Date of Award

1-1-1986

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology and Pharmacology

Abstract

The role of the central nervous system neurotransmitter serotonin was evaluated on the anticonvulsant activity of various compounds. Serotonin (5-hydroxytryptamine) is known to have an inhibitory role in central nervous system activity. A facilitation of the anticonvulsant activity of benzodiazepines has previously been attributed to increased serotonin activity.Male white mice of the ICR strain were administered varying doses of phenytoin, 5-ethyl, 5-methylhydantoin (EMH) and JAW-669, then challenged with maximal electroshock. The occurrence of seizures was used to evaluate the degree of protection provided by a given dose of anticonvulsant.The role of serotonin on the anticonvulsant activity of these compounds was determined utilizing agents which are known to selectively alter serotonergic activity and are devoid of anticonvulsant activity in doses administered.Enhanced serotonergic activity with pretreatment of tryptophan (100 mg/Kg, ip, 1 hour) or 5 hydroxytryptophan (50 mg/Kg, ip, 2 hour) increased the anticonvulsant activity of phenytoin and EMH. However, only 5-hydroxytryptophan increased the activity of JAW-669 which was decreased with tryptophan.Pretreatment with p-chlorophenylalanine (50 mg/Kg, ip, 2 hour or 300 mg/Kg, ip, 48 hour), a compound which has a time dependant biphasic affect on serotonergic activity initially increasing then decreasing the activity, produced decreased anticonvulsant activity when administered 48 hours prior to a dose of anticonvulsant. The 2 hour pretreatment had no influence on observed anticonvulsant compound activity.Methysergide (10 mg/Kg, ip, 0.5 hour) pretreatment blocked serotonergic receptors and resulted in decreased anticonvulsant activity for all three anticonvulsants.The effects of treatment with the benzodiazepine, diazepam (1.33 mg/Kg, ip), on ('3)H-serotonin binding in whole brain homogenates using male CF-1 white mice were evaluated in a pentylenetetrazol seizure model. Diazepam increased serotonin receptor affinity in all preparations from mice which received the compound, but increased receptor numbers above control only in preparations from those which were considered protected from convulsions.The study supports a facilitatory role of serotonin as a component of the anticonvulsant activity of selected compounds with an indication of a need for a sufficient number of available serotonin receptor sites to exhibit complete expression of anticonvulsant compound activity.

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