Abstract  Most nonanesthetics (inhaled compounds that neither cause anesthesia when given alone nor decrease the partial pressure of a known inhaled anesthetic required to produce anesthesia) and transitional compounds (inhaled compounds that are less potent than would be predicted by the Meyer-Overton hypothesis) cause convulsions. A possible exception is the perfluoroalkane series of nonanesthetics. The present study tested whether perfluoroalkanes do provide an exception. Further, we tested whether the convulsant effects of nonanesthetic and transitional compounds were additive. The nonanesthetic perfluoropropane caused convulsions at 7.5 +/- 0.7 atm (mean +/- SD). Convulsions also were produced by perfluorocyclobutane (0.976 +/- 0.002 atm), 1,2-dichlorotetrafluoroethane (0.358 +/- 0.011 atm), 2,3-dichlorooctafluorobutane (0.085 +/- 0.007 atm), 1,2-dichlorohexafluorocyclobutane (0.055 +/- 0.007 atm), and flurothyl (0.00156 +/- 0.00039 atm). Of these, 1,2-dichlorotetrafluoroethane is a transitional compound, the remainder being nonanesthetics. The combination of flurothyl plus 1,2-dichlorohexafluorocyclobutane gave evidence of antagonism (a 17% +/- 21% deviation from additivity; P < 0.05), whereas the combination of 1,2-dichlorotetrafluoroethane plus 2,3-dichlorooctafluorobutane gave evidence of synergy (a -13% +/- 8% deviation from additivity; P < 0.05). The combinations of perfluoropropane plus perfluorocyclobutane (-4% +/- 15%), and perfluoropropane plus 1,2-dichlorohexafluorocyclobutane (-1% +/- 26%) did not produce results that deviated significantly from additivity. We conclude that pairs of these compounds either produce convulsions in an additive manner, a finding consistent with (but not proving) a common mode of action; or deviate modestly from additivity, a finding suggesting that at least a portion of the mechanistic basis for convulsions might differ, particularly for flurothyl plus other nonanesthetics, or for the combination of non-anesthetics and transitional compounds.

Abstract  The effect of recurrent seizures in developing rats on subsequent long-term behavior was studied. Fifteen day old rats received a convulsant dosage of flurothyl three times daily for five consecutive days. When the rats were fully mature, they underwent behavioral testing using the water maze and auditory quality or location discrimination. With serial flurothyl administration seizure duration increased progressively but latency to seizure onset did not change. Compared to controls, flurothyl-treated rats had impaired performance in the water maze and on auditory location, but not on quality discrimination. Histological examination showed no gross cell loss in the hippocampus. This study demonstrates that serial seizures in the developing brain cause detrimental effects on visual and auditory spatial learning.

Abstract  We investigated the role of the GABAergic system of the substantia nigra in seizures of rat pups. Rat pups had bilateral cannulae implanted chronically either in the substantia nigra or 1.5 mm dorsal to it. At age 16 to 17 days, seizures were induced in the cannulated rats and naive (intact) controls by exposure to flurothyl following pretreatment with the GABA agonist, muscimol, or vehicle. Naive rats were the most resistant to flurothyl seizures. Bilateral nigral infusions of muscimol markedly facilitated the development of flurothyl seizures in a dose-response manner and differed significantly from the vehicle controls or rats infused with muscimol dorsally to the substantia nigra. In contrast, bilateral nigral muscimol infusions protected adult rats against the development of flurothyl seizures. Our data indicate that the effects of nigral GABA agonist infusions on seizures are age-dependent; the altered responsivity of the GABAergic nigral system in immature rats may be responsible in part for the increased seizure susceptibility of the developing central nervous system.

Abstract  During pregnancy mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The potential role of brain catecholamines in mediating this behavior was examined in the present study. The concentration and turnover of norepinephrine (NE) and dopamine (DA) were measured in hippocampus, striatum, midbrain and cortex in control, pregnant and delivery-day mice. There were no significant changes from control in DA levels during pregnancy and parturition. The turnover of DA was not altered during pregnancy, except for a small increase in turnover rate in the hippocampus. The concentration of NE decreased during pregnancy, and rose at parturition. This effect was most striking in the hippocampus. The turnover of NE was markedly depressed during pregnancy, with the hippocampus again being most affected. These data imply a role for NE, but not DA in the mediation of increased seizure susceptibility during pregnancy.

Abstract  The effects of electroconvulsive shock on the levels of acetylcholinesterase in several brain regions of the rat were studied. Hippocampus, mesencephalon, cortex, and striatum exhibited rapid changes in acetylcholinesterase activity during the first few minutes following the convulsion, whereas brainstem and basal forebrain levels remained unchanged. In both hippocampus and midbrain there was a sustained decrease in activity: the total acetylcholinesterase activity was decreased by up to 40% within 2 min of the convulsion and did not return to control values for another 3 h. Thirty minutes after a flurothyl-induced convulsion there was a similar fall in acetylcholinesterase activity in both these regions, whereas a subconvulsive electric shock produced no change. It is concluded that a convulsion produces significant short-term decreases in acetylcholinesterase activity in areas of the rat brain that are involved in the generation and propagation of seizures, and the question is raised of whether this is related to the increase in seizure threshold that follows a convulsion.

Abstract  Pregnant mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The possibility that the well-known increase in beta-endorphin concentration which accompanies pregnancy was involved in this effect was examined by testing whether naloxone administration could block the increased seizure susceptibility. Pregnant female, control female and male C3H mice were treated with 5-50 mg/kg naloxone 5 min before flurothyl seizure testing. Naloxone markedly increased clonic seizure susceptibility in all three groups at a dose of 50 mg/kg, but had little effect at lower doses. In contrast, naloxone had differential effects on myoclonic seizures in pregnant and control female mice, being anticonvulsant in the controls, but proconvulsant in the pregnant mice. A role for endogenous opiates is unlikely in mediating clonic seizures in pregnant mice, but may be involved in myoclonic seizures.

Abstract  Perinatal asphyxia has been implicated in the pathogenesis of persistent convulsive disorders later in life. Whether epilepsy is the result of oxygen deficiency alone or is due to the combined effect of hypoxia and ischemia is not known. In this report we studied the role of perinatal hypoxia alone on the development of epilepsy. One day and ten days old rat pups were exposed to prolonged hypoxia (6% O2). The subsequent susceptibility to focally elicited (kindled) or generalized (flurothyl) seizures was determined in the fourth week of age. Rats exposed to hypoxia were not more susceptible to the development of either type of seizures when compared to controls. Since the equivalent degree of hypoxia used for the 1 day old rat has previously been shown to result in lasting neurochemical and behavioral alterations and the degree of hypoxia used for the 10 day rat was lethal in over 35% of the animals, it is suggested that oxygen deficiency in and of itself may not be sufficient to lead to the development of epilepsy.

Abstract  In this report, the interaction between flurothyl convulsions and electrical kindling of the amygdala was investigated. Three flurothyl convulsions decreased the afterdischarge threshold of the amygdala and enhanced the rate of development of electrical kindling without affecting the intensity of postictal refractoriness. On the other hand, 3 generalized kindled convulsions did not alter the flurothyl convulsive threshold. The data suggest that the influence of generalized convulsions on future seizure susceptibility may depend on the agents used to induce the convulsions.

Abstract  Status epilepticus (SE) was induced for 40 min by flurothyl in well oxygenated rats. This insult resulted in selective destruction of up to 65% of the substantia nigra pars reticulata. We investigated the short and long term behavioral effects of this damage. No deficits were observed in sensorimotor reactivity, locomotor coordination, spontaneous or apomorphine-stimulated locomotor activity in the rats with induced epilepsy. However, these rats exhibited a long-lasting enhancement of amphetamine-stimulated locomotor activity. We propose that this selective impairment is caused by the necrosis of the pars reticulata. This damage might lead to deficient regulation either of mesostriatal dopamine neurons innervating nc. accumbens, or of neurons in the mesencephalic reticular formation mediating the locomotor response initiated in the nc. accumbens.

Abstract  Rats with 60--70% deficits in brain catecholamines produced by the intracisternal injection of 6-hydroxydopamine were examined by 3 tests of seizure susceptibility. In all procedures (minimal and maximal electroshock and flurothyl convulsions) evidence for increased sensitivity to seizures was obtained. All the animals displayed normal rectal temperature at the times of seizure testing and normal blood chemistry at approximately the time of the third seizure test. These observations strengthen the widely held hypothesis that brain catecholaminergic neurons play a fundamental role in governing sensitivity to convulsions.

Abstract  Dose-response comparisons of the ability of the selective delta antagonist ICI 154,129 (12.5-50 nmol), the nonselective antagonist naloxone (29-290 nmol), and the irreversible selective mu antagonist beta-fNA (1.3-21 nmol) to alter the threshold response to DADLE or etorphine was studied in the rat flurothyl seizure test. DADLE (35 nmol, i.c.v.) and etorphine (122 nmol/kg, s.c.) both caused increases in seizure threshold which were differentially antagonized by pretreatment (i.c.v.) with the respective antagonists. For DADLE, only ICI 154,129 and naloxone produced a dose-related blockade of the increase in seizure threshold, with ICI 154,129 being more potent than naloxone. In contrast, the anticonvulsant action of etorphine was not antagonized by ICI 154,129 (50 nmol), but was blocked by a low dose of naloxone (29 nmol) or beta-fNA (21 nmol). In addition, prior occupancy of mu-sites with beta-fNA (21 nmol) significantly diminished the abilities of either ICI 154, 129 (50 nmol) or naloxone (290 nmol) to antagonize the anticonvulsant action of DADLE. The results of this study demonstrated that the effects of DADLE to increase seizure threshold in the rat were primarily mediated by activation of a delta-opioid receptor system. Furthermore, evidence has been provided for a functional interaction between delta and mu receptors in the opioid regulation of seizure threshold.

Abstract  Neuronal necrosis in the brain resulting from status epilepticus of 15 to 120 minutes duration in ventilated and well-oxygenated rats was assessed. Seizures were induced by inhalation of the convulsant gas flurothyl, and terminated by withdrawal of flurothyl and a single injection of thiopental. The animals were allowed to recover for one week, and neuronal damage was assessed by cell counts following subserial sectioning of the brain and microscopical examination of the sections. Infarction of the pars reticulata of the substantia nigra occurred in 5 of the 6 animals with seizure duration of 30 minutes, and in all animals with longer seizure durations. There also was a common affectation of the central parts of the globus pallidus. The pars compacta of the substantia nigra was never affected. After 45 to 120 minutes of seizures, moderate neuronal necrosis was observed in the neocortex (layers 3 and 4), and after 60 to 120 minutes was seen in amygdaloid and thalamic nuclei, as well as in CA4 and CA1 hippocampal pyramidal cells. Notably, CA3 neurons were not damaged nor were dentate granule cells affected. After 120 minutes of seizures, damage regularly affected the neocortex and the ventral-posterior nuclei of the thalamus. A conspicuous feature was the localization of neuronal necrosis at sites close to the ventricles.

Abstract  The substantia nigra (SN) appears to be a crucial site involved in the modification of seizures. The aim of this study was to elucidate the role of the GABA nigral system in the expression of seizures by comparing the effects of multiple doses of a GABA agonist (muscimol) and a GABA antagonist (bicuculline methobromide) on the development of flurothyl seizures in 16-day-old rat pups. The drugs were infused bilaterally either in the SN or dorsal to the SN. An additional group of pups were infused with bicuculline in the corpus striatum. Results indicate that both drugs facilitated the development of seizures in a dose-related manner when infused into the SN. Infusions of muscimol dorsal to the SN had no effect on seizure latencies while infusions of bicuculline dorsal to SN or corpus striatum still increased the susceptibility of rat pups to seizures. The data suggest that only the effects of muscimol on seizures are specific for the SN and that early in life muscimol may exert its proconvulsant effects via a different receptor site or mechanism than bicuculline.

Abstract  Agonist, and antagonist effects of the proposed kappa opioid agonist, U50,488H (U50) have been studied in an experimental model of seizure activity (flurothyl-induced seizure threshold) (ST) and in the central modulation of spontaneous, volume-induced micturition contractions (bladder motility) (BM) in rats. Intracerebroventricular (i.c.v.) administration of U50 (at the doses tested) did not produce any agonist effect in either ST or in BM. In contrast, i.c.v. administration of [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAGO) or etorphine, agonists with activity at mu opioid receptors, produced an elevation of ST and inhibition of BM. The elevation in ST produced by etorphine (0.004 nmol) was prevented by prior treatment with U50. In contrast, the approximately equieffective elevation in ST resulting from DAGO was not affected by U50 pretreatment. Similarly, pretreatment of rats with U50 antagonized the approximately equieffective BM effects of etorphine, but not those of DAGO. As both DAGO and etorphine are thought to exert their effects via the opiate mu receptor, the results may be consistent with the view that subpopulations of mu receptors exist within the central nervous system; these sites may be differentially associated with the kappa receptor.

Abstract  1 Following administration to rats of an electroconvulsive shock (ECS) which resulted in a major tonic-clonic seizure, no changes in [3H]-diazepam binding characteristics were observed in cortex or hippocampus with either a well washed membrane preparation or a crude synaptosomal preparation. 2 No changes were observed in [3H]-diazepam binding in any other brain region examined 30 min after an ECS. 3 Thirty min following an ECS, regional brain gamma-aminobutyric acid (GABA) concentrations increased in hippocampus, cortex and hypothalamus. Only in the hippocampus did the increase occur within 5 min of the seizure. 4 Similar increases in GABA concentration were seen after a bicuculline-induced seizure but not after seizure induced by flurothyl; both treatments produced a tonic-clonic seizure. 5 Pretreatment of the rats with (+)-propranolol 5 min before the ECS abolished the tonic extension and prevented the brain GABA concentration changes that occur 30 min after the seizure. 6 No increase in GABA concentration was seen in hippocampus, cortex and hypothalamus 30 min after the final ECS of a course of 10 ECS given once daily for 10 days. In contrast a marked increase in striatal GABA concentration was observed. 7 These changes in GABA biochemistry following a seizure are discussed in relation to the post-ictal rise in seizure threshold that is occurring at the same time.

Abstract  Strong flurothyl treatment (1.7% v/v for 8 min) produces retrograde amnesia in chicks when administered as long as 24 hr after one-trial avoidance training with a strongly aversive stimulus. Mild flurothyl treatment (0.2% v/v for 8 min) produced retrograde enhancement when administered as long as 16 min after similar training with a moderately aversive stimulus. The moderate training followed by mild flurothyl treatment enhanced 24-hr retention to the level found after strong training alone. Enhanced retention persisted for at least 72 hr; nonspecific performance effects faded within 48 hr. The predominant dose-dependent and time-dependent enhancement effect of mild flurothyl treatment is interpreted as improved memory consolidation.

Abstract  The spontaneous upstream swimming of goldfish (N=1318) into a quiet well was suppressed in one trial by electric shock (2.0 V/cm). Independent groups of fish, at 25‡ C, retained this learned avoidance 1, 4, 16, and 64 h after training but not 256 h after training. When trained fish were treated, 3 min after training, with a 16-min exposure to convulsive solutions of flurothyl (Indoklon®), their retention of avoidance 16, 64, or 256 h later was facilitated. This retroactive facilitation (RF) of long-term memory in goldfish by flurothyl could not be attributed to proactive or aversive effects of the treatment. Goldfish treated in water saturated with carbon dioxide (80% CO2∶20% O2) showed retrograde amnesia (RA). Neither the RF from flurothyl nor the RA from CO2-treatment were diminished when training and treatment were given to goldfish at 20‡ or 15‡ C. The memory-enhancing effect of flurothyl convulsions, and its delayed onset, may relate to the dual stimulant-depressant action of the drug and differ from the RA effect reported for mice and chicks.