John W. Dailey

I. The genetically epilepsy-phone rat: An overview of seizure-prone characteristics and responsiveness to anticonvulsant drugs

The Genetically Epilepsy-Prone Rat (GEPR) is rapidly gaining support as a model of epilepsy. In addition to a marked sensitivity to both sound-induced and hyperthermic seizures, GEPRs exhibit unusual sensitivity to a number of seizure-provoking modalities, including various forms of electrical and chemical stimulation. The existence of a moderate seizure colony (GEPR-3) and a severe seizure colony (GEPR-9) allows pathophysiological studies of seizure susceptibility and severity. The consistency of seizures within each colony allows for comparisons in seizure naive GEPRs and seizure experienced GEPRs. The consistent seizure responses of the GEPR are also ideal for the testing of anticonvulsant drugs. Further, the relative potencies of anticonvulsant drugs between the two colonies of GEPRs predict the clinical efficacies of traditional antiepileptic drugs and may be able to predict novel anticonvulsants.

Neurobiology of seizure predisposition in the genetically epilepsy-prone rat

Seizure predisposition in the genetically epilepsy-prone rat (GEPR) is innately determined and these animals exhibit consistent and reproducible convulsive patterns. This epilepsy model is made up of 2 independently derived colonies of animals with each exhibiting a characteristic convulsive pattern. In response to a standardized acoustic stimulus, GEPR-3s exhibit moderate or clonic convulsions and GEPR-9s exhibit more severe tonic extensor convulsions. Besides exhibiting convulsions in response to sound stimulation, some GEPRs experience spontaneous and hyperthermic seizures. They are also abnormally sensitive to a number of seizure provoking stimuli that produce seizures in normal animals. The neurochemical basis for the seizure predisposition in GEPRs is increasingly well understood. Abnormalities in central nervous system norepinephrine and serotonin are widespread and may play a prominent role in regulation of seizures in the GEPR. Amino acid neurotransmitter systems are less well defined in the GEPR but abnormalities exist and may be, along with other documented deficiencies, responsible in part for the seizure predisposition that is characteristic of GEPRs.

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.

Serotonergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats

Seizure predisposition in Genetically Epilepsy-Prone Rats (GEPRs) is characterized by abnormal sensitivity to a number of seizure provoking stimuli. The GEPR model is composed of two independently derived colonies with each exhibiting a characteristic convulsive pattern. In response to a standardized sound stimulus, GEPR-3s exhibit moderate or clonic convulsions while GEPR-9s exhibit more severe tonic extensor convulsions. In order to further characterize the neurochemical abnormalities that underlie seizure predisposition in GEPRs, the current study examined serotonin concentrations in 14 discrete brain areas of controls, GEPR-3s and GEPR-9s. In all areas examined, serotonin concentrations were lower in either one or both GEPR types than in seizure resistant controls. In 6 of the 14 areas both GEPR-3s and GEPR-9s had levels significantly lower than controls. In an additional 7 areas GEPRs had serotonin concentrations of similar magnitude which were significantly lower than control when the GEPR values were combined. In cerebellum, GEPR-3s had significantly lower serotonin concentration than either controls of GEPR-9s while in the striatum, GEPR-9s had significantly lower serotonin levels than either GEPR-3s or controls. In summary, GEPRs have widespread deficits in serotonin concentration and that these abnormalities appear to contribute to the seizure predisposition that characterizes these animals.

Abnormalities in Monoamine Levels in the Central Nervous System of the Genetically Epilepsy-Prone Rat

Summary: Norepinephrine, dopamine, and 5‐hydroxytryptamine concentrations were determined in the central nervous systems of genetically epilepsy‐prone rats (GEPR) and in control rats. Norepinephrine concentrations were abnormal in all major areas of the central nervous system of the GEPR, with decrements existing in the telencephalon, hypothalamus‐thalamus, midbrain, pons‐medulla and spinal cord. An increment in the concentration of this neurotransmitter existed in the cerebellum. Dopamine concentrations were normal in all areas of the GEPR brain. Abnormalities in 5‐hydroxytryptamine concentrations were also present in the GEPR. They were exclusively decrements and occurred in the telencephalon, hypothalamus‐thalamus, midbrain, and pons medulla. Concentrations of this neurotransmitter were normal in the cerebellum and spinal cord. Coupled with our earlier pharmacologic data, these observations support our concept that noradrenergic and/or 5‐hydroxytryptaminergic decrements are etiologically important in seizure susceptibility in the GEPR. The lack of abnormalities in brain dopamine concentrations strengthens our hypothesis that dopaminergic transmission does not regulate seizure susceptibility in this model.

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.

Antidepressants and seizures: clinical anecdotes overshadow neuroscience.

Pharmacological treatment of depression in persons with epilepsy has been an area of controversy because some drugs commonly are perceived specifically to induce or exacerbate seizures in patients with seizure disorders. This prevailing misconception is unjustified by scientific studies, yet it continues to prevent afflicted persons from receiving appropriate therapy. The scientific literature shows that tricyclic antidepressant drugs cause seizures in overdose in both animals and humans. In lower doses, these drugs have anticonvulsant activity in humans and animals. Thus, the antidepressant drugs are like several antiepileptic drugs that can both prevent and cause seizures. The anticonvulsant activity of antidepressant drugs has been studied extensively in animals and almost certainly stems from their capacity to block norepinephrine and/or serotonin reuptake. The pharmacodynamic action responsible for their convulsant effects has not been well studied but may be due to their local anesthetic, antihistaminic, or antimuscarinic activity. The newer, more selective monoamine uptake blockers have very low convulsant liability, and it is suggested that their anticonvulsant activity, which is well documented in animals, be investigated further in humans. If their effects in humans are analogous to those in animals, these drugs can be used safely in epileptic patients with depression, and it is possible that their anticonvulsant activity can be exploited for use in the treatment of epilepsy.

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.

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.

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.