title: Reduction in firing rate of substantia nigra pars reticulata neurons by valproate: influence of different types of anesthesia in rats.
abstract: Nondopaminergic, presumably GABAergic neurons in the substantia nigra pars reticulata (SNR) are thought to function as a gating mechanism for seizure propagation. Systemic administration of anticonvulsant doses of the antiepileptic drug valproate (VPA) has previously been reported to inhibit the firing of nondopaminergic SNR neurons in anesthetized but not in awake, paralyzed and locally anesthetized rats, suggesting that the findings in anesthetized rats were due to an interaction between VPA and the general anesthetic used. In the present study, we determined the influence of different anesthetic measures on the effect of an anticonvulsant dose of VPA (100 mg/kg) on extracellularly recorded spontaneous single unit activity of nondopaminergic SNR neurons in rats. Rats were anesthetized by continuous infusion of the general anesthetic chloral hydrate, the dissociative anesthetic ketamine or the narcotic opioid fentanyl, or were only locally anesthetized and paralyzed. VPA significantly reduced SNR firing in all groups with a time course that matched its anticonvulsant time course in rodents. However, VPA's inhibitory effect on SNR firing was significantly less marked under anesthesia with chloral hydrate than in any of the other groups, indicating that this anesthetic suppresses the action of VPA, which may be related to an interaction with GABA-related processes in the SNR. The closest approximation to the effect of VPA in awake rats was obtained under anesthesia with ketamine, while VPA's inhibitory action on SNR neuronal firing seemed to be enhanced in the fentanyl group, which exhibited the highest baseline firing rates of all groups. Determination of VPA in the SN showed that the difference in VPA's inhibitory effect on SNR neurons was not secondary to differences in local drug concentrations. The data demonstrate that VPA is capable of significantly slowing the spontaneous activity of nondopaminergic SNR neurons, but that the magnitude of this effect depends on the anesthetic measures used. In view of the presumed role of SNR neurons in seizure propagation and the finding that VPA consistently inhibits these neurons at an anticonvulsant dose, the present data suggest that suppression of spontaneous SNR neuronal firing may be an important mechanism through which VPA exerts its anticonvulsant properties.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Löscher
authors.forename: A
authors.initials: A
authors.lastname: Rohlfs
authors.forename: C
authors.initials: C
authors.lastname: Rundfeldt
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects*; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000777:Anesthetics; D012965:Sodium Chloride; D014635:Valproic Acid; D007649:Ketamine