Biomedical subjects

U Ebert

Publications and source records attributed to U Ebert.

At least 37 records · Page 2Linked to original sources

PubMed2000

Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects.

OBJECTIVE: To study the effects of rifampicin, a potent inducer of the microsomal P450 enzyme system and of specific isoforms of the uridine 5'-diphosphate(UDP)-glucuronyl-transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P450 enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. METHODS: Ten healthy male subjects received a single oral dose of 25 mg lamotrigine after a 5-day pretreatment with (1) cimetidine 800 mg divided into two equal doses, (2) rifampicin 600 mg, or (3) placebo. Serum and urine samples were analyzed using high-performance liquid chromatography. Changes in electroencephalographic (EEG) power were determined up to 48 h after lamotrigine administration. RESULTS: The values of the pharmacokinetic parameters of lamotrigine were: clearance over bioavailability (CL/F) 2.60+/-0.40 l/h, renal clearance (CLR) 0.10+/-0.03 l/h, terminal half-life (t1/2) 23.8+/-2.1 h, mean peak serum concentration (Cmax) 0.29+/-0.02 microg/l, time to reach Cmax (tmax) 1.6+/-0.28 h, and total area under the serum concentration-time curve (AUC0-infinity) 703.99+/-82.31 microg/ ml/min (mean +/- SEM). The amount of lamotrigine excreted as glucuronide was 8.90+/-0.77 mg. Rifampicin significantly increased CL/F (5.13+/-1.05 l/h) and the amount of lamotrigine excreted as glucuronide (12.12+/-0.94 mg), whereas both t1/2 (14.1+/-1.7 h) and AUC(0-infinity) (396.24+/-60.18 microg/ml/min) were decreased (P<0.05). Cimetidine failed to affect pharmacokinetics of lamotrigine. Lamotrigine did not change EEG power. CONCLUSION: Rifampicin altered pharmacokinetics of lamotrigine due to induction of the hepatic enzymes responsible for glucuronidation, while coadministration of cimetidine to ongoing lamotrigine therapy has negligible effects on lamotrigine pharmacokinetics. Lamotrigine administered as a single dose of 25 mg has no effect on EEG power in healthy subjects.

Adult↗

PubMed2000

Kindling causes persistent in vivo changes in firing rates and glutamate sensitivity of central piriform cortex neurons in rats.

The present experiments were undertaken to study whether amygdala kindling induces persistent alterations in the functional status of neurons of the central piriform cortex, a subregion of the piriform cortex identified previously as a site involved in the kindling process. Extracellular, single-unit recordings of piriform cortex neurons were made in anesthetized fully kindled rats at an interval of at least five weeks after the last seizure. Electrode implanted but not kindled rats served as sham controls. An additional group of non-implanted rats was used as naive controls. Spontaneously firing piriform cortex neurons were characterized in all groups by smooth, sharp, biphasic (i.e. positive/negative) action potentials with a duration of 0.8-1.8 ms, and were primarily located at the border between piriform cortex layers II and III. In kindled rats, neurons in the central piriform cortex exhibited a significantly higher firing rate compared to controls. Based on median group values, the increase in basal activity in kindled rats averaged about 90%. The responsiveness of piriform cortex neurons to neurotransmitters was tested by microiontophoretic application of glutamate, N-methyl-D-aspartate and GABA. Piriform cortex neurons of kindled rats exhibited a significantly lower responsiveness to the excitatory effect of glutamate than naive controls. A lowered glutamate responsiveness was also seen in sham controls. No significantly altered transmitter sensitivities of piriform cortex neurons from kindled rats were seen with N-methyl-D-aspartate or GABA. The data indicate that amygdala kindling causes persistent interictal changes in both basal activity and glutamate responsiveness of central piriform cortex neurons which could contribute to the abnormal hyperexcitability characteristic of kindling.

Action Potentials↗

PubMed2000

Bilateral lesions of the central but not anterior or posterior parts of the piriform cortex retard amygdala kindling in rats.

The piriform cortex is thought to be involved in temporal lobe seizure propagation, such as that occurring during kindling of the amygdala or hippocampus. A number of observations suggested that the circuits of the piriform cortex might act as a critical pathway for limbic seizure discharges to assess motor systems, but direct evidence for this suggestion is scarce. Furthermore, the piriform cortex is not a homogeneous structure, which complicates studies on its role in limbic epileptogenesis. We have previously reported data indicating that the central part of the piriform cortex might be particularly involved during amygdala kindling. In order to further evaluate the role of different parts of the piriform cortex during kindling development, we bilaterally destroyed either the central, anterior or posterior piriform cortex by microinjections of ibotenate two weeks before onset of amygdala kindling. Lesions of the anterior piriform cortex hardly affected kindling acquisition, except that fewer animals exhibited stage 3 (unilateral forelimb) seizures compared to sham controls. Lesions of the central piriform cortex significantly retarded kindling, which was due to a decreased progression from stage 3 to stage 4/5 seizures, i.e. the lesioned rats needed significantly longer for the acquisition of generalized clonic seizures in the late stages of kindling development. Lesions of the posterior piriform cortex did not significantly affect kindling development. The data demonstrate that different parts of the piriform cortex mediate qualitatively different effects on amygdala kindling. The central piriform cortex seems to be a neural substrate involved in the continuous development of kindling from stage 3 to stages 4/5, indicating that this part of the piriform cortex may have preferred access, either directly or indirectly, to structures capable of supporting generalized kindled seizure expression.

Amygdala↗

PubMed2000

Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats.

We have previously shown that subgroups can be selected from large groups of amygdala kindled Wistar rats which either respond consistently or do not respond to the anticonvulsant effect of phenytoin. Phenytoin nonresponders were proposed as a model for pharmaco-resistant temporal lobe epilepsy. In the present study we examined whether the differences of individual rats in response to phenytoin are already present before kindling or are a consequence of kindling. For this purpose, 52 rats were once tested with phenytoin, then kindled, and then repeatedly tested with phenytoin for selection of subgroups. For subgroup selection after kindling, the phenytoin prodrug fosphenytoin was used because of its water solubility and its improved tolerability and absorption after i.p. administration in rats. Before kindling, phenytoin significantly increased the afterdischarge threshold (ADT), i.e. a sensitive measure of focal seizure activity, but there was large individual variation with only 32 of the 52 rats reacting with an ADT increase, while the remaining rats showed either no effect or ADT decreases. After kindling, the selection resulted in 16 rats with consistent ADT increases in response to phenytoin and ten nonresponders (the remaining 26 rats showed variable responses). Unexpectedly, in rats which were responders after kindling, phenytoin exerted no significant anticonvulsant effect before kindling, while kindled nonresponders were very sensitive to phenytoin before kindling, indicating that the kindling process was responsible for the loss of anticonvulsant efficacy in kindled nonresponders and the development of phenytoin's efficacy in kindled responders. The present results substantiate that kindled subgroups of Wistar rats with different response to phenytoin are a valuable source for studying the mechanisms underlying the development of pharmaco-resistant limbic seizures.

Amygdala↗

PubMed2000

Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats.

We evaluated the anticonvulsant efficacy of the new antiepileptic drugs (AEDs) gabapentin and levetiracetam 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, three 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 gabapentin and levetiracetam 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 gabapentin and levetiracetam proved to be effective anticonvulsant drugs in the kindling model by significantly increasing the ADT. In addition, both drugs markedly decreased seizure severity recorded at ADT currents, indicating that these drugs affect seizure threshold in the epileptic focus and seizure spread from the focus in the kindling model. When the threshold for secondary generalized seizures (GST) was determined in addition to ADT, gabapentin and levetiracetam strikingly increased this threshold compared to predrug control. In phenytoin nonresponders, gabapentin and levetiracetam significantly increased ADT and GST, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom older AEDs have failed. In phenytoin responders, gabapentin tended to be more efficacious in increasing ADT and GST than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. In contrast to gabapentin, levetiracetam was more efficacious in increasing ADT in nonresponders than in responders. The data of this study substantiate that phenytoin nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.

Acetates↗

PubMed2000

Effects of lesions of the perirhinal cortex on amygdala kindling in rats.

The perirhinal cortex (PRC), the region of temporal cortex adjacent to the rhinal sulcus, has been suggested as a critical substrate for the development and expression of generalized motor seizures in the late stages of kindling development. For further investigation of the role of the PRC in limbic kindling, excitotoxic lesions centered on PRC by microinjection of ibotenate were performed in rats 2 weeks before onset of amygdala kindling. Rats with large bilateral or unilateral PRC lesions showed the same rate and pattern of kindling development as sham-lesioned controls. The only significant difference to controls was a higher afterdischarge threshold in the fully kindled state of lesioned rats. These data do not indicate a critical role for the bilateral involvement of the PRC in kindling from other limbic brain regions.

Amygdala↗

PubMed2000

Physostigmine reversal of midazolam-induced electroencephalographic changes in healthy subjects.

OBJECTIVE: Midazolam is a water-soluble benzodiazepine. Flumazenil is a potent antagonist of midazolam-induced sedation. Physostigmine has also been shown to reverse benzodiazepine sedation in anecdotal reports. The aim of this study was to quantitatively characterize the reversal of midazolam-induced changes in electroencephalogram (EEG) by physostigmine compared to flumazenil and placebo. METHODS: Twelve healthy male subjects received 5 mg midazolam as an intravenous infusion over 15 minutes. Fifteen minutes after the end of infusion, single doses of either 0.4 mg flumazenil, 0.5 mg physostigmine, or placebo (physiologic saline solution) were administered as intravenous injections in a randomized crossover fashion. Midazolam serum concentrations were measured using liquid chromatography-tandem mass spectrometry. The time from the start of injection until awakening was noted and the EEG was measured. RESULTS: Four subjects were excluded from further pharmacokinetic and pharmacodynamic analysis because no midazolam-induced changes on EEG alpha power could be observed in each of the three study periods. The pharmacokinetics of midazolam were not influenced by flumazenil or physostigmine. Midazolam induced a decrease in EEG alpha power (7.50 to 11.25 Hz) compared with baseline (P < .05). After injection of flumazenil and physostigmine, an increase in EEG alpha power was observed, whereas placebo did not affect alpha power. Subjects opened their eyes 25.2 +/- 1.1 minutes after the placebo injection was begun, whereas subjects awoke after 6.2 +/- 2.7 minutes and 15.4 +/- 3.4 minutes after they received flumazenil and physostigmine, respectively (mean +/- SEM; P < .001). CONCLUSION: Physostigmine and flumazenil antagonized midazolam-induced sedation. This suggests that a reversible central anticholinergic mechanism may be involved in the sedative action of midazolam.

Adult↗

PubMed2000

Universal algebraic relaxation of velocity and phase in pulled fronts generating periodic or chaotic states

We investigate the asymptotic relaxation of so-called pulled fronts propagating into an unstable state, and generalize the universal algebraic velocity relaxation of uniformly translating fronts to fronts that generate periodic or even chaotic states. A surprising feature is that such fronts also exhibit a universal algebraic phase relaxation. For fronts that generate a periodic state, like those in the Swift-Hohenberg equation or in a Rayleigh-Benard experiment, this implies an algebraically slow relaxation of the pattern wavelength just behind the front, which should be experimentally testable.

Journal Article↗

PubMed2000

Subdiffusive fluctuations of "pulled" fronts with multiplicative noise

We study the propagation of a "pulled" front with multiplicative noise that is created by a local perturbation of an unstable state. Unlike a front propagating into a metastable state, where a separation of time scales for sufficiently large t creates a diffusive wandering of the front position about its mean, we predict that for so-called pulled fronts, the fluctuations are subdiffusive with root mean square wandering Delta(t) approximately t(1/4), not t(1/2). The subdiffusive behavior is confirmed by numerical simulations: For t</=600, these yield an effective exponent slightly larger than 1/4.

Journal Article↗

PubMed2000

Anticonvulsant efficacy of topiramate in phenytoin-resistant kindled rats.

PURPOSE: We evaluated the anticonvulsant efficacy of topiramate (TPM), a structurally novel antiepileptic drug (AED), in amygdala kindled rats that had been preselected with respect to their response to phenytoin (PHT). METHODS: 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 PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (PHT responders), rats that showed no anticonvulsant response (PHT nonresponders), and rats with variable responses (variable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonresponders. RESULTS: TPM proved to be an effective AED in the kindling model. At 40 mg/kg, significant ADT increases were obtained after both 1 and 4 h after administration. In addition to the effect on focal seizure threshold, seizure severity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonresponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT responders than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders). CONCLUSIONS: The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.

Amygdala↗

PubMed2000

Influence of grapefruit juice on scopolamine pharmacokinetics and pharmacodynamics in healthy male and female subjects.

OBJECTIVES: To investigate the effects of grapefruit juice on absolute bioavailability of scopolamine in healthy subjects and to evaluate differences in pharmacokinetics and pharmacodynamics between genders. SUBJECTS, MATERIAL AND METHODS: 14 healthy subjects (7 men and 7 women) received scopolamine 0.5 mg as intravenous infusion, and as oral ingestion with and without grapefruit juice on separate occasions. Serum and urine samples were analyzed using gas chromatography-ion trap tandem mass spectrometry. Changes in subjective state were determined up to 24 hours after drug administration. RESULTS: After oral administration, pretreatment with grapefruit juice led to a 30% increase in systemic bioavailability of scopolamine (p = 0.005) and a significant increase in time to reach peak serum concentration (tmax) of scopolamine (p < 0.001). The Cmax value (6.61+/-0.63 ng/ml) of scopolamine after i.v. administration in male subjects was significant higher compared with the value in female subjects (3.93+/-0.04 ng/ml; geometric mean +/- SEM; p = 0.007). No differences were found in urinary excretion rate of scopolamine and scopolamine glucuronide across genders and between the three different routes of scopolamine administration. Scopolamine produced time-dependent decrements in subjective alertness while contentment and calmness were not influenced. CONCLUSIONS: Pretreatment with grapefruit juice delayed the absorption and increased the bioavailability of scopolamine, whereas elimination was not significantly affected. This study identified an influence of gender on Cmax of scopolamine after i.v. infusion.

Adult↗

PubMed2000

High susceptibility of the anterior and posterior piriform cortex to induction of convulsions by bicuculline.

Accumulating evidence suggests that the piriform cortex (PC) plays a critical role in the development of limbic motor seizures. In the anterior piriform cortex (aPC), a functionally defined, discrete epileptogenic site has been previously identified by unilateral microinjection of bicuculline in Sprague-Dawley (SD) rats and termed the 'area tempestas' (AT). Compared to this site in the aPC, more posterior PC sites, particularly a site in the transition zone between the posterior and aPC (central PC) exhibited a greater susceptibility to electrical stimulation. However, it is not known whether central and posterior sites in the PC differ from the aPC, including the AT, with regard to their sensitivity to bicuculline. In the present study, unilateral focal microinfusion of picomole quantities of bicuculline induced behavioural (focal and generalized) seizures in deep layers of all parts of the PC in two rat strains, Wistar and SD. The incidence of generalized seizures was higher in the AT of SD rats, but no such difference was seen in Wistar rats, arguing against the previous proposal that the rat AT is unique in its sensitivity to induction of seizures by bicuculline compared to other locations within or outside of the PC. Injection of biotin-dextran in PC seizure-sensitive sites in SD rats showed clear differences in anterograde and retrograde labelling between the different PC sites. Therefore, although it was possible to evoke generalized seizures from all parts of the PC, the anatomical connections of the bicuculline injection sites were qualitatively different. The results suggest that the deep layers of the entire PC are highly sensitive to seizure induction by bicuculline, thus substantiating the notion that the PC may be important in seizure generation and propagation.

Amygdala↗

PubMed1999

Altered seizure susceptibility after high-frequency transcranial magnetic stimulation in rats.

The long-term effect of repetitive transcranial magnetic stimulation (rTMS) on the susceptibility of amygdala kindling was studied. Two weeks after a single high-frequency rTMS train (120 A/micros, 20 Hz for 3 s), the rats had a 55% higher threshold for induction of epileptic afterdischarges compared with sham-treated or control rats. However, subsequent kindling revealed no difference between rTMS-treated and control rats. Our data suggest that a single rTMS train has long-term effects on the neuronal excitability. These effects may be anticonvulsant and therefore support the safety of rTMS in clinical use.

Amygdala↗

PubMed1999

Changes in 5-HT1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats.

The effects of a single rapid-rate transcranial magnetic stimulation (rTMS) exposure on neurotransmitter binding sites in the rat brain 24 h after the stimulation were examined. Quantification by in vitro-autoradiography showed no differences for 3H-paroxetine binding (5-HT uptake sites) between rTMS-treated, sham and control animals. In contrast, the number of 5-HT1A binding sites (labeled with 3H-8-OH-DPAT) were selectively increased in the rTMS-group with significantly higher BMAX values in the frontal cortex, the cingulate cortex, and the anterior olfactory nucleus. A non-specific increase in NMDA binding sites (labeled with 125I-MK-801) in rTMS and sham animals was observed in the hippocampal formation. A selective increase of these binding sites after rTMS was detected in the ventromedial hypothalamus, the basolateral amygdala and layers 5-6 of the parietal cortex. These findings imply that a single rTMS exposure can result in persistent effects on NMDA and 5-HT1A binding sites even 24 h after stimulation and therefore may be of relevance with respect to the therapeutic action of rTMS reported from clinical studies.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1999

Extracellular single-unit recordings of piriform cortex neurons in rats: influence of different types of anesthesia and characterization of neurons by pharmacological manipulation of serotonin receptors.

In epilepsy research, there is a growing interest in the role of the piriform cortex (PC) in the development and maintenance of limbic kindling and other types of limbic epileptogenesis leading to complex partial seizures. Neurophysiological studies on PC or amygdala-PC slice preparations from kindled rats showed that kindling of the amygdala induces long-lasting changes in synaptic efficacy in the ipsilateral PC, including spontaneous discharges and enhanced susceptibility of PC neurons to evoked burst responses. These long-lasting electrophysiological changes in the PC during kindling appear to be due, at least in part, to impaired function of gamma-aminobutyric acid (GABA)ergic interneurons. The aim of the present study was to develop an anesthetic protocol allowing electrophysiological single-unit recordings from inhibitory, presumably GABAergic PC interneurons in vivo. In addition to recording of spontaneously active PC neurons, microiontophoretic application of glutamate was used to activate silent neurons. Anesthesia of rats with ketamine/xylazine was not suited for single-unit recordings in the PC because of marked cardiovascular depression. Anesthesia with chloral hydrate allowed recording of spontaneous or glutamate-driven single-unit activity in approximately 40% of all animals. A similar percentage was obtained when recordings were done with the narcotic opioid fentanyl (plus gallamine), after all surgical preparations were performed under anesthesia with repeated administration of the barbiturate methohexital. To avoid brain accumulation of methohexital by repeated applications, we modified the anesthetic protocol in that methohexital was only injected once for initiation of surgical anesthesia, followed by the short-acting anesthetic propofol which does not accumulate upon repeated application. Again, after surgical preparation, electrophysiological recordings were done under fentanyl (plus gallamine). By this procedure, spontaneous or glutamate-driven single-unit activity could be measured in all rats in either layer II or III of the PC. Based on shape and frequency of action potentials, two types of neurons were recorded. The predominant type was similar in its firing characteristics to GABAergic neurons in other brain regions, was mainly located in layer III, and could be suppressed by the serotonin2A receptor antagonist MDL 100,907, suggesting that this type of PC neuron represents inhibitory, putative GABAergic interneurons. This new in vivo preparation may be useful for evaluation of PC neurons in kindled rats.

Action Potentials↗

PubMed1999

Effects of captopril and enalapril on electroencephalogram and cognitive performance in healthy volunteers.

OBJECTIVE: Captopril and enalapril have been reported to influence cognitive functions and quality of life in hypertensive patients. METHODS: The effects of captopril (12.5 mg and 25 mg) and enalapril (5 mg and 10 mg) administered during 7-day periods on electroencephalogram (EEG), cognitive functions, and subjective assessments were investigated in healthy males. RESULTS: Neither captopril nor enalapril influenced EEG and cognitive functions compared with placebo. Captopril 12.5 mg decreased subjective activity compared with placebo. Enalapril did not alter subjective ratings. Both systolic and diastolic blood pressure were significantly lower after administration of captopril 25 mg, whereas blood pressure was unaffected by enalapril compared with placebo. CONCLUSION: Our results suggest that central effects of captopril and enalapril were minor and not constant in young healthy men.

Adult↗

PubMed1999

Anticonvulsant effects of eliprodil alone or combined with the glycineB receptor antagonist L-701,324 or the competitive NMDA antagonist CGP 40116 in the amygdala kindling model in rats.

The discovery that glutamate's activity at the N-methyl-D-aspartate (NMDA) receptor is positively modulated by glycine and polyamines has led to a new pharmacological strategy that NMDA receptor-mediated events could be antagonized indirectly at the strychnine-insensitive glycine co-agonist site (glycine(B) receptor) and the polyamine modulatory site. Recently we demonstrated that ifenprodil and L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinoline), polyamine and glycine, receptor antagonists, respectively, at subeffective doses markedly increased after-discharge threshold (ADT) when applied together in amygdala-kindled rats. Because ifenprodil and its derivative, eliprodil, exhibit different affinities for NMDA receptors composed of different subunits, our current question was whether a combination of eliprodil and the glycine, receptor antagonist, L-701,324, would produce a super-additive anticonvulsant action. In addition, we examined the combined treatment of eliprodil with a competitive NMDA receptor antagonist CGP 40116 (D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) in the kindling model. Eliprodil alone (10-40 mg/kg) had no consistent ADT-increasing activity. When eliprodil was combined with an ineffective dose of L-701,324 (2.5 mg/kg), a significant rise in ADT was observed. Likewise, other measures of seizure activity such as severity and duration were modestly but significantly reduced. With respect to behavioral impairments, no signs of synergistic interaction were observed after the drug combinations. On the other hand, no anticonvulsant effects were found when CGP 40116 was administered alone at doses of 1.25-5 mg/kg or CGP 40116 1.25 mg/kg combined with eliprodil 10 mg/kg. These data suggest that combination therapy with antagonists at the polyamine and glycine sites might potentially treat therapy-resistant complex partial seizures.

2-Amino-5-phosphonovalerate↗

PubMed1999

Immunohistochemical and neurochemical studies on nigral and striatal functions in the circling (ci) rat, a genetic animal model with spontaneous rotational behavior.

Asymmetrical spontaneous turning behavior or circling phenomena are often related to components of the dopaminergic system, particularly to an imbalance of nigrostriatal function. When a rotational preference is observed, it is typically in a direction away from the brain hemisphere with higher striatal dopaminergic transmission. We have recently described a rat mutant (ci) with spontaneous circling behavior and other signs of functional brain asymmetry. Neurochemical determinations showed that mutants of both genders have significantly lower concentrations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. In the present study, we used immunohistochemical, neurochemical, and autoradiographic techniques to characterize the dopaminergic abnormalities of the ci rat mutant in more detail. Age-matched non-affected controls of the same strain were used for comparison. Immunohistochemical labeling of dopaminergic neurons and fibers in substantia nigra pars compacta, ventral tegmental area, and striatum did not indicate any significant neurodegeneration or asymmetry that could explain the lateralization in dopamine levels in striatum of ci rats. Neurochemical determinations substantiated that ci rats of both genders have a significant imbalance in striatal dopamine metabolism, but a similar significant lateralization was also seen in non-affected female controls. Comparison of dopamine, serotonin, noradrenaline and several monoamine metabolite levels in substantia nigra, striatum, nucleus accumbens and frontal cortex of ci rats and controls did not disclose any marked difference between affected and non-affected animals which was consistently found in both genders. Quantitative autoradiographic determination of binding densities of dopamine transporter and D1 and D2 receptors in several parts of the striatum and substantia nigra indicated that ci rats have a significantly higher binding density of dopamine transporter and receptors than controls. Taken together, ci mutant rats of both genders exhibit an asymmetry in striatal dopamine and metabolite levels and an enhanced dopamine transporter and receptor binding, but the link of these differences in dopaminergic parameters with the rotational behavior of the animals is not clear yet. The lack of any significant dopaminergic cell loss in the substantia nigra and the locomotor hyperactivity observed in the mutants clearly suggest that the ci rat is not suited as a model of Parkinsonism but rather constitutes a model of a hyperkinetic motor syndrome.

Animals↗