the unoccluded side and control cortex. Dynorphin1-13 treatment reversed this effect, lowering the Kd to control level. In the dopamine uptake study, the Km was decreased and Vmax was increased significantly in unoccluded cortex, compared with that in the occluded cortex or in control cortex. Again, dynorphin1-13 reversed these effects, raising the Km and lowering the Vmax. However, the Km of occluded cortex was also increased so that it became significantly higher than that of control cortex. The Km of unoccluded subcortex in stroked cats treated with dynorphin1-13 was significantly reduced compared with control. In the GABA uptake study, there was no significant change in any parameter. The change in opioid binding observed here and its reversal by dynorphin1-13 are consistent with the notion that the peptide's beneficial effect on stroke is mediated through opiate receptors. Since opioid systems in the brain are known to have association with dopaminergic ones, the change in dopamine uptake could also be the result of an opioid effect.