Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures: effects of acute carbamazepine

This study addressed the anticonvulsant effect of carbamazepine (CBZ) in the guinea-pig kindling model to further test this model for the screening of anticonvulsant drugs. We analysed plasma concentrations of CBZ at various time intervals after intraperitoneal injection of either 10, 25 or 40 mg/kg CBZ. Behavioural toxicity was assessed at 0.5 h postinjection using quantitative locomotor tests, as well as scores on a sedation/muscle relaxation rating index. The anticonvulsant efficacy of CBZ was evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD), and behavioural seizure severity at three phases of kindling: non-kindled, kindling acquisition (early and late) and kindled (50+ ADs). ADD and seizure severity were also measured in response to both threshold and suprathreshold kindling stimulation. Plasma levels of CBZ were within, or higher, than the human therapeutic range at the time of behavioural testing and kindling. CBZ exerted slight effects in guinea-pigs on the sedation rating index but not the behavioural tests. CBZ increased ADT and reduced ADD and seizure severity throughout all phases of kindling, indicating that the guinea-pig model correctly predicts CBZ's anticonvulsant effect. CBZ in the guinea-pig kindling model produced consistent anticonvulsant activity that did not appear to be dependent on stimulation intensity.     

Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures: effects of acute phenytoin

This study addressed some of the controversial issues surrounding the anticonvulsant effect of phenytoin, and the predictive validity of the guinea-pig kindling model for the screening of anticonvulsant drugs. Following an intraperitoneal injection of either 50 or 75 mg/kg phenytoin, we analysed plasma concentrations of phenytoin at various time intervals. Behavioural toxicity was assessed at 0.5 h postinjection using quantitative locomotor tests, as well as scores on a sedation/muscle relaxation rating index. The anticonvulsant efficacy of phenytoin was evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD) and behavioural seizure severity at three phases of kindling: non-kindled, kindling acquisition (early and late) and kindled (50+ ADs). ADD and seizure severity were also measured in response to both threshold and suprathreshold kindling stimulation. Plasma levels of phenytoin corresponded to the human therapeutic range at the time of behavioural testing and kindling. Phenytoin did not exert significant adverse effects in guinea-pigs on both the behavioural tests and rating index. Phenytoin increased ADT in non-kindled and kindled guinea-pigs and effectively reduced ADD and seizure severity, indicating that the guinea-pig model correctly predicted phenytoin's anticonvulsant effect. Phenytoin produced reliable anticonvulsant activity in the guinea-pig at threshold stimulation but a somewhat reduced efficacy on seizure severity at suprathreshold stimulation intensities. Kindling in the guinea-pig is a valid model of human partial seizures.     

Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures: effects of repeated administration

This study addressed the anticonvulsant effects of repeated administration of phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide in kindled guinea-pigs in order to further substantiate this novel model of partial seizures for the screening of future anticonvulsant drugs. Behavioral toxic effects were assessed at 30 min following drug administration using scores on a sedation/muscle relaxation rating index. In response to suprathreshold stimulation, the anticonvulsant efficacy of the drugs were evaluated from measurements of afterdischarge duration (ADD) and behavioral seizure severity (SS) during a repeated drug treatment schedule in kindled guinea-pigs. All drugs exerted slight to moderate sedative effects in guinea-pigs on our rating index. We found that phenytoin, carbamazepine, and phenobarbital exhibited effective anticonvulsant properties in kindled guinea-pigs by reducing both ADD and SS. We found that valproate consistently reduced ADD throughout the treatment schedule but failed to significantly reduce SS. Lastly, ethosuximide failed to exhibit effective anticonvulsant properties. Our results indicate that the guinea-pig kindling model correctly predicted the actions of these common anticonvulsant drugs in the treatment of partial seizures. Guinea-pig amygdala kindling appears to serve as a useful and valid model for partial epilepsy.     

Activity-stress ulcer in the rat,hamster, gerbil and guinea pig

Rats, hamsters, gerbils and guinea pigs were housed in activity cages and fed 1 hr each day. By the end of the 21-day experimental period, 86, 100, 70 and 70% of rats, hamsters, gerbils and guinea pigs had developed lesions in the glandular stomach. This procedure was thus capable of producing lesions in species other than the rat, thereby increasing the value of the procedure as an ulcerogenic technique.     

Autoradiographic quantitation and anatomical mapping of GTP sensitive-galanin receptors in the guinea pig central nervous system

Galanin is a 29-amino acid peptide widely distributed in the mammalian central nervous system. Galanin receptors in the guinea pig brain were visualized using [¹²⁵I]galanin by in vitro receptor quantitative autoradiography. Scatchard analysis of [¹²⁵I]galanin binding to slide-mounted sections revealed saturable binding to a single class of high affinity receptors with a K_D of approximately 1 nM. Specific [¹²⁵I]galanin binding sites were detected in a large number of brain areas (concentration range: from non detectable to 99.32 fmol/mg of tissular proteins). The anatomical mapping revealed high densities essentially in the telencephalon (e.g. lateral septal nuclei, amygdala, hippocampal dentate gyrus) and the diencephalon (e.g. the anterodorsal and medial habenular thalamic nuclei, the paraventricular, dorsomedian and median mammillary hypothalamic nuclei, the posterior lobe of the pituitary). Addition of Mg²⁺ and GTP increased binding in some areas such as the zona incerta, the median eminence and the arcuate nucleus, and decreased it in other areas such as the amygdala, the hippocampus and the mammillary nuclei. This regional heterogeneity in the effect of Mg²⁺ and GTP can be interpreted as: (1) different rates of galanin receptor occupancy by endogenous peptide; (2) a differential coupling of GTP binding proteins to galanin receptors in the brain structures; and (3) a different nature of receptors. At any rate, this study provides evidence for a specific GTP-sensitive galanin receptor in guinea pig brain with an extensive distribution suggesting various physiological implications. Comparison with studies performed in several mammals shows that the overall distribution of galanin receptors is well preserved among species. These data suggest that galanin may posses similar functional properties in the different species tested so far. Nevertheless, very distinct differences were found in some areas like the cortex, the hippocampus and the pituitary.     

Statistical analysis of long-term potentiation of large excitatory postsynaptic potentials recorded in guinea pig hippocampal slices: binomial model

Summary Excitatory postsynaptic potentials (EPSPs) were recorded in guinea pig hippocampal slices (area CA1) from 15 neurones after stimulation of stratum radiatum (str. rad.) and stratum oriens. EPSP amplitudes increased in 8 neurones (10 post-tetanic regions) recorded 15 to 45 min after tetanic stimulation of str. rad. The increase was considered to represent long-term potentiation (LTP). Quantal analysis was performed by two methods assuming binomial statistics: the histogram method using deconvolution of noise and the variance method. According to both methods, LTP was associated with an increase in mean quantal content (m) which correlated with LTP magnitude. A statistically significant increase in quantal size (v) was found only by the histogram method and the increase was not correlated with LTP magnitude. A separate analysis of EPSPs with small LTP magnitude demonstrated that with the histogram method only v was increased but not m. A smaller increase in m for the pooled data of both methods did not correlate with LTP magnitude for this EPSP subset. The increase in m for the whole EPSP set corresponds to previous results on the quantal analysis of LTP in in vivo preparations and favours a presynaptic location of major mechanisms underlying LTP maintenance. The increase in v indicates the existence of another mechanism responsible for the maintenance of a small part of LTP. This mechanism might involve either pre- or postsynaptic changes or both.     

Delineation of the striate cortex,and the striate-peristriate projections in the guinea pig

Summary The size and position of the guinea pig area 17 were determined by transneuronal labeling after intraocular injections of ³H-proline or WGA-HRP. Area 17 occupies a large region of the occipital cortex located between two shallow fissures, the fissura sagittalis lateralis and the lateral groove. Area 17 extends for about 6 mm rostral from the occipital pole of the hemisphere, and encroaches occipitally for more than 1 mm upon the ventromedial surface of the hemisphere; the lateral width is up to 4.5 mm. Single injections of WGA-HRP into area 17 produced eight patches of transported tracer which formed the same general pattern in the peristriate cortex, regardless of the position of the injection within the visual field representation of area 17. Two of these patches were found in anteromedial peristriate cortex; three patches were distributed anterolateral and lateral of area 17; and three patches were located in posterolateral peristriate cortex. For several reasons, each of these patches was interpreted as representing a single striate projection onto a separate peristriate area. Comparison of these results with published findings indicates that the parcellation of the peristriate cortex into a variety of different areas, the pattern formed by these areas around area 17, and their reciprocal connections with area 17 follow a common plan in all hitherto studied terrestrial Old World and New World rodents. Lucifer Yellow injections into striate cells projecting to one of the recipient areas (AM) indicated that the pyramidal cells of this set of striate neurons are characterized by a short apical dendrite, and that the basal dendrites of the layer V pyramidal cells branch more profusely than those of the layer III pyramids.     

Cortical modulation of thalamo-cortical neurons relaying exteroceptive information: a microstimulation study in the guinea pig

Summary The nature and organization of cortical influences on somatosensory thalamic neurons were investigated in the guinea pig in order to ascertain if mechanisms subserving sensory-motor integration in the thalamus are as precise as has previously been demonstrated in the agranular frontal cortex (AGr) and granular parietal cortex (Gr). The study was carried out on 14 chronically-implanted awake animals. In each experiment one or two motor foci within AGr and Gr were identified according to the region of the movement evoked by intracortical microstimulation at the lowest threshold stimulation (usually 5–15 µA). Spontaneous activity of 182 thalamo-cortical single neurons was recorded in the nucleus ventralis thalami (VT). The neurons were also identified by their response to activation of cutaneous receptive fields (RFs) located in regions of vibrissae or limbs, and then tested for cortical stimulation with a pulse intensity equal to the threshold for evoking motor effects. During the cortico-thalamic tests, the duration of stimulating trains was reduced in order to avoid the appearance of limb or vibrissa movements which could activate somatosensory ascending pathways forwarding peripheral messages to VT. The cortical control on VT neurons appears to be organized in a very precise manner. It was seen that: 1) The influences on these neurons relaying exteroceptive signals specifically emanated from AGr and Gr areas which in turn received exteroceptive input. 2) The vibrissa units responded to stimulation of foci in either AGr or Gr but the reactivity was greater upon stimulation of Gr than AGr. The incidence of responses was very high when the vibrissa RF was overlapping or adjacent to the region of the cortically-evoked vibrissa movement. The response pattern was mostly excitatory. Responses were rarely observed when vibrissa RF lay distant from the vibrissa moved by cortical stimulation. 3) Neurons with limb RFs responded constantly to stimulation of Gr foci only when the RF was overlapping or adjacent to the region of the cortical motor target; in these two conditions the response pattern was excitatory and inhibitory, respectively. Inhibitions only concerned neurons with forelimb RFs. Responses to stimulation of AGr were rarely obtained. From a functional point of view, the excitatory nature of the cortical control on thalamo-cortical VT neurons suggests that a cortical signal inducing movement of a given body part is able to enhance the afferent transmission of somatosensory messages arising in the same body part. Concerning the control on forelimb neurons, this enhancement would be further amplified by a sort of descending surround inhibition which impairs transmission of messages coming by adjacent body parts.     

NMDA receptors contribute to the resting discharge of vestibular neurons in the normal and hemilabyrinthectomized guinea pig

Summary Excitatory amino acids (EAA) like L-Glutamate or L-Aspartate have been suggested to be the neurotransmitters at the synapses between primary vestibular afferents and second-order vestibular neurons. In the first part of our work, we have tested the possibility that EAA receptors are implicated in the control of posture by vestibular nuclei. Normal guinea pigs were implanted with minipumps delivering EAA antagonists in the vestibular nuclei. Their resting posture was monitored during the perfusion by using an X-ray photographic method. Chronic infusion of D-L-2-amino-5-phosphonovaleric acid (APV), a specific antagonist of NMDA receptors, in the vestibular nuclei induced a postural and oculomotor syndrome similar to the one observed following acute vestibular deafferentation. Administration of 6-cyano-7-nitro-quinoxaline-2-3-dione (CNQX), a specific antagonist of kainate and quisqualate receptors, failed to induce any postural syndrome or eye deviation. These results suggest that, under physiological conditions, N-methyl-D-aspartate (NMDA) receptors, contrary to kainate and quisqualate receptors, are essential for the maintenance of a symmetric posture and of a normal eye position at rest. Previous electrophysiological studies have demonstrated that following unilateral labyrinthectomy the recovery of a resting discharge in the deafferented vestibular nuclei plays a key role in the compensation of postural disorders. In the second part of this study, we have tested whether NMDA receptors could be implicated in this postural recovery. APV minipumps were implanted in hemilabyrinthectomized guinea pigs after complete compensation. A postural decompensation was induced, which occurred after delivery of the same amount of APV which provoked a vestibular syndrome in intact guinea pigs. This result favors the hypothesis that denervation supersensitivity resulting from an increase in either the number and/or the sensitivity of NMDA receptors could be a factor in the recovery of the static syndrome following hemilabyrinthectomy.     

Calcium-activated hyperpolarizations in neurons of the mediolateral part of the lateral septum: intracellular studies from guinea pig brain slices

Intracellular recordings were used to study the afterpotentials that followed a single spike and trains of spikes in class A neurons (n=85) of the mediolateral part of the lateral septum (LSml) of the guinea pig in in vitro slices. Following a single spike, LSml neurons (n=56) developed a slow afterhyperpolarization (sAHP), called early sAHP. These sAHP did not sum; other LSml neurons (n=8) showed a depolarizing afterpotential (DAP) that summed. Twenty-one neurons did not exhibit an afterpotential. Following a train of spikes, LSml neurons (n=79) developed a long-lasting sAHP, called late sAHP; these sAHP summed. Both the DAP and the early and late sAHP were markedly suppressed in amplitude by addition of Co²⁺ but persisted in the presence of tetrodotoxin (TTX). Increase in external K⁺ markedly depressed the early and late sAHP. Apamin and d-tubocurarine selectively blocked early sAHP, with no effect on late sAHP. These results indicate that the early and late sAHP are mainly generated by an activation of two types of Ca²⁺-dependent K⁺ conductances, with different time courses and pharmacological properties. In LSml neurons, late sAHP mediates the long-term adaptation of repetitive firing.     

水杨酸钠对豚鼠螺旋神经节NGB mRNA和蛋白表达的影响

目的： 观察水杨酸钠对豚鼠螺旋神经节NGB mRNA和蛋白表达的影响。方法: 48只成年健康豚鼠分4组进行，每组12只。A组：对照组；B组：水杨酸钠组Ⅰ（200 mg·kg^-1·d^-1）；C组：水杨酸钠组Ⅱ（300 mg·kg^-1·d^-1）；D组：水杨酸钠组Ⅲ（450 mg·kg^-1·d^-1）。各组均经腹腔注射给药，给药15d后处死检测；采用RT-PCR检测实验豚鼠螺旋神经节区NGB mRNA的表达；采用免疫组织化学染色分析NGB蛋白表达。结果: ①对照组豚鼠螺旋神经节区NGB mRNA表达明显高于3个水杨酸钠组（P<0.01）；3个水杨酸钠组NGB mRNA表达比较以D组表达最低，B组表达最高，C组与D组比较差异显著（P<0.05）。②免疫组织化学染色检测结果显示实验各组均表达NGB蛋白。A组NGB蛋白表达明显高于其它各组；3个水杨酸钠组以B组表达最高、D组表达最低。结论: 水杨酸钠可显著降低螺旋神经节神经元NGB mRNA和蛋白表达；水杨酸钠对螺旋神经节神经元NGB mRNA和蛋白表达是剂量依赖性的。     

In utero development and maturation of the retina of a non-primate mammal: A light and electron microscopic study of the guinea pig

Summary A light and electron microscopic examination of retinogenesis in the fetal guinea pig has revealed an early development of synapses and photoreceptor cells. Differentiation of the neural retina begins around day 23 of gestation. By 34 days the retina reaches its maximum thickness. It differentiates an inner plexiform layer in which vesicle-containing processes and primitive synapses are evident. Synaptic ribbons are found in processes of this layer by 43–45 days of gestation. An outer plexiform layer develops within the neuroblast layer at 40 days of gestation; from its first appearance the outer plexiform layer contains synapses complete with synaptic ribbons. Receptor terminals of the , paranuclear and type are present well before birth. Photoreceptor cells form inner segments by 40 days; the formation of outer segments is indicated by 45 days but not widespread until 49 days. The retina appears mature by day 51–57. It is clear that the primate is not unique in the early differentiation of its retinal synapses relative to the time of maturation of its photoreceptor cells. The potential functional capacities of precocious retinae, and the mechanisms of synapse development are discussed.Supported by Grants from the Medical Research Council.     

A comparison between the physiological and histochemical characterisation of urethral striated muscle in the guinea pig

In this in vitro study comparison has been made between the actomyosin ATPase activity and the contractile properties of the external urethral sphincter in the guinea pig. Histochemical analysis showed the external urethral sphincter to contain a mixture of alkali and acid stable actomyosin ATPase positive fibres in the ratio of 3:1. External urethral sphincter isometric contraction measurements were undertaken using specimens mounted transversely or longitudinally with respect to the urethral lumen. These contraction parameters have shown that the majority of fibres which constitute the external urethral sphincter correspond to the fast twitch type. In order to determine whether the relatively small fibre diameter of urethral striated muscle influenced the contraction results, when compared with controls, corrections for different volume ratios of slow and fast fibres were applied to the results. These modified values revealed close correlation between muscle fibre actomyosin ATPase content and isometric contraction responses.     

Some determinants of intake and patterns of feeding in the guinea pig

Regulation of food and water intake was studied in young and adult Guinea pigs by continuously monitoring ad lib feeding and drinking patterns and by examining the response to levels of celluflour dilution that ranged from 20–75%. Meal size and the duration of the intermeal interval were not systematically related to the sizes of preceding meals or interval lengths. Variations in food intake were mediated almost entirely by changes in meal size. This parameter increased during growth, was elevated in the first meal following food deprivation, decreased when water was withheld and increased when water was returned. The probability of drinking within 20 min of eating was 0.80. Celluflour dilution led to a decrease in apparent caloric intake without a proportional decrease in body weight. Regulation of energy balance and meal to meal control of feeding in this monogastric, herbivorous rodent is discussed in relation to the Guinea pig's digestive physiology and ecological niche.     

Embryonic and postnatal development of calcium-binding proteins immunoreactivity in the anterior thalamus of the guinea pig

Our recent studies have shown that the distribution of calretinin (CR) in the anterior thalamic nuclei (ATN) changes significantly during the development of the guinea pig. The present study was designed to reveal the distribution pattern of calcium-binding proteins, i.e. calbindin (CB) and parvalbumin (PV), as well as the colocalization pattern of all three proteins, including CR, in the ATN of guinea pigs ranging from the 40th embryonic day (E40) to the 80th postnatal day (P80). According to these patterns, CB appears exclusively in the perikarya of the anteromedial nucleus (AM) not before P20 and always colocalizes with CR. Moreover, CB and CR colocalize in fibers of thin bundles traversing the anteroventral nucleus (AV) since E50. The ATN also display CB-positive neuropil in all studied stages, especially a strong one in the ventral part of the AV. PV was not observed in the perikarya of the ATN in all the stages, but was abundantly present in the neuropil of the anterodorsal nucleus (AD). No colocalizations exist between PV and the rest of the studied proteins. In conclusion, our study reveals that the distribution of the studied proteins differs greatly. Nevertheless, the postnatal coexistence of CB and CR in the AM perikarya may indicate the cooperation of both of the proteins in some functions of the nucleus. Parvalbumin is limited mostly to the neuropil of the AD, suggesting different functions in comparison to CB and CR.     

Similarities and differences between cholinergic systems in the superior colliculus of guinea pig and rat

Summary We studied the distribution of acetylcholinesterase activity and choline acetyltransferase immunoreactivity in the superior colliculus of the guinea pig and the albino rat, using enzyme histochemical and immunohistochemical methods. Choline acetyltransferase-like immunoreactivity was localized in the neuropil throughout the colliculi, but the density of the immunoreactive neuropil varied among layers as well as between species. In the intermediate collicular layers the pattern of choline acetyltransferase immunoreactivity was closely matched by the distribution of acetylcholinesterase activity in guinea pig and rat, confirming our previous findings in the cat. Furthermore, in the guinea pig, but not in the rat, choline acetyltransferase-like immunoreactivity was localized in a prominent population of perikarya of the superficial gray layer.     

l-Lactate andd-lactate carriers on the fetal and the maternal side of the trophoblast in the isolated guinea pig placenta

The transfer of¹⁴C-labelledd- orl-lactate (test substance) relative to³H-l-glucose (control substance, extracellular marker) into the trophoblast of the isolated guinea pig placenta was determined during an open loop perfusion on both sides. Using a single passage, paired tracer dilution technique, the maximal lactate uptake (U _max) was derived from the venous concentration ratio of lactate tol-glucose.A significant metabolism ofl-lactate was not observed. The lactate uptake, which occurred in all placentas studied, was not significantly different on the fetal and maternal side. Within one placenta thel-lactate uptake was always higher than thed-lactate uptake. The uptake of bothl- andd-lactate could be inhibited by phloretin. The lactate uptake was inversely correlated with the pH of the perfusate fluid within the range from 6.2–8. A first order saturation kinetic (Hofstee-plot) was used to approximate the relationship between thel-lactate uptake and the chemicall-lactate concentration. We conclude that similar lactate carriers exist in the membranes on both the maternal and the fetal side of the trophoblast.Supported by the Deutsche Forschungsgemeinschaft     

The response of primary horizontal semicircular canal neurons in the rat and guinea pig to angular acceleration

Summary In rats and guinea pigs, primary afferent neurons from the horizontal semicircular canal were divided into two categories, regular and irregular, on the basis of the regularity of their resting activity. Regular neurons tend to have higher average resting rates than irregular neurons and in response to a constant angular acceleration stimulus of 16.7 deg/s² regular neurons tended to have lower sensitivity and longer time constants than irregular cells. Some irregular neurons are more sensitive to incremental accelerations than to decremental accelerations of the same magnitude, whereas regular neurons tend to show symmetrical sensitivity.In response to sinusoidal angular acceleration stimuli (fixed frequencies) in the range 0.01–1.5 Hz, cells which fired regularly at rest tended to have smaller gain and longer phase lag re acceleration at most frequencies than irregular cells. Transfer functions were obtained for averaged data for regular and irregular neurons separately in both species.In both species there is evidence of systematic variation between neurons within each category, and this systematic variation is obscured by averaging across neurons.     

Effort as determinant of intake and patterns of drinking in the guinea pig

The influence of effort (FR size) and duration of access to the drinking tube on the Guinea pig's daily water intake and pattern of drinking was studied. As FR size increased there was a reduction in the number of drinking bouts and in the daily intake. The Guinea pig adjusted to the decline in the number of drinking bouts by increasing the amount of water consumed per bout and compensated for the reduction in total intake by increasing the efficiency of utilization of water. These non-deprived animals were able to maintain control growth rates except during the most demanding schedules. These findings are discussed in relation to the hypothesis that the motivation for appetetive behavior arises from constraints on free feeding and drinking.