Biomedical subjects

W Löscher

Publications and source records attributed to W Löscher.

At least 37 records · Page 2Linked to original sources

PubMed2001

Multidrug resistance-associated protein is involved in the regulation of extracellular levels of phenytoin in the brain.

The mechanisms that lead to drug resistance in epilepsy are not known. Recently, overexpression of multidrug transporters, such as multidrug resistance-associated protein (MRP), has been reported in surgically resected epileptogenic human brain tissue and suggested to contribute to the drug resistance of epilepsy. However, it is not known to what extent multidrug transporters such as MRP are involved in transport of antiepileptic drugs. In the present study, we used in vivo microdialysis in rats to study whether the concentration of phenytoin in the extracellular fluid of the cerebral cortex can be enhanced by inhibition of MRP, using the MRP inhibitor probenecid. Local perfusion with probenecid via the microdialysis probe significantly enhanced the extracellular concentration of phenytoin. The data indicate that MRP critically participates in the regulation of extracellular brain concentrations of the major antiepileptic drug phenytoin.

ATP-Binding Cassette Transporters↗

PubMed2001

Evidence for microvesicular storage and release of glycine in rodent pinealocytes.

Prompted by previous studies suggesting a regulatory role for the inhibitory amino acid gamma-aminobutyric acid (GABA) within the mammalian pineal gland, we carried out a study of rat and gerbil pineal organs to elucidate whether there is evidence for a vesicular storage and release of GABA and/or glycine. Immunohistochemistry revealed the presence of the vesicular inhibitory amino acid transporter in pinealocytes. Moreover, we found that, in addition to glutamate and aspartate, cultured pinealocytes also released glycine upon stimulation by depolarizing concentrations of KCl, whereas the content of GABA in the culture medium did not exceed the detection limit either under control conditions or following KCl application. Therefore, we propose that glycine is a further component of the paracrine signaling system within the pineal organ which is based on the compartment of synaptic-like microvesicles (SLMVs) inside pinealocytes.

Amino Acid Transport Systems↗

PubMed2001

Do cocarcinogenic effects of ELF electromagnetic fields require repeated long-term interaction with carcinogens? Characteristics of positive studies using the DMBA breast cancer model in rats.

The carcinogenic or cocarcinogenic potential of extremely low frequency (ELF; 50 or 60 Hz) magnetic fields (MFs) has been evaluated worldwide in diverse animal model systems. Though most results have been negative, weakly positive or equivocal results have been reported in several cancer models, including the rat DMBA (7,12-dimethylbenz[a]anthracene) model of mammary cancer. Based on the experimental conditions used in studies in which cocarcinogenic effects of ELF MF were found, it was recently proposed that MF exposure may potentiate the effects of known carcinogens only when the animals are exposed to both MF and carcinogen during an extended period of tumor development, i.e., when the carcinogen is given repeatedly during MF exposure. This review summarizes a series of experiments from our group, showing cocarcinogenic MF effects in the DMBA breast cancer model in rats, to test whether the above proposal is confirmed by existing data. Flux densities of 50 or 100 microT significantly increased the growth of mammary tumors, independent of whether DMBA was given in a single administration or repeatedly over a prolonged period. Thus, these data do not substantiate the hypothesis requiring repeated doses of DMBA during MF exposure. Instead, several other aspects of study design and experimental factors are identified that seem to be critical for the detection of cocarcinogenic effects of MF exposure in the rat DMBA mammary cancer model. These include the rat subline used, the dose of DMBA, the duration of MF exposure, the flux density, the background (sham control) tumor incidence, and the location of mammary tumors in the mammary gland complex. These and other experimental aspects may explain why some laboratories did not detect cocarcinogenic MF effects in the DMBA model. We hope that direct comparison of MF bioeffects in different rat sublines and further evaluation of other experimental differences between studies on MF exposure in the DMBA model will eventually determine which genetic and environmental factors are critical for potential carcinogenic or cocarcinogenic effects of ELF MF exposure.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

Spontaneous paroxysmal circling behavior in the ci2 rat mutant: epilepsy with rotational seizures or hyperkinetic movement disorder?

Circling, turning, rotating, spinning, wheeling, and cursive hyperkinesia are all synonymous terms used to describe the active movement of an animal in a circular direction. Circling behavior can be evoked by unilateral electrical and chemical stimulation or lesions of various brain sites, but can also occur after systemic drug administration or spontaneously in normal animals or mutant rodents. In humans, stereotypic body rotation can occur as a distinctive entity of generalized and focal epilepsy, and may be due to involvement of the striatum. We have previously described a Lewis rat mutant (ci2) with a behavioral phenotype characterized by lateralized circling, hyperactivity, opisthotonus, and ataxia. In these rats, circling occurs in phases or bursts either spontaneously or in response to stress. Neurochemical data indicate that the circling behavior of the ci2 mutants is related to an abnormal asymmetry in dopaminergic activity in the striatum. Because of the similarities to rotational epilepsy, we used video and electroencephalographic recordings to study whether the rotational behavior of the ci2 mutant rat is a result of a partial or generalized epilepsy. Epileptic WAG/Rij rats were used for comparison. Video monitoring of ci2 rats in the absence of any stress or disturbance showed that circling occurs in paroxysmal bursts during active wakefulness, but not during passive wakefulness or sleep. Circling was not preceded or followed by any convulsive motor seizures and was not associated with epileptiform abnormalities in the electroencephalogram, whereas WAG/Rij rats exhibited myoclonic seizures and epileptic spike-wave discharges during passive wakefulness and sleep. As a result of the association of circling with active wakefulness, ci2 rats exhibited many more rotations during the dark (active) phase compared with the light (rest) period. Increase in active wakefulness during the light phase by transfer of the rats to a new environment induced or intensified circling behavior. Most ci2 rats showed a consistent lateral preference during circling, but some rats changed their preference from one session to another. The data indicate that spontaneous paroxysmal circling behavior in the ci2 rat is not a consequence of epilepsy but reflects a hyperkinetic movement disorder with abnormal lateralization of brain function.

Animals↗

PubMed2001

A novel black-hooded mutant rat (ci3) with spontaneous circling behavior but normal auditory and vestibular functions.

Abnormal circling behavior in rodents is usually attributed to vestibular dysfunction. In rats, all circling mutants described previously have inner ear defects resulting in auditory and vestibular dysfunctions. Here, we describe a new mutant rat with abnormal spontaneous circling behavior but normal auditory and vestibular functions. The new circling mutant rat was discovered in progeny of an apparently normal black-hooded (BH) rat inbred line [BH.7A(LEW)/Won] and was termed ci3, because we recently found two other mutant circling rats (ci1 and ci2) in a Lewis (LEW) inbred rat strain. The ci3 mutant is characterized by circling behavior and locomotor hyperactivity, which occur in phases or bursts either spontaneously or in response to stress, e.g., when rats are transferred to a new environment. Video monitoring of undisturbed rats in their home cage during the light and dark periods showed that circling behavior is much more intense during the dark period, i.e., during the active phase of the animals. Most ci3 rats show a lateral preference in their rotational behavior, i.e., they either rotate to the left or to the right. Brainstem auditory evoked potential testing and different tests of vestibular function did not disclose any auditory or marked vestibular defects in ci3 rats. Furthermore, no morphological abnormalities were seen during histological examination of the cochlear and vestibular nuclei in the brainstem. Neurochemical determination of dopamine and dopamine metabolite levels in striatum, nucleus accumbens and substantia nigra showed that ci3 rats have a significant asymmetry in striatal dopamine in that dopamine levels were significantly lower in the hemisphere contralateral to the preferred direction of turning. Consistent with this finding, immunohistological examination of dopaminergic neurons in substantia nigra and ventral tegmental area yielded a significant laterality in the medial part of substantia nigra pars compacta with a lower density of tyrosine hydroxylase-positive neurons in the contralateral hemisphere of mutant circling rats, while no laterality was seen in unaffected rats of the background strain [BH.7A(LEW)/Won].Thus, the novel mutant ci3 rat exhibits several features which clearly differ from previously described circling rat or mouse mutants. The behavioral phenotype occurs in the absence of auditory or obvious vestibular defects and is most likely a consequence of lateralized abnormalities found in the nigrostriatal circuit. Apart from the use of ci3 rats for studying the functional lateralization of brain functions, the ci3 mutant may serve as a new model for movement disorders with abnormal lateralization.

Animals↗

PubMed2001

Repeated low-dose treatment of rats with pilocarpine: low mortality but high proportion of rats developing epilepsy.

Systemic administration of pilocarpine in rats can result in a chronic behavioral state that is similar to human temporal lobe epilepsy. The pilocarpine model of epilepsy is widely used for studying the factors that contribute to the development of epilepsy as a consequence of status epilepticus (SE). For this purpose, pilocarpine is either administered alone at a high systemic dose or in combination with lithium, which markedly potentiates the convulsant effect of pilocarpine. Both experimental protocols, however, are associated with high mortality rates. In the present study, we evaluated whether mortality rate in rats can be decreased by repeated administration of low doses of pilocarpine. The time the rats spent in SE was limited by diazepam. Preliminary experiments in lithium-free rats indicated that repeated low-dose administration of pilocarpine is too time-consuming to produce SE compared to single high-dose administration. All subsequent experiments were performed in lithium-pretreated rats. Single-dose injection of 30 mg/kg pilocarpine produced SE in approximately 70% of the animals, but 45% of the rats died although SE was interrupted by diazepam after 90 min. Repeated i.p. administration of 10 mg/kg pilocarpine at 30-min intervals resulted in SE after 2-4 injections; the mean dose of pilocarpine needed to induce SE was 26 mg/kg. When SE was interrupted after 90 min, mortality rate was below 10%, which was significantly lower compared to the protocol with one single administration of 30 mg/kg pilocarpine. In contrast to mortality rate, the development of spontaneous recurrent seizures did not differ between experimental protocols. Almost all rats which had experienced a SE of at least 60 min developed chronic epilepsy. Average latency to the first spontaneous seizure was approximately 40 days. The frequency and severity of spontaneous seizures was not significantly different between protocols, although animal groups with repeated low-dose treatment tended to have higher frequencies of spontaneous seizures compared to single-dose administration. The present study demonstrates that systemic treatment of lithium-pretreated rats with several low doses of pilocarpine efficiently produces SE and chronic epilepsy with much lower mortality rates than single-dose pilocarpine.

Animals↗

PubMed2001

In vivo pharmacology of BIIR 561 CL, a novel combined antagonist of AMPA receptors and voltage-dependent Na(+) channels.

Glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype and voltage-gated Na(+) channels are associated with diseases of the central nervous system characterized by neuronal over-excitation as in epilepsy or cerebral ischaemia. In animal models, AMPA receptor antagonists and Na(+) channel blockers provide protection in these conditions. Dimethyl-[2-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxyl]-ethyl]-amine hydrochloride (BIIR 561 CL) combines both, AMPA receptor - and Na(+) channel blocking properties in one molecule. Here, BIIR 561 CL was investigated in vivo. BIIR 561 CL protected mice against AMPA-induced toxicity with an ED(50) value of 4.5 mg kg(-1) following subcutaneous (s.c.) administration. A 0.1% solution of BIIR 561 CL provided local anaesthesia in the corneal reflex test in rabbits. In mice, the compound prevented tonic seizures in the maximal electroshock (MES) model with an ED(50) value of 3.0 mg kg(-1) s.c. In amygdala-kindled rats, BIIR 561 CL inhibited seizures at doses of 3 and 11 mg kg(-1) following intraperitoneal (i.p.) injection. The data show that the combination of blocking AMPA receptor- and voltage-gated Na(+) channels in one molecule induces effective protection in animal models of neuronal over-excitation.

Animals↗

PubMed2001

Auditory and vestibular defects in the circling (ci2) rat mutant.

The circling rat is an autosomal recessive mutant (homozygous ci2/ci2) that displays lateralized circling behaviour, locomotor hyperactivity, ataxia and stereotypic head-movement. These abnormal behaviours occur in phases or bursts either spontaneously or in response to stress. Heterozygous (ci2/+) littermates display normal spontaneous behaviours. We have previously found that ci2/ci2 rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of rotation, indicating that the rats turn away from the brain hemisphere with higher striatal dopaminergic activity. In view of the similarities of the motor syndrome of the ci2/ci2 mutant rat to that of mouse deafness mutants, the present study evaluated the hearing ability of the circling rat mutant by recording brainstem auditory-evoked potentials. To test for vestibular dysfunction, a swimming test was conducted. Histological methods were used to examine the cochlear and vestibular parts of the inner ear and the cochlear and vestibular brainstem nuclei for defects. The absence of auditory-evoked potentials demonstrated a complete hearing loss in the adult ci2/ci2 mutant rat, whereas heterozygous littermates exhibited auditory-evoked potentials with thresholds resembling those of other laboratory strains. Furthermore, the mutant rats were unable to swim. Histological analysis of the inner ear of adult mutants revealed virtually complete loss of the cochlear neuroepithelium, while no such hair cell degeneration was seen in the vestibular parts of the inner ear. However, part of the vestibular hair cells showed protrusions into the endolymphatic space, suggesting alterations in the cytoskeletal architecture. The histological findings in mutant circling rats strongly indicate that the hearing loss of the mutants is of the sensory neural type, the most prevalent type of hearing loss. In the cochlear nuclei of the brain stem of mutant rats, neurons exhibited an abnormal shape, reduced size and increased density compared to controls. In contrast, no abnormal neuronal morphology was seen in the vestibular nuclei, but a significantly reduced neuronal density was found in the medial vestibular nucleus. Abnormal vestibular function would be a likely explanation for the disturbed balance of mutant rats as exemplified by the ataxia and the inability to swim, whereas the previous data on these rats strongly indicate an involvement of the basal ganglia in the abnormal circling behaviour. The genetic defect in the mutant rats, thus, results in a clinical syndrome with features also seen in human genetic disorders with deafness and hyperkinesia, making the ci2/ci2 rat an excellent model for investigating both cochlear/vestibular dysfunction and hyperkinetic movement disorders.

Animals↗

PubMed2001

In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats.

PURPOSE: The multidrug transporter P-glycoprotein (P-gp) is expressed at high levels in a variety of tissues such as the endothelial cells of the blood-brain barrier (BBB) capillaries, where it is thought to be involved in the exclusion of various drugs from the capillary endothelial cells, blocking their entry into brain. It was previously shown that pharmacoresistant partial epilepsy is associated with an increased expression of P-gp in brain capillary endothelium and astrocytes, leading to the hypothesis that increased P-gp expression may be involved in medically intractable epilepsy. However, it is not known whether the distribution of antiepileptic drugs (AEDs) into the brain is limited by P-gp. We used in vivo microdialysis in freely moving rats to study whether the concentration of the major AED phenytoin (PHT) in the extra-cellular fluid (ECF) of the cerebral cortex can be enhanced by inhibition of P-gp. METHODS: Three different P-gp inhibitors, sodium cyanide, verapamil, and PSC 833, were used. These drugs were given via the microdialysis probe in the right frontal cortex, while a probe in the left cortex served as vehicle control side. Perfusion with the inhibitor started 15-60 min before systemic (i.p.) administration of PHT, 50 mg/kg. RESULTS: PHT rapidly entered the brain ECF compartment, but ECF plasma ratios at time of maximal ECF levels were only approximately 0.04. All P-gp inhibitors significantly increased the ECF concentrations of PHT after local administration, indicating that P-gp in the BBB normally limits the distribution of PHT into the brain parenchyma. Cremorphor EL, the vehicle used to administer PSC, also was able to increase ECF PHT, which is explained by the previously reported inhibitory effect of cremophor on P-gp. CONCLUSIONS: Provided that multidrug transporters such as P-gp also are involved in the BBB outward transport of other AEDs, increased expression of multidrug transporters, leading to inadequate accumulation of AEDs in the brain, would be a likely explanation for pharmacoresistant epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

AWD 140-190: a potent anticonvulsant in the amygdala-kindling model of partial epilepsy.

PURPOSE: Evaluation of the effect of the new anticonvulsant drug, AWD 140-190 [4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester] on focally induced seizures and on epileptogenesis in the kindling model. METHODS: Effects of AWD 140-190 were studied in amygdala kindled rats after oral and intraperitoneal administration. In addition, the effect on kindling development was evaluated. In all experiments, behavioral changes in the rats in response to AWD 140-190 were monitored closely. RESULTS: AWD 140-190 exerted potent anticonvulsant activity against focal seizures. After intraperitoneal and oral administration in fully kindled rats, the substance dose-dependently increased the threshold for induction of afterdischarges starting at 15 mg/kg. AWD 140-190 only weakly influenced the seizure severity of the animals after stimulation at the elevated afterdischarge threshold current. No adverse effects were observed up to 30 mg/kg after intraperitoneal and oral administration in the open field and in the rotarod test. No differences were found between kindled and nonkindled rats when comparing neurotoxicity of AWD 140-190. Prolonged treatment with AWD 140-190 during kindling acquisition did not prevent kindling, but significantly retarded the development of fully kindled seizures during the treatment. CONCLUSIONS: This study demonstrates that AWD 140-190 has anticonvulsant effects in the amygdala kindling model in rats, suggesting that the substance is particularly effective against partial seizures. AWD 140-190 is orally active and devoid of neurotoxic effects in anticonvulsant doses, thus indicating that this compound has potential for antiepileptic therapy. AWD 140-190 retards the kindling development during the treatment. This effect could be explained by the acute anticonvulsant effect of the substance.

Administration, Oral↗

PubMed2000

Deficit of striatal parvalbumin-reactive GABAergic interneurons and decreased basal ganglia output in a genetic rodent model of idiopathic paroxysmal dystonia.

The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of paroxysmal dystonia, the dt(sz) mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbumin-immunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA(A) receptor agonist muscimol on severity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings in dt(sz) hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dt(sz) hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.

Action Potentials↗

PubMed2000

The new antiepileptic drugs lamotrigine and felbamate are effective in phenytoin-resistant kindled rats.

We evaluated the anticonvulsant efficacy of the antiepileptic drugs (AEDs) lamotrigine (LTG) and felbamate (FBM) in amygdala kindled rats that had been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e., a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, 3 groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses LTG and FBM exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both LTG and FBM proved to be effective anticonvulsant drugs in the kindling model by markedly increasing the ADT. Seizure severity and duration recorded at ADT currents were hardly reduced, indicating that both drugs predominantly affect induction of focal seizures and not seizure spread from the focus. In phenytoin nonresponders, LTG and FBM significantly increased ADT, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, LTG and, more markedly, FBM were clearly more efficacious in increasing ADT in phenytoin responders than in nonresponders, substantiating that the difference in phenytoin response between these groups of kindled rats extends to other AEDs. The data in this study reveal that phenytoin nonresponders are a unique model for the search for new AEDs with improved efficacy in refractory partial epilepsy.

Amygdala↗

PubMed2000

Strong olfactory stimulation reduces seizure susceptibility in amygdala-kindled rats.

Seizures in human temporal lobe epilepsy are characterized by paroxysmal activity in the limbic system. The primary olfactory or piriform cortex is a central part of the limbic system. Since a relationship between olfactory sensation and limbic seizures has been described, we were interested in the effect of strong olfactory stimulation on the seizure susceptibility of amygdala-kindled rats, a model of human temporal lobe epilepsy. Olfactory stimulation with toluene was able to suppress seizures in most kindled rats after stimulation at 20% above the threshold for eliciting epileptic afterdischarges. Olfactory stimulation with toluene or ammonia increased the threshold by 27 and 25% compared to control conditions. Our data substantiate that olfactory brain regions, such as the piriform cortex, are involved in amygdala-kindled seizures and suggest that strong physiological stimulation of this nucleus interferes with on-going seizure activity in the limbic system. Thus, olfactory stimulation could contribute to anticonvulsant therapy.

Ammonia↗

PubMed2000

Paradoxical aggravation of paroxysmal dystonia during chronic treatment with phenobarbital in a genetic rodent model.

Recent studies in mutant hamsters (dt(sz)), an animal model of primary paroxysmal dystonia, indicated that altered function of the gamma-aminobutyric acid (GABA)ergic system plays a critical role in the pathogenesis of dystonia. In the present study, dt(sz) hamsters were chronically treated with phenobarbital, which has been found to exert antidystonic effects in mutant hamsters after acute administration. In untreated dt(sz) hamsters, the severity of dystonia follows an age-dependent time course with a maximum between the 30th and 40th day of life, followed by a continuous decline of severity until complete remission occurs at the age of about 70 days. In contrast to acute effects, chronic treatment with phenobarbital via drinking water starting at an age of 21 days (i.e., after weaning) worsened dystonia and retarded the spontaneous remission. The unexpected prodystonic effect was more marked after administration of higher doses and when chronic treatment with phenobarbital started at an age of 1 day (neonatal administration via breast milk). After withdrawal of phenobarbital at the age of 70 days, the severity rapidly declined in all treated groups. When phenobarbital was readministered 1 week later, the hamsters again exhibited severe dystonia. The mechanism of these unexpected findings is unknown. Tentatively, activity-dependent GABA-mediated excitation caused by chronic treatment with phenobarbital may be important for the prodystonic effects under pathological conditions in dt(sz) hamsters.

Aging↗

PubMed2000

Piracetam and levetiracetam, two pyrrolidone derivatives, exert antidystonic activity in a hamster model of paroxysmal dystonia.

The effects of the nootropic drug piracetam and its analogue, the antiepileptic drug levetiracetam (ucb L059) on severity of dystonic attacks were studied in a mutant hamster model of idiopathic generalized dystonia. Both drugs significantly decreased the severity of dystonia. In contrast to seizure models, in which levetiracetam is much more potent as an anticonvulsant than piracetam, the antidystonic potency of levetiracetam was only moderately higher than that of piracetam. The antidystonic activity of piracetam and levetiracetam was not associated with any behavioral side effects. The data indicate that piracetam and levetiracetam are interesting novel treatments for idiopathic dystonia.

Animals↗

PubMed2000

Development of kindling and spontaneous seizures after massed stimulation of different loci in the rat piriform cortex.

Massed electrical stimulation of the anterior piriform cortex (PC) in rats using short (5 min) interstimulus intervals has previously been reported to induce severe chronic epilepsy with spontaneous seizures and has thus proposed to represent a novel model of temporal lobe epilepsy. In the present study, we used this stimulation protocol to evaluate the frequency and severity of recurrent spontaneous seizures produced in this way. In addition to the locus in the anterior PC previously used for massed stimulation (MS), we also stimulated rats via a locus in the transition zone between anterior and posterior PC ("central PC"), which previously was found to be more sensitive to electrical stimulation than various other loci in the anterior or posterior PC. During MS (71 stimulations for 1 s each at twice afterdischarge threshold), focal and infrequent secondary generalized seizures occurred in both groups, but there was no consistent progressive increase in seizure severity with increasing number of seizures, possibly as a result of postictal inhibitory processes. Following MS, rats were restimulated after 1, 2, 4, and 7 weeks, using five stimuli at 5-min interstimulus periods at each retest period. In both PC-implanted groups, seizure severity and seizure duration progressively increased over the period of the retests, indicating a delayed development of kindling. Spontaneous seizures were only observed rarely, so that MS of the PC is certainly no effective means of producing recurrent spontaneous seizures.

Animals↗

PubMed2000

Gabapentin-lactam, a close analogue of the anticonvulsant gabapentin, exerts convulsant activity in amygdala kindled rats.

The cyclic GABA analogue gabapentin (GBP), which recently has been marketed for treatment of epilepsy, is particularly effective against complex-partial seizures as occurring in temporal lobe epilepsy. In the present study, we compared the effects of GBP and its lactam analogue (GBP-L) in the amygdala kindling model of temporal lobe epilepsy. In fully kindled rats, GBP (50 mg/kg and 100 mg/kg i.p.) dose-dependently increased the threshold for focal seizures and inhibited the progression from focal to generalized seizures. This effect was not associated with any marked adverse effects. In contrast, GBP-L (10-50 mg/kg) induced myoclonic activity and generalized clonic seizures in kindled rats, demonstrating a striking qualitative difference between the two compounds. By comparison with non-kindled rats it was shown that kindling markedly enhanced the sensitivity of rats to the convulsant activity of GBP-L. The finding that the anticonvulsant efficacy of GBP is lost by lactam formation indicates that GBP and GBP-L differ in their mechanism(s) of action.

Acetates↗

PubMed2000

A microdialysis study of striatal dopamine release in the circling rat, a genetic animal model with spontaneous lateralized rotational behavior.

The circling rat is an autosomal recessive mutant (homozygous ci2/ci2) that displays lateralized circling behavior, locomotor hyperactivity, hyperexcitability, ataxia, and stereotypic head-movement. These abnormal behaviors are induced or intensified by stress. Heterozygous (ci2/+) littermates display normal spontaneous behaviors. We have previously found that ci2 rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of rotation, indicating that the rats turn away from the brain hemisphere with higher striatal dopaminergic activity. For further evaluation as to whether the spontaneous turning behavior of the mutant rats results from specific disturbances within the nigrostriatal circuitry, we used microdialysis in freely moving mutant rats and their unaffected littermates to measure extracellular levels of dopamine and its metabolites in the striatum of both hemispheres. Rats were habituated to the experimental procedures, so that mutant animals behaved as normal during a first phase of microdialysis ("rest phase"), which was followed by a "stress phase" with induction of lateralized circling by handling-stress. During rest, no significant imbalance in striatal dopamine release was observed in mutant rats, their unaffected littermates, and a second control group consisting of normal, unaffected rats from the same Lewis/Ztm strain. Stress induced a significant increase in dopamine release in the contralateral striatum of mutant rats of both genders, whereas no significant alterations in dopamine release were seen in either the left or right striatum of control groups. When amphetamine (100 or 500 microM) was added to the perfusion medium, the evoked dopamine release in the contralateral striatum of female mutant rats was significantly higher than that in the ipsilateral striatum, whereas no such asymmetry was observed in male mutants or unaffected female and male controls. The data further substantiate that mutant circling rats possess a genetically mediated dysfunction of the central dopaminergic system, but it remains to be determined whether neurochemical disturbances in other regions contribute to the behavioral phenotype of the ci2 rat. The continued study of this mutant may provide important new insights into the anatomical, neurochemical and molecular basis of hyperkinetic motor syndromes and other disorders related to dopaminergic dysfunction.

Amphetamine↗