Effects of diphenylhydantoin and diazepam on hippocampal evoked responses

Diphenylhydantoin and diazepam were compared with regard to their effects on responses to single stimuli, and on post-tetanic potentiation of evoked potentials within the hippocampus of anaesthetized rats. Interhippocampal afferents to pyramidal cells were stimulated electrically, while extracellular field potentials were recorded at successive depths within the contralateral hippocampus. Recording electrodes penetrated perpendicularly from a surface point homotopic to the site of stimulation. The anticonvulsants (40 mg/kg diphenylhydantoin, 5 mg/kg diazepam), 30 min after intravenous infusion, depressed post-tetanic potentiation in the stratum radiatum. At these doses, responses to single stimuli were essentially unaltered. Doses nearer the toxic range (80 mg/kg diphenylhydantoin, 10 mg/kgdiazepam) also reduced post-tetanic potentiation in the stratum radiatum, but increased (up to 150%) post-tetanic potentiation recorded from granule cells in the area dentata. The results indicate that diphenylhydantoin and diazepam have: (1) selective actions on hippocampal post-tetanic potentiation which are site and dose dependent; (2) qualitatively similar end-effects on post-tetanic potentials in two hippocampal subregions; (3) minimal effects on responses to single stimuli at doses which depress or enhance hippocampal post-tetanic potentiation.     

Effect of agmatine on long-term potentiation in morphine-treated rats

Agmatine is an endogenous amine derived from l-arginine that potentiates morphine analgesia and inhibits naloxone precipitated abstinent symptoms in morphine dependent rats. In this study, the effects of agmatine on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus (DG) on saline or morphine-treated rats were investigated. Population spikes (PS), evoked by stimulation of the LPP, was recorded from DG region. Acute agmatine (2.5-10 mg/kg, s.c.) treatment facilitated hippocampal LTP. Acute morphine (30 mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and agmatine (10 mg/kg, s.c.) restored the amplitude of PS that was attenuated by morphine. Chronic morphine treatment resulted in the enhancement of hippocampal LTP, agmatine co-administered with morphine significantly attenuated the enhancement of morphine on hippocampal LTP. Imidazoline receptor antagonist idazoxan (5 mg/kg, i.p.) reversed the effect of agmatine. These results suggest that agmatine attenuated the effect of morphine on hippocampal LTP, possibly through activation of imidazoline receptor.     

Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence

This paper reviews the biochemical and behavioural evidence that the increased anxiety that occurs during benzodiazepine withdrawal is caused by increased 5-HT activity. In hippocampal slices taken from rats withdrawn for 24 h from chronic diazepam treatment (2 mg/kg/day for 21 days) there was a significant increase in K⁺-evoked release of [³H]5-HT and in⁴⁵Ca²⁺ uptake and both of these changes were reversed by the GABA_B agonist, baclofen. Baclofen also reversed the anxiogenic response that is detected on withdrawal from chronic diazepam treatment. Other drugs that reduce 5-HT function (tianeptine which increases 5-HT uptake; buspirone, a 5-HT_1A receptor agonist/partial agonist; zacopride, a 5-HT₃ receptor antagonist) also reversed this anxiogenic response. Finally, we present data from a group of rats that did not develop tolerance to the anxiolytic effects of diazepam (2 mg/kg), even after 5 weeks treatment. This group failed to show an anxiogenic response on withdrawal from diazepam, nor was there an increase in hippocampal 5-HT release. We discuss the extent to which increased hippocampal 5-HT release can be causally linked to the increased anxiety during benzodiazepine withdrawal.     

Differential attenuation of somatovisceral and viscerosomatic reflexes by diazepam, phenobarbital and diphenylhydantoin.

In the chloralose-anaesthetized cat, stimulation of forelimb cutaneous afferent nerves evoked a response in the preganglionic splanchnic nerve, consisting of a short duration spinal reflex followed by a supraspinal component of longer duration. Diazepam (0·1–1·4 mg/kg, i.v.) markedly attenuated the supraspinal reflex but had a considerably lesser effect on the segmental response. On the other hand, diphenylhydantoin (10–40 mg/kg, i.v.) reduced predominantly the spinal component, whilst the supraspinal reflex was frequently enhanced after the initial dose of 10 mg/kg. This effect of diphenylhydantoin on the spinal reflex was direct, since it also occurred in the spinal cat. Phenobarbital (10–40 mg/kg, i.v.) was approximately equally potent in reducing both the spinal and supraspinal reflex. Visceromotor reflexes were markedly depressed by very small doses of diazephm (0·001 mg/kg, i.v.) and by larger doses of phenobarbital (10–20 mg/kg, i.v.). Diphenylhydantoin, although reducing this reflex, did not completely block it at the highest total dose tested (40 mg/kg, i.v.). The results indicate that the three CNS depressants differentially affect the spinal and supraspinal components of the somatosymphetic reflex. Furthermore, the three drugs also differ quantitatively from each other in depressing the spino-bulbo-spinal transmission of the viscerosomatic reflex.     

Chronic lithium: desensitization of autoreceptors mediating serotonin release

The effect of chronic lithium treatment on K⁺-induced release of preloaded [³H] serotonin ([³H]5-HT) from brain slices and its regulation by the presynaptic serotonin autoreceptors were investigated in superfused cortical, hippocampal and hypothalamic brain slices. Three weeks of treatment with a lithium-containing diet increased stimulation-induced [³H]5-HT overflow in the three brain regions examined. The sensitivity of the inhibitory serotonin autoreceptors was tested by determining K⁺-elicited release inhibition or potentiation in response to exposure to the agonist, LSD or to the antagonist, methiothepin, respectively. A reduced maximal inhibitory response to LSD was obtained in lithium-treated animals. The potentiation by methiothepin was also markedly diminished in the treated animals. These results suggest that chronic lithium treatment induces a desensitization of serotonin autoreceptors which may result in increased serotonin release from the serotonin nerve terminals.     

Effects of linopirdine (DuP 996) and X9121 on age-related memory impairments and on the cholinergic system

Linopirdine (DuP 996) has been shown to enhance K⁺-stimulated release of acetylcholine from cerebral cortex, striatum, and hippocampus of rats in vitro. X9121 is a structurally different compound identified as having similar release properties. The present experiments compare the effects of linopirdine and X9121 on cognitive deficits in aged rats, and on the pharmacological properties in young rats. For cognitive testing, aged male Fischer-344 rats (24 months old, n = 116) received either vehicle or one of 5 doses of linopirdine or X9121 prior to behavioral testing; young rats (4 months old, n = 13) were controls and received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze, and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. Linopirdine (0.25, 2.5, and 8.5 mg/kg po [0.64, 7.4, and 25 μmol/kg]) and X9121 (0.85 and 8.5 mg/kg po [2.1 and 24 μmol/kg]) moderately improved place discrimination. None of the doses tested improved repeated acquisition or sensorimotor function. No behavioral indications of toxicity were observed. Acetylcholine release, acetylcholinesterase (AChE) inhibition, and nicotinic and muscarinic binding were measured in vitro in cerebral cortical tissue from young male Wistar rats (2 months old). Both linopirdine and X9121 enhanced K⁺-stimulated release from cerebral cortex; X9121 produced greater release with a broader range of active concentrations. Linopirdine weakly inhibited AChE (1,000 × weaker than physostigmine) and X9121 did not. Neither drug bound significantly to muscarinic or nicotinic cholinergic receptors. These results support the hypothesis that linopirdine and X9121 have some cognition enhancing properties which may be due to enhancement of stimulation induced acetylcholine release. These results suggest that linopirdine and X9121 may be useful in treating disorders involving cognitive impairment. © 1994 Wiley-Liss, Inc.     

Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors.

Clinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (AChE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01-1.0 mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant AchE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0 mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine's effect was also prevented by the alpha7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-D-aspartate antagonist CGP39551 (2.5 mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.     

Effects of citrinin on renal function and structure

Citrinin is a nephrotoxic mycotoxin produced by Penicillia and Aspergilli. This study defines, functionally and histopathologically, the effects of citrinin on the rat kidney. Rats were anesthetized, prepared surgically, and then infused with [³H] inulin and p-aminohippurate (PAH) in saline prior to and during renal function and clearance studies. One group of rats served as the control and animals in this group were not treated with citrinin. Rats in 2 additional groups received either 5 or 50 mg/kg [¹⁴C] citrinin (i.v.) and were used immediately for clearance experiments. Four days after pretreatment with 50 mg/kg citrinin (i.p.), rats in a fourth group which showed signs of acute renal failure were given an additional 5 mg/kg [¹⁴C] citrinin (i.v.). Control rats developed saline diuresis, reaches a peak urine volume of 1.94 ml/20 min at 80 min, and cleared inulin and PAH at 2.4 and 7.45 ml/min, respectively. Non-pretreated rats receiving 5 and 50 mg/kg [¹⁴C] citrinin at time zero cleared inulin at 2.26 and 1.65 ml/min, respectively, and cleared PAH at 4.02 and 3.88 ml/min, respectively. “Nephrotoxic” rats did not develop saline diuresis. “Nephrotoxic” rats also cleared inulin and PAH at rate significantly lower than controls: 0.25 and 0.2 ml/min for inulin and PAH, respectively. The PAH/inulin clearance ratio was significantly lower in all treatment groups than in controls. Na⁺ excretion followed a pattern similar to urine excretion for each group, however, the rate of K⁺ excretion was significantly lower in all treatment groups than in the control group. The fractional K⁺ reabsorption in non-pretreated rats receiving 5 (63%) and 50 (83%) mg/kg [¹⁴C] citrinin was increased significantly over controls (46%). Filtered K⁺ reabsorbed by “nephrotoxic” rats was a negative 35%, i.e. K⁺ secretion occurred. Clearance of [¹⁴C] citrinin in non-pretreated rats receiving 5 and 50 mg/kg was 6.8 and 4.1 ml/min, respectively. Rats which exhibited nephrotoxicity (“nephrotoxic rats”) cleared the labelled citrinin at a rate of 1.25 ml/min. Histopathological changes observed in kidneys of rats treated with 50 mg/kg citrinin (i.p.) could be classed as reversibly or irreversibly injured by citrinin. Rats which excreted a high urine volume and excess protein and glucose on day 3 or 4 after treatment showed irreversible cellular injury, primarily located in the proximal convoluted tubules.     

DuP 996 (3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one) enhances the stimulus-induced release of acetylcholine from rat brain in vitro and in vivo

DuP 996, in micromolar concentrations, enhances the K⁺ -stimulated release of acetylcholine (ACh) in rat cerebral cortex, hippocampus, and caudate nucleus slices in vitro, without effect on basal release. DuP 996 has very weak affinity for rat brain muscarinic or nicotinic receptors and does not inhibit acetylcholinesterase activity of rat brain. Upon subcutaneous administration, DuP 996, in doses of 0.1 to 1 mg/kg, increase the output of ACh from the cerebral cortex of awake, freely moving rats. In the mouse, scopolamine-induced hyperactivity is reduced by DuP 996 in doses of 0.3–0.5 mg/kg (s.c.). In addition, pancuronium HBr-induced neuromuscular blockade is reversed by DuP 996 (ED₅₀ = 1.7 mg/kg s.c.). The enhancement by DuP 996 of K⁺ -stimulated transmitter release is not limited to the cholinergic system but is also observed in the dopaminergic system in the rat caudate nucleus and in serotonergic systems. K⁺ -stimulated release of gamma-aminobutyric acid and glutamic acid in rat cerebral cortex, however, is only slightly enchanced by DuP 996, whereas no effects are observed on K⁺ -stimulated release of cortical norepinephrine. DuP 996 may have therapeutic value in the treatment of diseases involving chlinergic and minoaminergic deterioration, like Alzheimer's Disease.     

Effects of lithium on cerebral RNA metabolism in vitro and in vivo

The effect of Li⁺ on cerebral RNA metabolism has been studied in rats. Li⁺ could not replace Mg²⁺ as an essential co-factor for RNA polymerase but stimulated the enzyme in the presence of optimum concentrations of Mg²⁺. The stimulation was less than that achieved with Na⁺ and K⁺ and differed from these in being biphasic with respect to concentration. A similar biphasic effect of Li⁺ was seen with liver RNA polymerase and brain Poly C synthetase. The action of Li⁺ on pancreatic and brain ribonuclease resembled that of Na⁺. Li⁺ did not reduce the inhibitory effect of Mg²⁺.Chronic LiCl treatment in rats (0.15 mg/g/day for 13 days) did not significantly alter the rate of RNA synthesis, the RNA content nor RNA composition in the brain. It is concluded that the changes in uric acid excretion in human manic depressives during lithium-induced remission are not reflections of a direct or indirect effect of Li⁺ on cerebral RNA metabolism.     

Reversal of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced depression of ouabain biliary excretion by pregnenolone-16 alpha-carbonitrile and spironolactone in isolated perfused rat livers.

Perfusate disappearance and biliary excretion of ouabain were depressed in isolated perfused livers of adult male rats 10 days after treatment with a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 25 μg/kg). When TCDD-treated rats were given pregnenolone-16α-carbonitrile (PCN, 75 mg/kg/day) or spironolactone (S, 75 mg/kg/day) on Days 6–9, the depression in ouabain perfusate disappearance and biliary excretion on Day 10 was reversed, but the degree of reversal afforded by PCN was greater than S. Liver surface membrane (LSM) Mg²⁺ ATPase and Na⁺, K⁺ ATPase activity were also depressed 10 days after TCDD treatment and when TCDD-treated rats were given S on Days 6–9 the depression in both ATPase activities was completely reversed but treatment with PCN was less effective. Liver excretory function for ouabain and LSM Na⁺, K⁺, or Mg²⁺ ATPase activity in control and TCDD-treated rats were altered independently by PCN and S treatment. Adrenalectomy on Day 6 after TCDD treatment did not reverse the depressant effects of TCDD on ouabain disposition but did prevent the increase in liver weight observed on Day 10. In view of the dissociation between hepatic excretory function for ouabain and LSM ATPase activities it is suggested that LSM Mg²⁺ ATPase and Na⁺, K⁺ ATPase are not directly involved in hepatic ouabain transport. We postulate that a LSM ouabain carrier unit, separate and distinct from these ATPases, is responsible for hepatic uptake and biliary excretion of ouabain.     

Reversal of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced depression of ouabain biliary excretion by pregnenolone-16α-carbonitrile and spironolactone in isolated perfused rat livers

Perfusate disappearance and biliary excretion of ouabain were depressed in isolated perfused livers of adult male rats 10 days after treatment with a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 25 μg/kg). When TCDD-treated rats were given pregnenolone-16α-carbonitrile (PCN, 75 mg/kg/day) or spironolactone (S, 75 mg/kg/day) on Days 6–9, the depression in ouabain perfusate disappearance and biliary excretion on Day 10 was reversed, but the degree of reversal afforded by PCN was greater than S. Liver surface membrane (LSM) Mg²⁺ ATPase and Na⁺, K⁺ ATPase activity were also depressed 10 days after TCDD treatment and when TCDD-treated rats were given S on Days 6–9 the depression in both ATPase activities was completely reversed but treatment with PCN was less effective. Liver excretory function for ouabain and LSM Na⁺, K⁺, or Mg²⁺ ATPase activity in control and TCDD-treated rats were altered independently by PCN and S treatment. Adrenalectomy on Day 6 after TCDD treatment did not reverse the depressant effects of TCDD on ouabain disposition but did prevent the increase in liver weight observed on Day 10. In view of the dissociation between hepatic excretory function for ouabain and LSM ATPase activities it is suggested that LSM Mg²⁺ ATPase and Na⁺, K⁺ ATPase are not directly involved in hepatic ouabain transport. We postulate that a LSM ouabain carrier unit, separate and distinct from these ATPases, is responsible for hepatic uptake and biliary excretion of ouabain.     

Effects of diazepam and diphenylhydantoin on elicited and spontaneous seizures in kindled rats: a double dissociation

Diazepam (1 mg/kg) was more effective than diphenylhydantoin (100 mg/kg) in suppressing motor seizures elicited in kindled rats by amygdaloid stimulation; however, the effect of these drugs on the incidence of spontaneous motor seizures in rats kindled by amygdaloid stimulation was just the opposite. At the same doses, diphenylhydantoin effectively suppressed spontaneous motor seizures, but diazepam did not. This double dissociation suggests the need for caution in drawing inferences concerning spontaneously recurring seizures from studies of elicited seizures.     

Analysis of the action of CNS depressant drugs on somato-somatic reflexes in the cat.

The effects of diazepam (0·01–0·1 mg/kg, i.v.) diphenylhydantoin (DPH) (10–40 mg/kg, i.v.) phenobarbital (5–40 mg/kg, i.v.) and chlorpromazine (0·5–2·0 mg/kg, i.v.) were compared in the chloralose-anaesthetized cat. Responses were studied to stimulation of hindlimb muscle extensor and flexor afferents, and hind- and forelimb cutaneous afferents. In this preparation, stimulation of hindlimb afferents produced an initial short latency segmental spinal discharge (monosynaptic and polysynaptic potentials) followed by a longer latency supraspinal reflex. Forelimb cutaneous afferent stimulation produced only a supraspinal discharge. All segmental reflexes studied were depressed moderately by diazepam and DPH and more strongly by phenobarbital and chlorpromazine. Unlike diazepam, the low dose of DPH often augmented some of these reflexes. All supraspinal reflexes examined were completely blocked by diazepam and phenobarbital, whereas they were merely reduced, but never completely inhibited, by chlorpromazine. Diphenylhydantoin had a mixed effect: spino-bulbo-spinal reflexes evoked by hindlimb muscle afferents were blocked, whereas the response to forelimb cutaneous afferents was particularly resistant to DPH. Decerebellation did not prevent the inhibition of the supraspinal reflex by the various drugs. It is concluded that the four compounds exhibit a different profile in regard to their effect on somato-somatic reflexes.     

Acute and chronic diuretic effect of ethanolic extract of leaves of Cocculus hirsutus (L.) Diles in normal rats

Objectives The objective of this study was to evaluate the acute and chronic diuretic effect of the ethanolic extract of the leaves of Cocculus hirsutus (L.) Diles. Methods The ethanolic extract was administered (100, 200 and 400 mg/kg, p.o.) in Wistar rats. In the acute study, rats received drugs orally and urine was collected after 1, 2, 3, 4, 5 and 6 h. The chronic study involved repeated administration of ethanolic extract for 28 days and urine was collected on day 1, 7, 14, 21 and 28. The parameters were total urine volume, concentration of Na⁺, K⁺ and Cl^‐ ions, creatinine in urine and serum. Urine output, electrolytes (Na⁺, K⁺ and Cl^‐ ions) and creatinine were determined on day 7, 14, 21 and 28. Key findings The highest dose (400 mg/kg) of the ethanolic extract significantly (P < 0.01) enhanced urine output. Excretion of cations (Na⁺ and K⁺ ions) and anions (Cl^‐ ions) increased significantly with respect to the control (gum acacia 2% dissolved in saline, 10 ml/kg) group. The increase of cations in the urine after treatment with ethanolic extract was dose dependent. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) did not significantly change the concentration of Na⁺, K⁺ and Cl^‐ ions in serum. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) increased the excretion of creatinine in urine but with a corresponding decrease in serum. Conclusions It was concluded that the ethanolic extract of the leaves of C. hirsutus (400 mg/kg) had significant diuretic effect in rats.     

Effects of substantia nigra stimulation on suralis-evoked spinal reflex activity: comparison with the effects of morphine and stimulation in the periaqueductal gray matter

The effects on spinal reflex activity of morphine and conditioning stimulation of the substantia nigra (SN) or the periaqueductal gray matter (PAG) were compared. Reflex activity was evoked by stimulation of various afferents in the sural nerve. In spinal rats. morphine (2 mg/kg, i.v.) did not significantly affect the ventral root short-latency reflex response to sural nerve stimulation but depressed the long-latency reflex response. Naloxone (0.2 mg/kg, i.v.) abolished this depressant effect of morphine. In rats with prenigral decerebration, trains of conditioning stimuli delivered to the SN or PAG (1) enhanced the short-latency reflex response to sural nerve stimulation, (2) depressed the long-latency reflex response to stimulation of the skin nerve and (3) evoked potentials in ventral and dorsal roots. The effects of stimulation of the SN or PAG were markedly reduced by lesioning of the dorsolateral funiculi. Morphine enhanced the potentials evoked in ventral and dorsal roots by brainstem stimulation with short trains of impulses, not those evoked by stimulation with long trains of impulses. Neither morphine nor naloxone exerted an effect on the unconditioned ventral root long-latency reflex response or on the conditioned long-latency reflex response in rats with prenigral decerebration and an intact spinal cord.Since, in rats with prenigral decerebration, SN stimulation depressed the C fibre evoked long-latency reflex response as well as did conditioning stimulation of the PAG, or as did morphine in spinal rats, it is concluded that the SN inhibits transmission of nociceptive impulses in the rat spinal cord.     

Effect of potassium channel blockers on isolated rat atrium

This study describes a sensitive in vitro assay using isolated right atrium of adult Wistar rats to discover new compounds as K⁺ channel antagonists. For the purpose, several well-known K⁺ channel antagonists were investigated and compared with other compounds that modulate cardiac function. Potassium channel antagonists used in this study were barium chloride (BaCl₂), 4-aminopyridine (4-AP), tetraethylammonium (TEA), and E-4031. The concentration-dependent chronotropic and inotropic effect of K⁺ channel antagonists were determined under physiological condition and under depressed cardiac condition induced by stimulation of cholinergic M receptor with carbachol. Under physiological conditions, these K⁺ channel antagonists showed a negative chronotropic and positive inotropic response. When the spontaneous beat rate was decreased by cholinergic stimulation, these agents enhanced the beat rate and the force of contraction simultaneously. Study on new compounds found that agents S94052 and S94056 were similar to the above K⁺ channel antagonists in functional response. Current and voltage-clamp study demonstrated that both new compounds prolonged the duration of action potential and reduced the steady-state K⁺ outward currents. The functional study described here can provide a sensitive and reproducible atrium model to discover new K⁺ channel antagonists. Drug Dev. Res. 39:161–166. © 1997 Wiley-Liss, Inc.     

Levetiracetam has no significant gamma-aminobutyric acid-related effect on paired-pulse interaction in the dentate gyrus of rats

Gamma-aminobutyric acid (GABA)ergic mechanisms of the novel antiepileptic drug, levetiracetam (Keppra), have been both favored and rejected. Since paired-pulse interaction is accepted in functionally assessing GABAergic mechanisms, we investigated whether levetiracetam affects the paired-pulse inhibition/facilitation of the field potentials, evoked in the dentate gyrus of urethane-anesthesized rats. This model revealed a strong paired-pulse inhibition at 20-ms interstimulus interval, a noteworthy paired-pulse facilitation at 80-ms interstimulus interval, and a moderate paired-pulse inhibition at 500-ms interstimulus interval. Bicuculline (3 mg/kg/h, i.v.) and baclofen (10 mg/kg, i.v.) markedly depressed paired-pulse inhibition at 20-ms interstimulus interval, while clonazepam (1 mg/kg, i.p.), diazepam (10 mg/kg, i.v.), and phenobarbital (40 mg/kg, i.v.) enhanced it. Bicuculline also depressed paired-pulse inhibition at 500-ms interstimulus interval. Bicuculline, baclofen, and diazepam reduced paired-pulse facilitation at 80-ms interstimulus interval. Distinct from these GABA(A) receptor- and GABA(B) receptor-related drugs, levetiracetam (17 and 540 mg/kg, i.v.) had no significant effect on either paired-pulse interaction in this model, a result not favoring any major role of GABAergic mechanisms in its antiseizure action.     

Effects of intrapallidal opiate receptor agonists on striatally evoked head turning

The effects of intraperitoneal and intrapallidal administration of opiate drugs on the time course of the contralateral head turn evoked by striatal stimulation were investigated in conscious rats. Neither morphine, leucine enkephalin nor a more stable analogue of leucine enkephalin, D-ala2, D-leu⁵-enkephalin, had any effect on the head turn. Naloxone (10 mg/kg i.p.) caused a small facilitation of the response. In contrast, ethylketocyclazocine, injected intraperitoneally or into the pallidum, caused a pronounced, naloxone-sensitive slowing of the motor response. These results suggest the presence of opiate kappa receptors in the rat globus pallidus.     

Blockade of a sympathetic nervous system reflex by diphenylhydantoin.

The responses to bilateral carotid occlusion were determined in Dial-urethane anaesthetized cats before and after the administration of diphenylhydantoin (Dilantin^®). Five milligrams of diphenylhydantoin per kilogram reduced the reflex-induced tachycardia. Ten or 20 mg/kg of diphenylhydantoin per kilogram, reduced the hypertensive responses as well as the tachycardia. In this regard 20 mg/kg was no more effective than 10 mg/kg, although the larger dose did produce greater cardiovascular depression of basal values. Diphenylhydantoin did not reduce the sensitivity of the heart or vasculature to activation by alpha or beta receptor stimulation with norepinephrine or isoproterenol. These data indicate that diphenylhydantoin suppresses the sympathetic nervous system response to a carotid occlusion challenge by an action on neural substrates.