Steven L. Peterson

Neurotransmitter and neuromodulator function in the kindled seizure and state

Introduction 1.1. Importance of paradigm 1.2. The kindling process or acqmsition 1.3. Distinction between kindled seizures and the kindled state 1,4. Cross-sensitivity and synergistic effects between chemical and electrical kindling Biogenic amines in kindling 2,1. Kindling process 2.2. Kindled seizure 2.3. Kindled state 2.4. Cyclic nucleotides and kindling 2.5. Biogenic amines as possible modulators of kindling 2.6. Biogenic amines: kindled seizures vs. kindled state Cholinergic systems 3.1. Kindling process 3.2. Kindled seizures and kindled state 3.3. Chemical kindling and cross-sensitivity Opiate systems 4.1. Kindling process 4.2. Kindled seizures and kindled state GABAergic systems 5.1, Kindling process 5.2. Kindled seizures vs. kindled state 5.3, Chemical kindling and GABA Benzodiazepine system Concluding remarks Acknowledgements References 237 238 238 238 240 242 242 251 253 254 254 255 255 255 256 257 258 258 259 260 260 261 262 263 263 265 266

ANTICONVULSANT DRUG POTENTIATION BY GLYCINE IN MAXIMAL ELECTROSHOCK SEIZURES IS MIMICKED BY D-SERINE AND ANTAGONIZED BY 7-CHLOROKYNURENIC ACID

This study evaluated a possible mechanism by which glycine potentiates the activity of anticonvulsant drugs against maximal electroshock seizures in rats. Administered concurrently, glycine (40 mmol/kg p.o.) significantly enhanced the anticonvulsant effect of phenobarbital, carbamazepine and phenytoin as determined by the occurrence of tonic hindlimb extension. Likewise, concurrent administration of the strychnine-insensitive glycine receptor agonist, D-serine (20 mmol/kg p.o.) significantly enhanced the anticonvulsant effect of phenobarbital, carbamazepine and phenytoin. L-Serine was ineffective. Administration of the strychnine-insensitive glycine receptor antagonist, 7-chlorokynurenic acid (100 nmol i.c.v.), significantly antagonized the potentiation of anticonvulsant activity induced by glycine co-administered with either phenobarbital or phenytoin. 7-Chlorokynurenic acid did not block tonic hindlimb extension when administered alone and did not affect the activity of the anticonvulsants in the absence of glycine. These results provide evidence for the potentiation of certain anticonvulsant drugs by glycine as a specific effect that may be mediated by the strychnine-insensitive glycine receptor.

Infusion of NMDA antagonists into the nucleus reticularis pontis oralis inhibits the maximal electroshock seizure response

The nucleus reticularis pontis oralis (RPO) is necessary for the expression of tonic hindlimb extension (THE) in maximal electroshock (MES) seizures of rats. Previous work in this laboratory has demonstrated that both systemic administration and focal RPO microinfusion of D-cycloserine inhibits THE. The purpose of the present study was to characterize specific components of the NMDA receptor/ionophore complex that regulate the anticonvulsant activity mediated by the RPO. Bilateral RPO microinfusion of the competitive NMDA antagonists (-)AP7 and D-CPP as well as the uncompetitive antagonist dizocilpine ((+)MK-801) inhibited THE in a dose-related fashion. Bilateral RPO microinfusion of NMDA did not affect the THE response to MES but did induce convulsions resembling audiogenic seizures in genetically epilepsy prone rats. Bilateral RPO microinfusion of the strychnine-insensitive glycine site partial agonist D-cycloserine and the antagonist 5,7-dichlorokynurenic acid inhibited THE. The strychnine-insensitive glycine partial agonists (+)HA-966 and ACPC, as well as the agonists glycine and D-serine, did not significantly affect the THE response. Strychnine microinfusions in the RPO had no effect on THE. The results support a hypothesis that the RPO is a site of anticonvulsant drug action in MES and indicate that either competitive or uncompetitive NMDA antagonist action regulates the anticonvulsant activity mediated by the RPO. The role of the strychnine-insensitive glycine site in the regulation of the anticonvulsant activity medicated by the RPO is uncertain.

The anticonvulsant activity of D-cycloserine is specific for tonic convulsions

D-Cycloserine has been shown to exert anticonvulsant activity in maximal electroshock seizures. The purpose of the present study was to evaluate the spectrum of D-cycloserine anticonvulsant activity using other experimental models of epilepsy. D-Cycloserine induced a dose-related decrease in the incidence of tonic convulsions induced by 120 mg/kg of pentylenetetrazol. The ED50 of D-cycloserine for the inhibition of the tonic convulsions was 109 mg/kg. The anticonvulsant activity was specific for the D-isomer at L-cycloserine (400 mg/kg) had no effect on the tonic convulsions. D-Cycloserine had no effect on the pentylenetetrazol-induced clonic convulsions induced by either 70 or 120 mg/kg pentylenetetrazol, electrically induced nonkindled hippocampal seizures or kindled amygdala seizures. D-Cycloserine had no effect on strychnine-induced tonic convulsions. These results indicate that D-cycloserine is inactive against clonic convulsions and may be active only against tonic convulsions mediated by brainstem sites.

Cis-flupentixol antagonism of the rat prefrontal cortex neuronal response to apomorphine and ventral tegmental area input

This study was designed to characterize the response of a select population of prefrontal cortex neurons to exogenous and endogenous dopaminergic influences. Of particular interest were neurons with efferent projections to the ventral tegmental area (VTA) which are part of a reciprocal innervation between the prefrontal cortex and the VTA. Extracellular single unit recording techniques were used to determine the response of cortical neurons to electrical stimulation of the VTA in chloral hydrate anesthetized rats. The neurons were selected on the basis of their electrophysiological characteristics (large amplitude with positive initial deflection) and were classified as to whether or not they were antidromically activated from the VTA. Apomorphine (25 micrograms/kg, IV) significantly reduced the spontaneous activity of both the antidromically identified and the unidentified prefrontal cortex neurons. The apomorphine (25 micrograms/kg, IV) response was antagonized by cis-flupentixol (1.0 mg/kg, IV) in both antidromically identified and unidentified cortical neurons. Stimulation of the VTA also induced a synaptically mediated inhibition of the cortical neuron spontaneous activity. The orthodromic VTA stimulus-evoked inhibition was antagonized by cis-flupentixol (1.0 mg/kg, IV) for both the antidromically identified and the unidentified neurons (63 and 71% of the neurons respectively). The results indicate that a select population of prefrontal cortex neurons respond specifically to exogenous and endogenous dopaminergic influences and that the response is independent of efferent projections to the VTA.

Potentiation by glycine of anticonvulsant drugs in maximal electroshock seizures in rats

This study evaluated the potentiation by glycine of anticonvulsant drugs in maximal electroshock seizures in rats. Administered alone, glycine (40 mmol/kg, p.o.) induced no anticonvulsant effect or neurotoxicity. Administered together with the anticonvulsants, glycine significantly enhanced the anticonvulsant potency of phenobarbital and carbamazepine. Glycine also potentiated the anticonvulsant actions of MK-801 and diazepam but did not improve the selectivity of the drugs, as effective doses were still associated with neurotoxicity. Glycine did not potentiate phenytoin or sodium divalproate. Administration together with glycine had no significant effect on the concentrations of phenobarbital or carbamazepine in the brain. Administration together with phenobarbital had no relevant effect on the concentration of glycine in the brain but administration of glycine and carbamazepine together resulted in an increased concentration of glycine in the hippocampus and brainstem. These findings indicate a possible glycine-sensitive component in the mechanism of action of phenobarbital, carbamazepine and diazepam in maximal electroshock seizures. Although the mechanism may not be mediated by a glycine-GABA interaction, the evidence does implicate a possible interaction between glycine and anticonvulsant drugs at NMDA receptors.

Chronic but not acute treatment with antidepressants enhances the electroconvulsive seizure response in rats.

The effects of the chronic administration of antidepressants on threshold electroconvulsive (ECS) seizures were evaluated in rats. Initially, tonic-clonic seizures were induced in 90% of the animals. Of those animals responding with tonic-clonic seizures, 42% had hindlimb extension (extensors); the remainder showed only hindlimb flexion (flexors). No alteration in the pattern of seizures was observed 24 hr after a single oral dose of any of the antidepressant drugs. The rats were then treated with a total of 20 consecutive daily doses of antidepressants and threshold electroconvulsive seizure responses were evaluated 24 hr after the last dose. A significantly greater percentage of rats responded with extensor seizures after chronic treatment with amoxapine, chlorimipramine, parglyine and mianserin. There was no change in the pattern of seizures of the rats treated chronically with desipramine, but the duration of the clonic phase was reduced. After a 7 day period free of drugs a significantly greater percentage of animals had extensor seizures in the groups treated with amoxapine, chlorimipramine, pargyline and desipramine but not mianserin. In the light of evidence that chronic treatment with antidepressants reduces the activity of norepinephrine- or isoproterenol-sensitive adenylate-cyclase, and that the norepinephrine system is an important endogenous anticonvulsant factor in electroconvulsive seizures, these results suggest that the same mechanism may mediate both the therapeutic and proconvulsant effects of the chronic administration of antidepressants.

Cocaine enhances medial prefrontal cortex neuron response to ventral tegmental area activation.

Extracellular single unit recording techniques were used to characterize the effect of cocaine on the response of identified medial prefrontal cortex (mPFC) neurons to electrical stimulation of the ventral tegmental area (VTA) in chloral hydrate anesthetized rats. The select population of neurons studied were identified as cortical efferent cells by action potential characteristics and antidromic activation from the VTA. Stimulation of the VTA also induced a synaptically mediated inhibition of the spontaneous activity of the mPFC neurons. Administration of 2.0 mg/kg cocaine (IV) produced an increase in the duration of the VTA stimulus-evoked inhibition that differed significantly from the effect of 4.0 mg/kg procaine (IV). In contrast, microiontophoretic cocaine and procaine produced no significant changes in the duration of the VTA stimulus-evoked inhibition. This study provides evidence that systemic but not microiontophoretic cocaine administration enhances dopamine receptor-mediated inhibitory VTA input to a select population of mPFC efferent neurons.

Glycine potentiates the anticonvulsant action of diazepam and phenobarbital in kindled amygdaloid seizures of rats

The effect of glycine on the anticonvulsant activity of diazepam and phenobarbital in fully developed kindled amygdaloid seizures in rats was determined. Glycine alone had no significant effect on the seizure response, either when administered orally 1 hr prior to the seizure test or when given chronically in a 0.5 M solution as the source of water. Administration of glycine (10 mmol/kg, oral) together with diazepam produced a significant reduction in both cortical epileptiform afterdischarge and the severity of seizures at doses of diazepam which had no significant effect on the seizures when administered alone. Glycine potentiated the effects of phenobarbital on the cortical afterdischarge but not the severity of the seizures. The observed potentiation of the effects of diazepam and phenobarbital suggests a glycinergic mechanism in the anticonvulsant action of these drugs which may be mediated in part by the inhibitory gamma-aminobutyric acid (GABA) systems.

Glycine potentiation of anticonvulsant drags in pentylenetetrazol seizures in rats

This study evaluates the glycine potentiation of anticonvulsant drugs in subcutaneous pentylenetetrazol seizures in rats. Administered alone, glycine (30 or 40 mM/kg, PO) induced no anticonvulsant effect or neurological deficit. Coadministered with anticonvulsants, glycine significantly enhanced the anticonvulsant potency of diazepam and sodium valproate without affecting the neurological deficit induced by the anticonvulsants. Glycine did not significantly alter the anticonvulsant activity of ethosuximide or phenobarbital. These findings indicate a possible glycine-sensitive component in the mechanism of action of diazepam and sodium divalproate in subcutaneous pentylenetetrazol seizures. With the possible exception of sodium valproate, the present study provides little support for a glycine and gamma-aminobutyric acid (GABA) interaction as a mechanism of anticonvulsant activity in SC PTZ seizures. Further studies are required to determine the role of strychnine-sensitive and strychnine-insensitive glycine receptors in this experimental model of absence epilepsy.