Biomedical subjects

P C Jobe

Publications and source records attributed to P C Jobe.

At least 37 records · Page 2Linked to original sources

PubMed1997

Fos in locus coeruleus neurons following audiogenic seizure in the genetically epilepsy-prone rat: comparison to electroshock and pentylenetetrazol seizure models.

Seizures in genetically epilepsy-prone rats (GEPRs) may result from hypoactivity of locus coeruleus (LC) neurons during seizures. This study examined Fos-like-immunoreactivity (FLI) in the LC following audiogenic seizures in two strains of GEPRs (GEPR-9s and -3s), and following pentylenetetrazol (PTZ) or maximal electroshock seizures (MES) in normal rats. After tonic seizure, GEPR-9s showed an identical LC-FLI response to that of normal rats following tonic seizures induced by either PTZ or MES. GEPR-3s, having clonic seizures, had less FLI in the LC. Therefore, stimulus-transcription coupling in the GEPR LC is apparently normo-typic in its FLI response to seizure and thus is not likely the root cause of NE abnormalities in this seizure model.

Animals↗

PubMed1997

Dizocilpine (MK-801) increases not only dopamine but also serotonin and norepinephrine transmissions in the nucleus accumbens as measured by microdialysis in freely moving rats.

The extracellular concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the nucleus accumbens (NACC) of freely moving rats were monitored simultaneously via intracerebral microdialysis. Local infusion of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) (5-250 microM) produced significant increases in extracellular levels of DA, NE and 5-HT in a concentration-dependent fashion. Perfusion with tetrodotoxin (TTX, 1 microM) blocked the ability of focal MK-801 (50 microM) to increase DA, NE and 5-HT in the dialysate. Systemic administration of MK-801 (0.3 mg/kg, i.p.) also produced small, but statistically significant, increases in extracellular concentrations of DA, NE and 5-HT in the NACC. Our microdialysis results are consistent with the hypothesis that, in addition to dopaminergic, serotonergic and noradrenergic neurotransmissions in the NACC are involved in the mechanism by which MK-801 alters behavior in rats. Also, the present study gives further support to the concept that NMDA receptors within the NACC do not regulate DA release through direct excitatory control.

Animals↗

PubMed1997

Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+.

Carbamazepine administration causes large increases in extracellular serotonin concentration and dose-related anticonvulsant effects in genetically epilepsy-prone rats (GEPRs). In order to determine the generality of the effect on serotonin, we determined the anticonvulsant ED50 for carbamazepine against maximal electroshock seizures in outbred, non-epileptic Sprague-Dawley rats. We then administered anticonvulsant carbamazepine doses to Sprague-Dawley rats and observed extracellular serotonin concentration in hippocampi by way of microdialysis. We found that administration of carbamazepine, either systemically or through the dialysis probe, resulted in significant and dose-related increases in extracellular serotonin concentration. Basal serotonin release was decreased by tetrodotoxin administration through the dialysis probe. Tetrodotoxin administration through the dialysis probe did not decrease the effect of systemically or focally administered carbamazepine on extracellular serotonin concentration. Similarly, elimination of Ca2+ from the dialysate did not alter the release of serotonin caused by carbamazepine. These findings suggest that the serotonin releasing effect of carbamazepine does not take place by exocytosis and does not require action potentials in the brain area in which the release takes place. Further they suggest that the effect is mediated by an action of carbamazepine directly on serotonergic nerve terminals.

Animals↗

PubMed1997

Anticonvulsant doses of carbamazepine increase hippocampal extracellular serotonin in genetically epilepsy-prone rats: dose response relationships.

The antiepileptic drug carbamazepine produces dose related anticonvulsant effects in genetically epilepsy-prone rats (GEPRs) and most other animal seizure models. Carbamazepine releases serotonin as part of the pharmacodynamic action by which it suppresses convulsions in GEPRs and it releases serotonin in non-epileptic Sprague-Dawley rats. The two strains which make up the GEPR seizure model (moderate seizure GEPR-3s and severe seizure GEPR-9s) experience anticonvulsant effects in response to different doses of carbamazepine (GEPR-3 ED50 = 25 mg/kg; GEPR-9 ED50 = 3 mg/kg). The present study determined that carbamazepine produces a dose related increase in extracellular serotonin in each of the two GEPR strains. The doses of carbamazepine required to increase extracellular serotonin are similar to the doses required for an anticonvulsant effect in each of the strains. This result provides further support for the hypothesis that release of serotonin by carbamazepine is an important part of the pharmacodynamic action by which this drug suppresses seizures.

Analysis of Variance↗

PubMed1997

Seizures and proto-oncogene expression of fos in the brain of adult genetically epilepsy-prone rats.

The mechanisms and brain circuitry that render genetically epilepsy-prone rats (GEPRs) susceptible to acoustically induced seizures are not completely known. The present study explores the neuroanatomy of acoustically induced seizures by immunohistochemical analysis of the proto-oncoprotein fos after intense acoustic stimulation (AS) with and without seizures. Acoustic stimulation induced tonic convulsions in GEPR-9s, but not in control rats. Locations of brain nuclei showing fos-like immunoreactive (FLI) neurons following AS with and without seizures were mapped. Semiquantitative methods were used to compare FLI neuron numerical densities in AS control rats and GEPRs. Many brain areas exhibited profound FLI in AS control rats and GEPRs. Unexpectedly, the cochlear nuclei and the central nucleus of the inferior colliculi (ICc), both of which are requisite for AGS initiation, exhibited a diminished fos expression in animals having seizures compared to AS controls. In contrast, GEPRs displayed a significant increase in FLI neurons within the dorsal cortex of the IC (ICd) compared to AS controls. This finding may suggest a seizure-related amplification of the auditory signal between the ICc and the ICd. Other nuclei, known to be involved in auditory transmission (i.e., superior olivary complex; trapezoid nucleus; dorsal nucleus of the lateral lemniscus, DNLL), did not show differential FLI densities between seizure and AS control animals. In contrast, seizure-induced FLI was observed in many nonauditory brain nuclei. Of particular interest was the identification of an intensely labeled nucleus in the GEPR. This nucleus resides in the most posterior and dorsal-lateral part of the pedunculopontine tegmental nucleus-pars compacta (PPTn-pc) immediately adjacent to the DNLL and extends posteriorly into the superior lateral subnucleus of the lateral parabrachial area (SLPBn). Therefore, we have tentatively termed this nucleus the PPSLPBn. The PPSLPBn lies in a region previously described as a mesencephalic locomotor region and a suspected functional involvement of this nucleus in display of seizure activity is under investigation. Other brain stem nuclei showing differential fos expression between GEPRs and AS control rats are also described.

Acoustic Stimulation↗

PubMed1997

Anticonvulsant and proconvulsant roles of nitric oxide in experimental epilepsy models.

The effect of acute (120 mg/kg) and chronic (25 mg/kg, twice a day, for 4 days) intraperitonial injection of the nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG) was evaluated on seizure induction by drugs such as pilocarpine and pentylenetetrazole (PTZ) and by sound stimulation of audiogenic seizure-resistant (R) and audiogenic seizure-susceptible (S) rats. Seizures were elicited by a subconvulsant dose of pilocarpine (100 mg/kg) only after NOS inhibition. NOS inhibition also simultaneously potentiated the severity of PTZ-induced limbic seizures (60 mg/kg) and protected against PTZ-induced tonic seizures (80 mg/kg). The audiogenic seizure susceptibility of S or R rats did not change after similar treatments. In conclusion, proconvulsant effects of NOS inhibition are suggested to occur in the pilocarpine model and in the limbic components of PTZ-induced seizures, while an anticonvulsant role is suggested for the tonic seizures induced by higher doses of PTZ, revealing inhibitor-specific interactions with convulsant dose and also confirming the hypothesis that the effects of NOS inhibitors vary with the model of seizure.

Animals↗

PubMed1996

Focal ethanol elevates extracellular dopamine and serotonin concentrations in the rat ventral tegmental area.

The present study describes the effects of local perfusion with ethanol on extracellular dopamine and serotonin (5-hydroxytryptamine, 5-HT) concentrations in the ventral tegmental area. Various concentrations of ethanol in artificial cerebrospinal fluid (ACSF) (0.1-10%, v/v) were administered through a microdialysis probe into the ventral tegmental area of freely moving Sprague-Dawley rats. A significant and concentration-dependent increment in dialysate output of both dopamine and serotonin was observed after local infusion of ethanol. Perfusion with Ca(2+)-free medium or tetrodotoxin (1 microM in ACSF) produced a significant reduction in basal extracellular dopamine and serotonin concentration but failed to block dopamine or serotonin release produced by infusion of 10% ethanol. Perfusion with 100 mM K+ before and after infusion of 10% ethanol revealed that the second perfusion with high K+ solution still produced an increase in dopamine and serotonin concentration, similar in magnitude to the first response, indicating that perfusion with 10% ethanol did not cause irreversible damage to either dopamine cell bodies or serotonin terminals in the ventral tegmental area. These results suggest that dopamine and serotonin release from the ventral tegmental area produced by focal application of 10% ethanol is mediated, at least in part, by a non-exocytotic mechanism. Direct stimulation of the ventral tegmental area dopamine neurons by ethanol might be involved in the reinforcing properties of the drug.

Animals↗

PubMed1996

Neurochemical correlates of antiepileptic drugs in the genetically epilepsy-prone rat (GEPR).

The GEPR model is composed of two independently derived strains of rats each characterized by a broad-based seizure predisposition. Moderate seizure GEPRs (GEPR-3s) exhibit generalized clonus with loss of righting reflex in response to a standardized sound stimulus. The same stimulus in severe seizure GEPRs (GEPR-9s) produces a tonic-clonic convulsion much like that produced by supramaximal electroshock. The numeric descriptors (3 and 9) derive from the ordinal rating scale developed by Jobe and coworkers for evaluation of convulsion intensity. GEPRs experience an anticonvulsant effect in response to all established and many experimental antiepileptic drugs and distinctions between the classes of drugs can be made. Since serotonin plays an anticonvulsant role in nearly all animal seizure models, we examined the effects of antiepileptic drugs on serotonin using microdialysis. Among clinically effective anticonvulsants, carbamazepine, antiepilepsirine (used in China) and loreclezole produced dose-related anticonvulsant effects and increases in extracellular serotonin in GEPRs. Similarly, drugs known to block serotonin reuptake and increase extracellular serotonin (fluoxetine and sertraline) produce dose related anticonvulsant effects in GEPRs and other animal models. Accentuation of serotonin release by treating GEPRs with fluoxetine and 5-hydroxytryptophan enhances the anticonvulsant effect produced by fluoxetine. Depletion of serotonin greatly decreased the anticonvulsant effect produced by carbamazepine, antiepilepsirine and fluoxetine. Phenytoin produced a dose related anticonvulsant effect in GEPRs but did not increase extracellular serotonin. Depletion of serotonin did not diminish the anticonvulsant effect produced by phenytoin. Thus, serotonin appears to play a role in the anticonvulsant effect of several but not all anticonvulsant drugs.

Animals↗

PubMed1996

Effect of 5,7-dihydroxytryptamine on audiogenic seizures in genetically epilepsy-prone rats.

To further assess the role of 5-HT in the modulation of audiogenic seizures (AGS) in the Genetically Epilepsy-Prone Rat (GEPR), changes in AGS severity after widespread chronic depletion of brain 5-HT by intracerebroventricular administration of 5,7-dihydroxytryptamine (5,7-DHT) were examined in moderate seizure GEPRs (GEPR-3s). Following treatment with 5,7-DHT (150 micrograms/30 microliters), a significant increase in seizure severity was observed at 2, 3 and 4 weeks as compared to vehicle-injected controls. The increase in seizure severity was evidenced by a significant increase in the incidence of tonic convulsions in 5,7-DHT treated animals (53% in treated animals compared to 0% in vehicle treated controls) over the testing period. Interestingly, the latency to wild running was increased in 5,7-DHT treated GEPRs, suggesting that depletion of brain 5-HT may slow initiation of AGS. Neurochemical analysis revealed marked depletion of 5-HT in the cortex (-96%), hippocampus (-94%), thalamus (-80%), hypothalamus (-62%), midbrain (-51%) and pons-medulla (-52%) in animals that received 5,7-DHT. However, no significant reductions in brain norepinephrine content were observed in any of the regions assayed due to the pretreatment of all animals with protriptyline. The present findings lend further support for an inhibitory action of brain 5-HT on audiogenic seizures in GEPRs.

5,7-Dihydroxytryptamine↗

PubMed1996

Abnormalities in 5-HT1A and 5-HT1B receptor binding in severe-seizure genetically epilepsy-prone rats (GEPR-9s).

The present study was designed to determine whether abnormalities in serotonin receptor binding co-exist with the presynaptic serotonergic deficits that have previously been identified in the genetically epilepsy-prone rat (GEPR) brain. In vitro binding of [3H]8-OH-DPAT (0.16-10.3 nM) to 5-HT1A receptor sites was found to be decreased in the hippocampus of severe seizure GEPRs (GEPR-9s) when compared to nonepileptic control rats, while no difference in [3H]8-OH-DPAT binding was observed in the GEPR-9 corpora quadrigemina or midbrain tegmentum. The decreased binding of [3H]8-OH-DPAT to hippocampal membranes was due to a decrease in Bmax (P < 0.001), rather than to a change in the Kd. Conversely, in vitro binding of [125I]cyanopindolol (2-400 pM) to 5-HT1B receptor sites was increased in the GEPR-9 hippocampus, corpora quadrigemina and midbrain tegmentum when compared to nonepileptic control rats. The increased binding of [125I]cyanopindolol in all three regions resulted from an increase in the Bmax (P < 0.05), rather than a change in the Kd. These finding suggest that in addition to the innate reduction in 5-HT presynaptic markers, GEPR-9s also exhibit abnormalities in the density of 5-HT1A and 5-HT1B receptors in some regions of the brain. Inasmuch as serotonin acts to attenuate audiogenic seizures in GEPRs, these abnormalities in 5-HT receptor binding may contribute to the seizure susceptibility exhibited by these animals.

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

PubMed1996

Amygdala kindling of forebrain seizures and the occurrence of brainstem seizures in genetically epilepsy-prone rats.

Forebrain seizures were kindled in rats by daily electrical stimulation of the amygdala. Genetically epilepsy-prone rats scoring 9 (GEPR-9s) on the seizure severity scale during audiogenic seizure (AGS) screening ("brainstem seizure-experienced") required fewer stimulations to achieve fully kindled seizures (forelimb clonus with rearing and falling) than control rats. AGS-naive GEPR-9s required an intermediate number of stimulations, indicating a role for both genetic predisposition and previous acoustically evoked brainstem seizure experience. Other forebrain kindling indices such as afterdischarge threshold/duration and seizure latency/duration also involved genetic as well as phenotypic (previous seizure experience) factors. In most GEPR-9s in both groups, severe brainstem seizures occurred after forebrain stimulation. The occurrence of brainstem seizures had a random nature and was not related to the sequence of kindling-dependent forebrain seizure progression. The lack of a difference in the occurrence of brainstem seizures between seizure-experienced and AGS-naive GEPR-9s suggest that genetic predisposition is the major factor in forebrain seizure-induced activation of brainstem seizure circuitry. This brainstem seizure activity appears to model pertinent aspects of secondary generalization observed in human partial seizures.

Acoustic Stimulation↗

PubMed1996

Abnormalities in brain serotonin concentration, high-affinity uptake, and tryptophan hydroxylase activity in severe-seizure genetically epilepsy-prone rats.

We characterized the nature of the deficit in brain serotonin (5-HT) exhibited by genetically epilepsy-prone rats (GEPR-9s) by regionally assessing three markers for 5-HT terminals/neurons (5-HT content, 5-HT uptake into the P2-synaptosomal fraction, and tryptophan hydroxylase activity) in GEPR-9s and nonepileptic control rats. As compared with controls, GEPR-9s had reduced brain 5-HT concentration, synaptosomal 5-HT uptake, and tryptophan hydroxylase activity (measured in vivo and in vitro) in most regions of the forebrain and in selected regions of brainstem. Analysis of kinetic constants for synaptosomal [(3)H]5-HT uptake and in vitro tryptophan hydroxylase activity showed that the decrements in these parameters exhibited by GEPR-9s resulted from reductions in V(max) rather than changes in K(m). In general, the reduction in each of the presynaptic markers for 5-HT terminals/neurons was similar in both magnitude and in their regional distribution in the GEPR-9 brain. An exception to this was noted in the midbrain tegmentum of GEPR-9s, which displayed a significant reduction in tryptophan hydroxylase activity without showing alterations in 5-HT concentration or in high-affinity 5-HT uptake. The present findings support the hypothesis that there is a widespread reduction in the number of serotonergic/neurons in GEPR-9 brain.

Acoustic Stimulation↗

PubMed1995

Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response.

D-20443 is an experimental antiepileptic drug. Its mechanism of antiepileptic action is unknown. We evaluated the anticonvulsant effectiveness of D-20443 against sound-induced seizures in genetically epilepsy-prone rats (GEPRs). This compound produced anticonvulsant effects against sound-induced seizures in moderate seizure GEPRs (GEPR-3s) at significantly lower doses than in severe seizure GEPRs (GEPR-9s). Based on these data and on the responses of GEPRs to other antiepileptic drugs, we predict that D-20443 will be a broad spectrum antiepileptic agent in humans. That is, we predict that D-20443 will suppress both tonic/clonic and absence seizures in humans.

Animals↗

PubMed1995

Further evidence of anticonvulsant role for 5-hydroxytryptamine in genetically epilepsy-prone rats.

1. This study was designed to evaluate further the role of 5-hydroxytryptamine (5-HT) in regulating susceptibility and/or intensity of audiogenic seizures in genetically epilepsy-prone rats. 2. The effects of sertraline, a highly selective and potent inhibitor of 5-HT uptake, on both the intensity of the audiogenic seizures and the extracellular concentrations of 5-HT in the thalamus were evaluated in severe seizure genetically epilepsy-prone rats. 3. Sertraline (7.5, 15 and 30 mg kg-1, i.p.) produced a dose-dependent reduction in the intensity of the audiogenic seizures. 4. Brain microdialysis studies showed that the same doses of sertraline also caused dose-dependent increases in the extracellular 5-HT concentration in the thalamus of the freely moving rats. 5. The peak anticonvulsant effect correlated temporally with the peak increases in the extracellular 5-HT concentration for this drug. 6. It is concluded that enhancement of 5-hydroxytryptaminergic transmission may contribute to the anticonvulsant effect of sertraline in severe seizure genetically epilepsy-prone rats. 7. The present results coupled with earlier investigations support the hypothesis that 5-HT plays an anticonvulsant role in genetically epilepsy-prone rats.

1-Naphthylamine↗

PubMed1995

Alteration in levels of expression of brain calbindin D-28k and calretinin mRNA in genetically epilepsy-prone rats.

Variations in the concentration of free calcium in neurons is believed to play a major role in regulating neuronal excitability. Because calcium-binding proteins such as calbindin D-28k and calretinin help to regulate intracellular calcium, we investigated the possibility that the expression of these proteins may be affected in genetically epilepsy-prone rats (GEPRs). The mRNA levels of both proteins were compared across several brain regions using in situ hybridization histochemistry and Northern blot analysis with semiquantitation by optical density measures in autoradiograms from two GEPR strains that differ in the severity of audiogenic seizures (GEPR9 and GEPR3) and from Sprague-Dawley rats. Results revealed a lower level of expression in calbindin D-28k mRNA in the in the caudate putamen-accumbens nuclei in GEPR3 (-30%) and GEPR9 (-60%) relative to controls. The calbindin D-28k mRNA level was also lower in the reuniens nucleus of the thalamus (-41% in GEPR3; -34% in GEPR9). The calretinin mRNA level was lower in the substantia nigra compacta of both GEPR rat strains (-31% in GEPR3 and -34% in GEPR9 relative to controls). No changes in mRNA were detected in other brain regions expressing calbindin D-28k or calretinin mRNA. These results indicate that the expression of these related calcium-binding proteins is altered in the GEPRs before the induction of seizures. This initial defect could alter either the calcium-buffering capacity or regulation of calcium-mediated processes by these proteins and thus play a role in the molecular cascade of events inducing the genetic susceptibility to, and the generalization of, seizures in these rat strains.

Animals↗

PubMed1994

The anticonvulsant effect of the broad spectrum anticonvulsant loreclezole may be mediated in part by serotonin in rats: a microdialysis study.

Loreclezole is an experimental anticonvulsant drug. We found previously that several established anticonvulsants increase extracellular serotonin as measured by microdialysis. We have concluded that the increase in extracellular serotonin and the anticonvulsant effect produced by these anticonvulsant drugs are related in a cause and effect manner. To determine if anticonvulsant doses of loreclezole increase extracellular serotonin, we determined anticonvulsant dose-response relationships in genetically epilepsy-prone rats (GEPRs). Then, we administered ED99 doses of loreclezole to GEPRs and determined the effect on extracellular serotonin as measured by microdialysis in the striatum. We conclude that loreclezole produces a dose-related anticonvulsant effect in GEPRs and that anticonvulsant doses of loreclezole increase extracellular serotonin in these animals.

Acoustic Stimulation↗

PubMed1994

Evidence that a serotonergic mechanism is involved in the anticonvulsant effect of fluoxetine in genetically epilepsy-prone rats.

Fluoxetine (15 mg/kg i.p.) decreased the audiogenic seizure intensity in 33% of severe seizure genetically epilepsy-prone rats (GEPR-9s). 5-Hydroxytryptophan (5-HTP, 12.5 mg/kg i.p.) produced no anticonvulsant effect in GEPR-9s. When GEPR-9s were treated with a combination of these two drugs, the combination treatment decreased the audiogenic seizure intensity in 83% of the animals tested. Brain microdialysis studies showed that the same combination of 5-HTP and fluoxetine also produced a marked potentiation of the increase in the extracellular serotonin concentration in the thalamus of freely-moving GEPR-9s when compared with administration of either drug alone. A negative correlation between audiogenic seizure intensity and extracellular serotonin concentration existed after either fluoxetine alone or the combination treatment. No significant changes in extracellular norepinephrine concentrations were observed after the combination treatment. These results coupled with our earlier reports strongly suggest that a serotonergic mechanism is involved in the anticonvulsant effects of fluoxetine in GEPRs.

5-Hydroxytryptophan↗

PubMed1994

Role of norepinephrine in forebrain and brainstem seizures: chemical lesioning of locus ceruleus with DSP4.

The role of norepinephrine in regulating brainstem seizures has been well documented. These seizures are characterized by running/bouncing clonus and tonic extensor convulsions. Evidence for noradrenergic regulation of brainstem seizures comes partially from studies with genetic models of epilepsy which are characterized by innate noradrenergic deficits and from selective lesioning of noradrenergic neurons and/or pathways. The present study was conducted to evaluate whether destruction of the noradrenergic system using DSP4 (N-(2-chloroethyl)-N-2-bromobenzylamine) influences forebrain seizure severity. Accordingly, 90 female Sprague-Dawley rats (49-55 days old) received DSP4 (50 mg/kg ip) after a pretreatment of desipramine (a norepinephrine reuptake inhibitor), fluoxetine (a serotonin reuptake inhibitor), or saline. A control group of 30 animals received two administrations of saline. Three weeks later, these animals were tested for facial and forelimb clonus (FFC) threshold (convulsive current50; CC50) via corneal electroshock stimulation. The FFC CC50 thresholds in the animals treated with saline plus DSP4 were significantly reduced compared to control (vehicle-vehicle) values. Also, desipramine pretreatment, which partially protected the noradrenergic system from the neurotoxicity of DSP4, completely obviated the reduction in FFC thresholds. A subsequent evaluation of brainstem seizure response using maximal electroshock through earclip electrodes confirmed the noradrenergic influence on brainstem seizure regulation. These observations provide additional support for a noradrenergic role in forebrain as well as brainstem seizure regulation.

Animals↗