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This study investigates the effect of the gamma-aminobutyric acid (GABAB) agonist, baclofen, on amygdala kindling in adult rats. Baclofen has been reported to be anticonvulsant in a variety of seizure models and prevents kindling in immature rats. These experiments describe the effects of baclofen (2, 5 and 10 mg/kg, i.p.) on the afterdischarge threshold and kindling rate. Baclofen, 10 mg/kg, significantly increased the afterdischarge threshold in the amygdala. Baclofen at 5 and 10 mg/kg, retarded the rate of kindling as measured by the number of stimuli required to advance to subsequent seizure stages. These results suggest that baclofen may decrease the local excitability of the amygdala and retard the rate of seizure spread (or generalization) throughout the brain. Baclofen, acting at GABAB receptors exerts an anticonvulsant effect on amygdala kindling in these experiments.

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The calcium channel blockers verapamil (VPM) and nimodipine (NMD) were administered to adult or immature (16-day-old) rats to determine their effects on amygdala-kindled seizures. The afterdischarge threshold (ADT) kindling rate and degree of postictal refractoriness were determined for two doses of VPM (0.5 and 5.0 mg/kg in rat pups and 2 and 10 mg/kg in adult rats) or 30 mg/kg nimodipine (NMD). Neither VPM nor NMD affected the ADT of the amygdala in adult or immature rats. VPM retarded the rate of kindling in both adult and immature rats in a dose-dependent manner; the number of stimulations required to progress through seizure stages were increased. NMD 30 mg/kg reduced the kindling rate and AD duration in both adult and immature rats. Neither drug was able to suppress recurrent seizures elicited by repetitive stimulation. These results suggest that verapamil, and possibly NMD may be of clinical utility in treatment of epilepsy, especially complex partial seizures.

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Administration of the organophosphate insecticide, chlorpyrifos to immature rats exerted a proconvulsant effect on seizures induced by kindling. Chlorpyrifos was administered to 16 or 17 day old rats in a dose range of 0.3 to 10 mg/kg, subcutaneously. Amygdala kindling was performed by stimulating the rats every 15 minutes to a total of 20 stimulations. Kindling occurred more rapidly in the chlorpyrifos treated rats than vehicle treated rats, the proconvulsant effect was dose-dependent. The proconvulsant effect of chlorpyrifos was more pronounced in the early stages of kindling, indicating a possible increase in local excitability of the amygdala in the presence of chlorpyrifos. Chlorpyrifos also reduced the after discharge threshold in the amygdala in a dose-dependent manner and increased the duration of after discharges elicited by electrical stimulus, indicating an increase in excitability of the amygdala. The effects of chlorpyrifos on kindling were additive with xylene: the proconvulsant effect in the early stages of kindling was greatly enhanced by xylene. Xylene, administered alone as a 0.2% solution, reduced the after discharge threshold of the amygdala, increased the after discharge duration and increased the rate of kindling. These experiments demonstrate a proconvulsant effect of chlorpyrifos in amygdala kindling and this proconvulsant action is additive with xylene.

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DURSBAN (DB; active ingredient chlorpyrifos) is a widely-used organophosphate insecticide. The teratogenic and neurotoxic potential of DB was evaluated in rats in utero by exposing embryos on days 0-7 or days 7-21 of development. These prenatal exposures to DB (0.03, 0.1 or 0.3 mg chlorpyrifos/kg, ip) induced physical abnormalities and embryotoxicity. Rat pups which had been exposed to 0.3 mg chlorpyrifos/kg prenatally demonstrated significant behavioral neurotoxicity on postnatal day 16 in the rotorod test compared to time-matched saline-infused litters. Exposure to DB on postnatal day 3, 10 or 12 also caused neurotoxicity as evaluated by the rotorod test. Our studies suggest prenatal exposure to relatively low concentrations of DB may be associated with embryotoxicity, fetal lethality and behavioral neurotoxicity.

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Infusions of 2-amino-7-phosphonoheptanoic acid (AP7) or ketamine into the substantia nigra pars reticulata (SNPR) of adult rats increase the latency of onset to seizures induced by the convulsant ether flurothyl. Nigral infusions of AP7 or ketamine in concentrations up to 10 times greater than the adult dose are ineffective in 16-day-old rats. These results suggest that differences in seizure susceptibility between adult and immature rats may be related to differences in excitatory amino acid neurotransmission in the SN.

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Iminohydantoins selectively substituted at position C-5 and their 1-carbobenzoxy derivatives have been synthesized, and their anticonvulsant activity was evaluated in mice. In general, the more lipophilic 1-carbobenzoxy iminohydantoins were more potent than the unsubstituted counterparts. Evaluation of the individual enantiomers of the chiral iminohydantoins showed that the anticonvulsant activity resided primarily in the S isomers. In this study, (S)-(+)-1-carbobenzoxy-5-isobutyl-2-iminohydantoin (9a) was the most active member. This compound was not nearly as active as phenytoin against electrically induced convulsions, but was also active against pentylenetetrazole-induced seizures, suggesting a broader clinical potential. The closest analogue of phenytoin, viz., 5,5-diphenyl-2-iminohydantoin (1), failed to show any significant activity. Methylation on N-3 or the imino nitrogen of 1 also did not provide a compound with substantial activity. 2-Thiophenytoin was not active against electroshock seizures and showed only a weak activity against pentylenetetrazole. This study suggested that the structure-activity relationship of 2-iminohydantoins was quite different from that of 2-hydantoins.

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The possible effectiveness of systemic infusions of baclofen (a GABAB receptor agonist) in the modification of seizures in developing animals has not yet been established. In this report, we studied the effects of systemic baclofen infusions on amygdala kindling in 16-day-old rat pups. Baclofen suppressed the development of kindling without altering the local afterdischarge threshold. Moreover, baclofen suppressed the severity and duration of established kindled seizures and increased the intensity of postictal refractoriness. The data suggest that baclofen may be a useful antiepileptic agent in this age group.

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The substantia nigra GABA-sensitive system is important for the modification of seizures. In adult rats, nigral infusions of baclofen (GABAB agonist) had no effect on flurothyl seizures. This suggests that the nigral GABAB receptor system may not be involved in the mediation of flurothyl seizures in this age group. The present study examines whether the nigral GABAB receptor is involved in the modification of flurothyl seizures in rat pups and whether systemic infusions of baclofen could alter their seizure susceptibility. Baclofen (50-200 ng/0.25 microliters) was intranigrally administered to 16-day-old rat pups which were then exposed to flurothyl seizures. Results indicated that intranigral infusions of baclofen (100 and 200 ng/0.25 microliters) protected the rat pups against seizures. Systemic injections of baclofen also protected pups from flurothyl seizures suggesting that it may be worthwhile to examine baclofen as a potential antiepileptic drug in children.

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Concentrations of striatal dopamine (DA), serotonin (5-HT) and their metabolites were measured following infusions of the GABAA receptor agonist, muscimol, or GABAA receptor antagonist, bicuculline, into the substantia nigra (SN) or areas dorsal to the SN in adult rats and 16-day-old rat pups. Results indicated that intranigral infusions of muscimol produced site-specific increases in the concentrations of striatal DA metabolites in adults, while in pups, intranigral muscimol infusions produced site-specific increases in the concentrations of striatal DA. Intranigral infusions of bicuculline had no effect on striatal DA or its metabolites in either age group. Neither GABAergic drug had any effect on striatal 5-HT or its metabolite. The data suggest that the effect of nigral GABAA agonist infusions on the activity of the nigrostriatal pathway is age-specific. The lack of opposing effects following the nigral infusion of a GABAA receptor antagonist indicates that the influences of GABAA agonists may be mediated by different mechanisms as a function of age.

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Several studies have implicated the substantia nigra GABAergic system in the mediation of seizures in adult rats. The present study examines whether the different GABA receptors (GABAA and GABAB), are preferentially involved in this GABAergic seizure suppression mechanism. Adult rats were intranigrally infused with muscimol (GABAA receptor agonist), bicuculline (GABAA receptor antagonist) or baclofen (GABAB receptor agonist) and were exposed to flurothyl seizures. Results indicated that while infusions of muscimol had an anticonvulsant effect, infusions of bicuculline had a proconvulsant effect. Baclofen infusions were found to have no effect on seizures. These findings suggest an involvement of the nigral GABAA receptors in the mediation of seizures in adult rats.

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Receptor binding studies of the substantia nigra (SN) and cerebellum revealed two affinity sites for muscimol binding in the SN and cerebellum of adult and 16-day-old rats. Scatchard analysis revealed a paucity of high-affinity muscimol receptors in the SN of 16-day-old rat pups. These results suggest that the lack of anticonvulsant action of muscimol in the SN of 16-day-old rat pups may be due to the paucity of high-affinity muscimol receptors as compared to adult rats.

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Barrel rotation (BR) is an abnormal, long-axis rotation induced by intracerebroventricular (i.c.v.) injections of peptides, including somatostatin (SRIF) and arginine-vasopressin (AVP). This study examined the effects of two i.c.v. doses of SRIF and combined injections of SRIF and AVP in conscious, adult Wistar and Sprague-Dawley rats. Mortality after i.c.v. SRIF was dose-dependent; 0/16 rats died after a 20 microgram dose, while 21/43 died after 40 micrograms SRIF. On the other hand, BR incidence was similar after the two doses, but the hazard function of the BR latency data was shifted to the left by the higher dose. Although the incidence data imply that BR and mortality are independent, the hazard function of BR latency data is predictive of mortality. An interaction study employing a combined i.c.v. dose of 20 micrograms SRIF and 0.5 micrograms AVP established that the effects add non-linearly. This is illustrated by a marked increment in mortality (0/16 for 20 micrograms SRIF, 1/25 for 0.5 micrograms AVP and 12/18 for SRIF + AVP). The hazard plot shows a similar, non-linear interaction. In addition, SRIF, but not AVP, produced a characteristic pattern of Purkinje cell death in cerebellar regions projecting to the fastigial and lateral vestibular nuclei. These results imply that SRIF and AVP act at independent sites to produce BR and mortality, and that the effects summate non-linearly at a common central site. This raises the issue of whether these neuropeptides, endogenous in human CSF, interact to produce similar biological effects.

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Regional cerebral metabolic rates of glucose (rCMRglu) were measured in conscious rats grouped according to three treatments: control, bicuculline (5.5 mg/kg s.c.), and intracerebroventricular arginine vasopressin (0.5 micrograms/5 microliter). Rats in the latter group were pre-exposed to the peptide 48 h earlier to render them 100% susceptible to a motor output termed barrel rotation (BR). Marked increases in rCMRglu occurred in all brain areas investigated after bicuculline. Increases after intracerebroventricular arginine vasopressin were smaller and occurred in fewer brain areas. Opposite to bicuculline, arginine vasopressin reduced rCMRglu in hippocampus and auditory cortex. The data confirm marked stimulation of rCMRglu during bicuculline-induced seizures and provide initial data for an endogenous peptide that causes BR. Generalized seizures and BR may share some neural substrates, but they produce distinct changes in rCMRglu. The rCMRglu changes are compatible with the interpretation that BR is initiated by brainstem/cerebellar areas that process visual-vestibular information, with subsequent involvement of higher brain structures.

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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.

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A relationship between the subcommissural organ (SCO) and the adrenal glands has long been suspected. This report provides further information about the effects of a continuous D-aldosterone infusion into the SCO area of conscious, adult male Sprague-Dawley rats. A 6-day aldosterone infusion (5 ng/h) increased urinary sodium excretion, decreased adrenal medullary cross-sectional area, elevated adrenal corticosterone content and terminal plasma epinephrine concentration. Mineralocorticoid infusions directly into a lateral cerebral ventricle did not affect these parameters but, unlike SCO area infusions, decreased consummatory behavior. Infusions of tritiated aldosterone into the SCO area revealed that radioactivity was mainly confined to dorsomedial portions of the brain near the SCO, whereas the pineal body contained only background radioactivity. The data support the concept that the SCO area interacts with physiological systems related to both the adrenal cortex and medulla.

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Microinfusions of muscimol into the substantia nigra pars reticulata produced marked increases in striatal dopamine (DA) utilization without affecting striatal DA concentration in adult rats. In contrast, muscimol increased striatal DA concentration and decreased DA utilization in 16-day-old rat pups. The striatal norepinephrine concentration was not altered in either group. Since previous studies have shown that similar infusions of muscimol are anticonvulsant in adults and proconvulsant in rat pups, our results suggest that the nigrostriatal pathway may play an important role in mediating the nigral effects on seizures.

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Intracerebroventricular (i.c.v.) arginine-vasopressin (AVP) injections evoke 'barrel rotation' (BR) in rats. This motor system abnormality was studied in a protocol where conscious rats were injected on day 1 with 1 microgram i.c.v. AVP and reexposed to 0.5 micrograms on day 3. Three paradigms modifying visual/vestibular systems were employed: labyrinthectomy, 3-acetylpyridine (3-AP) destruction of the inferior olive and atropine pretreatment. Ambient illumination (light vs dark) was also modified. Initial (day 1) incidence of BR, increased incidence (i.e. sensitization) on day 3, and day 3 BR latency were differentially affected by the various paradigms and suggest a complex role of visual/vestibular input in modifying i.c.v. AVP-induced BR. For example, 3-AP rats tested in light and atropinized rats had a reduced responsiveness to the peptide on day 1. 3-AP-treated rats tested in dark conditions showed a normal incidence of BR on day 1, but the expected sensitization to AVP on day 3 did not occur. Combined labyrinthectomy and darkness did not modify BR incidence on either day, but altered the distribution of latency data. Four diverse antiepileptic drugs were tested for efficacy against i.c.v. AVP-induced BR in sensitized rats: phenytoin, diazepam, valproic acid and phenobarbital; all drugs reduced the proportion of rats with BR and prolonged the latency. We conclude that brain AVP may be involved in abnormal motor conditions that are modified by visual/vestibular neuronal circuits. The unusual motor output (barrel rotation) can be inhibited by diverse antiepileptic drugs.

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Intracerebroventricular (i.c.v.) arginine-vasopressin (AVP) injections in rats evoke an unusual motor response termed 'barrel rotation' (BR). This report documents several aspects of BR after i.c.v. AVP in conscious, adult male Sprague-Dawley rats: single i.c.v. AVP injections (100-1000 ng/5 microliters) evoke BR in about 50% of naive rats with no relationship to dose and 20% mortality; no directional preference exists for BR, and sensitivity to BR does not vary over a weight range of 301-475 g; continuous i.c.v. AVP infusions at doses of 50-2500 ng/h evoked BR in 13 and 50% of rats tested at the extreme ranges; latency to BR was always within 3-6 min in infusion experiments; a protocol where rats received a single i.c.v. AVP injection (1 microgram) on day 1 followed on day 3 by 0.5 micrograms, increased the proportion of rats with BR from 51% to 83% (P less than 0.05), indicating a sensitization phenomenon; latency to BR after single i.c.v. injections did not fit the assumption of single underlying normal distribution; a novel method to analyze these data, hazard plotting, revealed two phases to the BR latency under ambient illumination. The following paper presents evidence of visual/vestibular involvement and the efficacy of anti-seizure drugs. Collectively, the data are compatible with the hypothesis that brain vasopressin pathways are involved in some abnormalities of motor output.

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D-Aldosterone (5 ng/microliter/h) was infused for 6 days into the region of the subcommissural organ (SCO) of conscious, adult male Sprague-Dawley rats. Aldosterone increased urinary sodium loss and the sodium/potassium ratio. Although probably central in origin, these effects still occurred when cannulae were displaced up to 1 mm from the targeted SCO placement. Aldosterone decreased adrenal medullary cross-sectional area without affecting cell density. This effect was highly dependent on proper cannula placement and was not observed when the cannula tip was not in contact with the cerebrospinal fluid of the pineal recess over the rostral two-thirds of the SCO. We conclude that aldosterone increases sodium excretion by an action in the SCO and/or adjacent structures. We also postulate a negative trophic relationship between mineralocorticoids and the adrenal medulla mediated by the SCO.

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