Antagonists of gamma-aminobutyric acid (GABA)- or glycine-mediated neurotransmission, muscarinic cholinergic agonists, and excitatory amino acids and their analogues are all considered to be potent chemoconvulsant agents. However, although systemic injections of these agents have been used to create experimental models of generalized epilepsy, there has been no identification of a specific locus at which any of these drugs act to initiate generalized seizures. We recently located a forebrain region from which seizures can be elicited by the GABA antagonist bicuculline, and now report that manipulations of excitatory amino acid transmission and cholinergic transmission can also elicit seizures from this site. Bilateral clonic seizures can be elicited after unilateral application of picomole amounts of bicuculline, kainic acid or carbachol and micromole amounts of glutamate. Local application of the GABA agonist muscimol prevents the appearance of seizures on subsequent microinjection of all convulsant agents examined, whereas local application of the muscarinic antagonist, atropine, only prevents seizures induced by carbachol. This region is therefore a site of action for the epileptogenic effects of neuroactive agents with diverse mechanisms of action; it may also represent a site at which GABA agonists could function therapeutically to control epileptogenesis.

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Valproic acid (VPA) was determined by EMIT assay in plasma, tears, saliva, and cerebrospinal fluid (CSF) of patients with epilepsy. Closer correlation was shown between tear/plasma and tear/CSF ratios than between saliva/plasma and saliva/CSF ratios. The VPA CSF/serum ratio was in good agreement with data in the literature. Salivary levels were extremely erratic, while those for tears were much more reliable. Determination of VPA in tears is therefore the best method of studying the VPA free fraction in those cases in which investigations of protein binding of the drug are necessary.

In awake paralyzed Wistar rats, the following effects of an acute nontoxic dose of phenytoin (PHT) on different parameters of cerebellar electrical activity were evaluated: spontaneous discharge rate of single Purkinje cells (P-cells), field potentials, and responses of P-cells generated by electrical stimulation of a forelimb nerve. Variations of the response of single neurons located in the inferior olive were also studied, in order to assess the effects of PHT on this precerebellar relay station. The drug was administered orally and plasma and cerebellar levels regularly estimated. The results indicate that an acute, nontoxic dose of PHT is associated with an increase of P-cell firing rate. This finding is supported by the analysis of the frequency distribution of interspike intervals, and by the field potentials, P-cell, and olivary responses induced by stimulation of a radial nerve. In addition, it was observed that the increase in P-cell firing was mainly depending upon a higher activity of the climbing fibers. The increase in the response of P-cells and olivary cells was correlated with plasma and cerebellar drug levels. The conclusion was reached that PHT increases the cerebellar cortical activity through two mechanisms: (a) by acting directly on the cerebellar P-cell; and (b) indirectly by acting on the origin of climbing fibers at the inferior olive nucleus.