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D N Stephens

Publications and source records attributed to D N Stephens.

At least 73 records · Page 4Linked to original sources
PubMed1992

Effects of the beta-carboline abecarnil on epileptic activity, EEG, sleep and behavior of rats.

The profile of the anxiolytic beta-carboline isopropyl 6-benzyloxy-4-methoxymethyl beta-carboline-3-carboxylate (abecarnil; ZK 112 119), a partial agonist at benzodiazepine receptors, was determined in two experiments. In the first, abecarnil was given to WAG/Rij rats; these rats generate spontaneously occurring spike-wave discharges and are regarded as a model for absence epilepsy. Effects were measured on epileptic activity, together with those on the spectral content of the background electroencephalograph (EEG), as well as on ongoing behavior. In a second experiment, effects on sleep and behavior were investigated in Wistar rats. It was found that, similarly to classical benzodiazepines, abecarnil possessed a strong antiepileptic character and also changed the background EEG to more high-frequency waves and less spindle activity. It also produced more immobile behavior. Abecarnil induced only small, marginally significant increases in slow-wave sleep while reducing REM sleep as a proportion of total sleep. It also reduced the number of REM periods. These observations are consistent with the proposed partial agonist activity of abecarnil, a drug with interesting therapeutic implications.

Animals↗
PubMed1992

Relief of experimental spasticity and anxiolytic/anticonvulsant actions of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline.

Spasticity is characterized by pathological overactivity in spinal stretch reflex circuits and may be associated with disturbances in excitatory amino acid-mediated transmission in the cord. A genetically determined syndrome of spasticity in the rat permits the quantitative evaluation of the antispastic effects of drugs by recording activity in the electromyogram (EMG) from a hind limb extensor muscle. In genetically spastic rats, systemic administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline (NBQX), normalized pathologically increased EMG activity, whereas the AMPA agonist, alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionate (ATPA), exacerbated the EMG measures of spasticity. The reflex mechanisms in the spinal cord can be studied in mice using EMG recordings from the tibial muscle (Hoffmann reflex) or from the plantar foot muscle (flexor reflex) after electrical stimulation of the tibial nerve. Systemic and i.t. administration of NBQX blocked Hoffmann reflexes in mice, leaving flexor reflexes unchanged. ATPA enhanced Hoffmann, and had no effect on flexor reflexes. The effects of NBQX on spinal reflexes were seen in doses which do not affect locomotor activity, but show anxiolytic and some antiepileptic activity in rodents. These data suggest that the design of novel muscle relaxant drugs acting at the AMPA subtype of glutamate receptors may be feasible.

Animals↗
PubMed1991

Apparatus for ultrasound tissue characterization of excised specimens.

Apparatus is described for measurement of sound speed and ultrasound attenuation coefficients by the substitution technique in the frequency range 3 to 8 MHz. Phase-cancellation artifacts leading to overestimation of attenuation coefficients are avoided by use of an acoustoelectric transducer. Specimens confined by polystyrene windows can be interrogated by focused ultrasound beams at selected locations spaced on a grid of 3 x 3 mm voxels. Pulse time of flight is measured with an accuracy of 30 ns, yielding sound speeds accurate to +/- 6.7 m/s, for samples 10 mm thick. Uncertainties in measured insertion losses range from 0.1 dB in low-loss (10 dB) specimens to 0.5 dB in high-loss (25 dB) specimens.

Algorithms↗
PubMed1990

Differential effects of the excitatory amino acid antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), on spinal reflex activity in mice.

Intrathecal administration of the preferential quisqualate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in anesthetized mice depressed Hoffmann (H)-reflexes, while flexor reflexes remained unaffected. The depressant effect of CNQX on H-reflexes was dose-dependent (range 0.1-10 nmol). The intrathecal administration of the selective N-methyl-d-aspartate (NMDA) antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) reduced flexor reflexes (range 10-100 nmol) and had no effect on H-reflexes. These results suggest that H-reflexes in mice are mediated by spinal non-NMDA receptors, while flexor reflexes involve NMDA receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1990

Drug discrimination models in anxiety and depression.

Drug discrimination is a technique for investigating the stimulus properties of centrally active drugs. Although many studies have employed animals to investigate the stimulus properties of substances used clinically for the treatment of anxiety and depression, it would be a mistake to consider the internal discriminative stimuli as being related specifically to the anxiolytic or antidepressant properties of these drugs. Rather drug cues are better considered as relating to the pharmacological action of classes of compounds. Thus, benzodiazepine cues generalize to other compounds acting at benzodiazepine receptors, but not to substances (anxiolytic or otherwise) acting at 5-HT1A receptors. Similarly, antidepressants with different pharmacological properties, for example the tricyclic imipramine, or the phenylaminoketone buproprion produce distinct, unrelated discriminative stimuli. For this reason, the limits of drug discrimination techniques for investigating novel anxiolytic or antidepressant drugs should be clearly recognized. Attempts to identify an anxiogenic discriminative stimulus using pentylenetetrazole have also been misguided. In this technique it has proven difficult to separate unequivocally the pharmacological proconvulsant effects of the drug from the psychological construct anxiety. Nevertheless, drug discrimination remains a valuable technique for investigating pharmacological interactions in animals and man.

Animals↗
PubMed1990

Differential effects of antiepileptic drugs and beta-carbolines on seizures induced by excitatory amino acids.

Agonists acting at subtypes of glutamate receptors, N-methyl-D-aspartate, kainate and quisqualate, induce convulsions in rodents. Clonic seizures induced in mice by intracerebral administration of N-methyl-D-aspartate, kainate or quisqualate were used to study the anti- and proconvulsant potential of antiepileptic drugs and beta-carbolines. Systemic administration showed that the benzodiazepines clonazepam and midazolam blocked convulsions induced by kainate and had no effect on seizures triggered by N-methyl-D-aspartate and quisqualate. In contrast, diazepam blocked convulsions induced by either excitatory amino acid, as did valproate. The benzodiazepine receptor agonist beta-carboline ZK 93423 blocked convulsions induced by kainate but had no effect on seizures induced by N-methyl-D-aspartate or quisqualate. The antagonist beta-carboline ZK 93426 did not affect convulsions induced by excitatory amino acids, while the inverse agonists FG 7142 and ethyl-beta-carboline-3-carboxylate increased the sensitivity of mice to kainate. Phenobarbital and 2-chloroadenosine protected mice against seizures induced by quisqualate and kainate, while baclofen was active against convulsions produced by kainate. MK-801 selectively blocked convulsions induced by N-methyl-D-aspartate, and enhanced the susceptibility of mice to seizures triggered by kainate and quisqualate. Ethosuximide increased the susceptibility of mice to N-methyl-D-aspartate and had little or no effect on other types of seizures. Diphenylhydantoin enhanced the convulsant potential of quisqualate. Trimethadione and carbamazepine did not affect convulsions induced by N-methyl-D-aspartate, kainate or quisqualate. Intracerebral administration of midazolam protected mice against seizures induced by kainate. Ethosuximide increased the susceptibility of mice to N-methyl-D-aspartate, while diphenylhydantoin to quisqualate convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors.

Abecarnil (isopropyl 6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a novel ligand for central benzodiazepine (BZ) receptors, possessing anxiolytic and anticonvulsant properties, but with considerably reduced muscle relaxant effects in comparison to diazepam (DZP). In vitro, abecarnil inhibited the binding of the BZ [3H]lormetazepam to rat cerebral cortex membranes with an IC50 value of 0.82 nM in comparison to 56 nM for DZP. The ability of abecarnil to displace [3H]lormetazepam was enhanced 1.24-fold in the presence of 30 microM gamma-aminobutyric acid; the corresponding value for DZP was 2.8-fold. DZP and abecarnil were equally effective in enhancing the binding of t-[35S]butylbicyclophosphorothionate to rat cortical membranes. In vivo, abecarnil exhibited a 3- to 6-fold higher affinity to forebrain BZ receptors than DZP. Abecarnil was from 2 to 10 times more potent than DZP in most rodent tests of anxiolytic activity, and in reducing locomotor activity in mice and rats thoroughly habituated to the test chamber. However, in rats newly exposed to a novel cage, abecarnil was less potent than DZP in reducing locomotor activity. In tests of motor coordination, abecarnil, in contrast to DZP, showed no or only weak activity, and in potentiating the effects of ethanol and hexobarbital on motor performance abecarnil was 4 to 25 times less potent than DZP. Abecarnil antagonized the effects of BZs in the chimney and loss of righting reflex tests, but not in the rotarod test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Anticonvulsant action of the beta-carboline abecarnil: studies in rodents and baboon, Papio papio.

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboxylate) is a metabolically stable beta-carboline derivative with potent anxiolytic and few sedative and ataxic effects in rodents. The anticonvulsant and muscle relaxant actions of abecarnil have been evaluated in mice, rats, gerbils and baboons. Abecarnil raised the threshold for tonic electroconvulsions in mice after corneal but not after auricular application, had no effect on maximal electroshock-induced tonic convulsions triggered by either method, protected mice against the tonic hindlimb extension in PTZ-, picrotoxin- and 3-mercaptopropionate-induced seizures and blocked clonus after PTZ, DMCM (methyl-4-ethyl-6,7-dimethoxy-9H-pyrido-(3,4-b)-indol-3-carboxylate) and 3-mercaptopropionate. Abecarnil had no effect on convulsions induced by bicuculline and strychnine. Furthermore, abecarnil blocked kindled seizures after chronic administration of PTZ and FG 7142 (beta-carboline-3-carboxylic acid methylamide) and protected mice and rats against limbic convulsions induced by pilocarpine. Severity and afterdischarge duration of amygdala-kindled seizures were reduced in rats treated with abecarnil. Abecarnil also antagonized selectively convulsions induced by i.c.v. administration of kainate, but not those triggered by N-methyl-D-aspartate or quisqualate. In genetic models of reflex epilepsy, abecarnil was effective against sound-induced convulsions in DBA/2 mice, against air blast-induced generalized seizures in gerbils and against myoclonus in baboons Papio papio. The anticonvulsant effect of abecornil in a PTZ seizure model in mice was potentiated by ethosuximide, whereas no significant potentiation was found with diazepam, clonazepam, diphenylhydantoin, carbamazepine and phenobarbital. Electromyographic monitoring in a etorphine model of muscle rigidity in rats showed no or little muscle relaxant effect of abecarnil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Partial GABA agonist activity of SR 95531 on the binding of [35S]TBPS, [3H]DMCM and [3H]lormetazepam to rat brain membranes.

A recently developed series of pyridazinyl-GABA derivatives has been classified as GABA antagonists in electrophysiological, behavioral and biochemical experiments. These substances seemed superior to the classical GABA antagonist bicuculline because of their water-solubility, high potency and apparent selectivity for GABAA receptors. In the present study the most potent representative of this class, SR 95531 almost completely reversed the stimulatory or inhibitory effect of GABA on [3H]lormetazepam and [35S]TBPS binding, respectively. To a lesser extent, it antagonized the inhibition of [3H]DMCM binding by GABA. However, the interaction of SR 95531 with the GABA receptor seems to be of a complex nature since the compound enhanced the binding of [3H]lormetazepam by 28% at 37 degrees in the presence of 200 mM Cl-. Bicuculline inhibited [3H]lormetazepam binding under these conditions, presumably by antagonizing the effect of residual endogenous GABA. Similar to GABA and THIP, SR 95531 potently inhibited the binding of [3H]DMCM and [35S]TBPS, suggesting SR 95531 to be a partial agonist at the GABAA receptor.

Animals↗
PubMed1989

Blockade of FG 7142 kindling by anticonvulsants acting at sites distant from the benzodiazepine receptor.

Repeated administration of the beta-carboline FG 7142 results in sensitisation to its convulsant effects (chemical kindling); acutely FG 7142 is not convulsant, but following several treatments full seizures develop. It has been suggested that the increased sensitivity results from changes in benzodiazepine (BZ)/GABA receptor function. The present experiments studied the ability of BZ receptor ligands and anticonvulsant drugs with diverse mechanisms of action to block the expression and development of kindling to once daily injection of FG 7142 (40 mg/kg, i.p.) in mice. In fully kindled mice, the BZ receptor agonists clonazepam, ZK 93,423 and CL 218,872, and the antagonists flumazenil and ZK 93,426 prevented FG 7142 convulsions, as did 2 anticonvulsants, sodium valproate, possibly acting by influencing GABAergic transmission, and ethosuximide. A further two substances, MK 801 and 2-chloradenosine which act respectively via glutamatergic and purinergic mechanisms were also effective. When administered concomitantly with repeated FG 7142, all of these substances prevented or strongly reduced the development of kindling. Phenytoin and carbamazepine were ineffective in protecting against FG 7142 convulsions in kindled mice, and in preventing the development of kindling when administered repeatedly together with FG 7142. Since MK 801 and 2-chloradenosine prevented kindling, these results suggest that an interaction of FG 7142 with BZ receptors is not sufficient to induce kindling, which may instead result from secondary changes in sites distant from BZ/GABA receptors.

Animals↗
PubMed1989

Clinical percutaneous imaging of coronary anatomy using an over-the-wire ultrasound catheter system.

This manuscript describes initial applications of a unique new intravascular ultrasound imaging catheter. This 5.5F catheter uses an over-the-wire design and incorporates a phased array transducer at its tip. There are no moving parts. A 360 degree image is produced perpendicular to the catheter axis using a 20 MHz center frequency. A dedicated minicomputer is used for initial image processing, as well as enhancement and analysis. Initial studies using phantoms demonstrated excellent accuracy for linear dimensions (r = 0.99, range 3.0 to 7.6 mm, image = 1.0 phantom + 0.1). Serial imaging of the same arterial segment in vitro showed good reproducibility (coefficients of variance 2.5-5.2%). Likewise, intra- and inter-observer variability in image analysis was minimal (r = 0.92-0.99). Initial in vivo studies were performed in dogs. The catheter was easily passed over a wire into mesenteric, cerebral and coronary vessels without evidence of significant vessel trauma. Subsequently, 20 patients had percutaneous coronary imaging performed during cardiac catheterization. Cardiac motion was rarely a problem and acceptable images were obtained in all but two patients. Areas of calcification, mild stenoses, branching vessels and graft atherosclerosis could be identified. We conclude that intracoronary ultrasound imaging will be useful for assessing vascular pathology, for studying both rapid change in vessel size as well as chronic progression or regression of atherosclerosis, and for assisting with new therapeutic interventions.

Angioplasty, Balloon↗
PubMed1988

Co-existence of kindling induced by the beta-carboline, FG 7142, and tolerance to diazepam following chronic treatment in mice.

The effect of chronic treatment with the beta-carboline, FG 7142, followed by chronic treatment with diazepam (DZP) on the acute effects of DZP and FG 7142 were studied. Mice were treated for 16 days with FG 7142 (40 mg/kg i.p.) followed by treatment with DZP (5 or 20 mg/kg i.p.) for 9 days. At the end of this period, the anticonvulsant, antipunishment and locomotor sedative properties of a test dose of DZP were assessed, as were the convulsant properties of FG 7142. During the chronic treatment with FG 7142, 80% of the mice developed clonic convulsions in response to the beta-carboline, and this increased sensitivity to FG 7142 (kindling) remained following the chronic DZP treatment. Thus long-term treatment with DZP does not reverse the changes which occur during FG 7142-induced kindling. Chronic treatment with DZP for 9 days gave rise to tolerance to its pharmacological effects as assessed in the 4-plate test of antipunishment activity, in a test of locomotor sedation, and by its ability to increase the convulsant threshold of intravenously administered pentylenetetrazol. The development of tolerance to DZP was not affected by a prior chronic treatment with FG 7142. Nor were the acute effects induced by DZP altered by a prior chronic treatment with FG 7142. Apart from reducing its own convulsant threshold, chronic treatment with FG 7142 had no effect in any of the experiments. These results suggest that kindling induced by FG 7142 and tolerance to DZP depend on different mechanisms. In neither case were the pharmacological changes induced by chronic administration reflected by changes in the biochemical measures of the coupling between benzodiazepine binding sites and gamma-aminobutyric acid (GABA) receptors.

Animals↗
PubMed1988

Bidirectional nature of benzodiazepine receptor ligands extends to effects on vigilance.

The classification of benzodiazepine receptor ligands into agonists, antagonists and inverse agonists is based on biochemical, electrophysiological and behavioural evidence. Agonists potentiate the effects of gamma-aminobutyric acid (GABA) and exhibit anxiolytic, anticonvulsant, hypnotic, amnesic and muscle-relaxant properties; inverse agonists show mirror-image effects in that they may be convulsant and anxiogenic and may increase muscle tone. Antagonists antagonise the effects of both agonists and inverse agonists. Some of the most interesting ligands, however, are those substances with actions intermediate between either those of the agonists and the antagonists, or between those of the antagonists and the inverse agonists. These partial agonists and partial inverse agonists possess only some of the properties of the agonists and inverse agonists, respectively. The present experiments show that the agonist and inverse agonist properties of benzodiazepine receptor ligands can also be revealed in an animal continuous attention task in which rats were required to detect a brief signal during which operation of a lever was rewarded by food. Benzodiazepines and a beta-carboline benzodiazepine receptor agonist, ZK 93423, disrupted performance of this task, as did the antimuscarinic substance, scopolamine. Another beta-carboline, ZK 91296, which has anxiolytic and anticonvulsant properties like benzodiazepines, did not affect performance of the continuous attention task, demonstrating a separation of anxiolytic and sedative properties of such substances. A partial inverse agonist beta-carboline, FG 7142, was able to antagonise the disruptive effects of scopolamine on this task, as was, to a smaller extent, the antagonist ZK 93426. These results are discussed in terms of vigilance-enhancing properties of the inverse agonist beta-carbolines, and the possibility that such vigilance-enhancing effects might contribute to improvement of performance in learning tasks.

Animals↗