Biggs, Christopher Stuart; (1994) Effects of sodium valproate on release of neurotransmitters and their metabolites in vivo: Relationship to motor seizures in the rat. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The effects of the anticonvulsant sodium valproate (VPA) on central neurotransmitter release and metabolism, during acute and sub-chronic administration, were investigated using in vivo microdialysis in conscious rats. In addition, an attempt was made to relate these neurochemical effects to the modulation of seizure activity in two rodent models of convulsive epilepsy. Neurotransmitters and metabolites were quantified using high performance liquid chromatography. 1. VPA dose-dependently increased extracellular (EC) levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) in the ventral hippocampus (VH). VPA differentially affected levels of DA and 5-HT measured in the anterior and posterior striatum. 2. Prolonged dosing of rats with VPA (2 x 200 mg/kg/day for 2, 4, 7 and 14 days) resulted in alterations of basal and high potassium-evoked release of hippocampal aspartate (ASP), glutamate (GLU), taurine (TAU), glutamine (GLN), GABA, DA, 5-HT and their major metabolites. 3. Studies utilizing tetrodotoxin (TTX) in conjunction with in vivo microdialysis assessed the effects of blocking voltage-dependent neurotransmitter release in the VH on the acute pharmacodynamic actions of VPA previously observed (1.). Under these conditions, the effects of VPA (400 mg/kg) on EC accumulation of DA, 5-HT, and GABA were differentially attenuated, whilst EC levels of ASP were increased. 4. Seizures induced in rats using the convulsant isonicotinic acid hydrazide (INH) were observed concurrently with measurement of VH amino acid levels in vivo. INH administration alone resulted in reductions of EC GABA levels, deficits which correlated closely with seizure progression. ASP and GLU levels increased non-significantly during these episodes. Co-administration of INH with VPA (400 mg/kg) resulted in complete reversal of both behavioural and neurochemical deficits. 5. The possible involvement of DA and 5-HT in the anticonvulsant action of VPA against seizures induced in rats with pilocarpine was investigated. Blockade of central 5-HT1A receptors and stimulation of D1 receptors was found to severely impair the anticonvulsant effects of VPA in this model.

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