PubMed Health⌕ Search

Biomedical subjects

D N Stephens

Publications and source records attributed to D N Stephens.

At least 19 recordsLinked to original sources
PubMed1996

AMPA antagonists differ from NMDA antagonists in their effects on operant DRL and delayed matching to position tasks.

The effects of NBQX (1.56-7.5 mg/kg, i.p.), a competitive antagonist at the AMPA type of glutamate receptor, were studied in two operant behavioural paradigms, differential reinforcement of low response rates (DRL), and delayed matching to position (DMTP), which have been shown to be sensitive to the antagonists of the NMDA type of glutamate receptor. Additionally, the non-competitive AMPA antagonist, GYKI 52466 (7.5-15 mg/kg, i.p.), was studied in the DRL procedure. As a positive control, the non-competitive NMDA antagonist, MK 801 (0.0125-0.1 mg/kg, i.p.) was studied in both procedures. During performance of the DRL schedule, MK 801 increased response rates in a dose dependent manner, and decreased the number of reinforcers obtained. The increase in response rates could be attributed to both a shift in the median inter-response time (IRT) to shorter intervals, and to a marked, dose dependent increase in the occurrence of bursts of responses (responses occurring within 3 s of a previous response). In contrast, NBQX and GYKI 52466 both decreased response rates in a dose dependent fashion, and did not shift the distribution of the IRTs, or increase the occurrence of burst responding. In the DMTP procedure, accuracy of matching decreased with increasing delay (up to 30 s, between presentation of sample and opportunity to respond). NBQX disrupted responding at a dose of 7.5 mg/kg, but lower doses were ineffective in influencing accuracy of performance of the discrimination. In contrast, MK 801 (0.1 and 0.2 mg/kg) reduced accuracy of matching at all delays, while tending to increase the speed of responding. These data demonstrate differences in the effects of AMPA and NMDA antagonists on performance of well trained operant behaviour.

Animals↗
PubMed1996

N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4- isoxazoleproprionate (AMPA) glutamate-receptor antagonists have different interactions with the discriminative stimuli of abused drugs.

The effects of the AMPA-receptor antagonists NBQX and GYKI 52466 were compared with those of the NMDA-receptor channel blocker dizocilpine in two drug discrimination tests. In the first, rats were trained to discriminate morphine (2 mg/kg) from saline and in the second, to discriminate ketamine (7 mg/kg) from saline, using a two-lever food reinforced method. NBQX (1-6 mg/kg) did not substitute for either morphine or ketamine, even at a dose which reduced response rates (6 mg/kg). Likewise, the noncompetitive antagonist GYKI 52466 (5 and 10 mg/kg) produced only saline lever responding in the ketamine trained rats. When tested in combination with the training drug, NBQX (4.5 mg/kg) did not alter the morphine generalisation gradient, and similarly, neither NBQX (3 mg/kg) nor GYKI 52466 (5 and 10 mg/kg) interacted with the ketamine cue. In contrast, dizocilpine (0.05 mg/kg) significantly disrupted discrimination of morphine and produced clear drug lever responding (0.0125-0.1 mg/kg) in ketamine trained rats. These results suggest that AMPA-receptor antagonists and non-competitive NMDA-antagonists have different stimulus properties.

Analysis of Variance↗
PubMed1996

"Anxiolytic" action of diazepam and abecarnil in a modified open field test.

The effects of acutely administered diazepam and the beta-carboline abecarnil were examined in two animal models of anxiety in rats, and for their effects on food intake and locomotor activity. In the elevated x-maze diazepam (0.6-2.5 mg/kg) and abecarnil (0.03-0.3 mg/kg) induced anxiolytic-like effects. The second paradigm is based upon the suppression of feeding by exposure to a novel environment, adapted from Bodnoff et al. (1989). Food-deprived rats were placed in a corner of the open field containing food in the centre. The number of rats beginning to eat in the first 5 min was recorded. Diazepam (2.5-5.0 mg/kg) and abecarnil (0.01-0.3 mg/kg) increased the number of rats eating. Flumazenil, the benzodiazepine antagonist, was without effect, but antagonised the effects of diazepam and abecarnil. In a seperate series of experiments the effects of diazepam and abecarnil on feeding and locomotor activity were excluded as having influenced the the anxiolytic effects of these compounds in the animal models of anxiety.

Animals↗
PubMed1995

Discriminative stimulus effects of midazolam and abecarnil in rats treated chronically with diazepam or abecarnil.

Abecarnil (ABC) is a beta-carboline that acts as an agonist at benzodiazepine (BZD) receptors. It possesses anxiolytic and anticonvulsant properties, but produces little sedation and is without muscle relaxant effects. To explain this unusual profile of activity, two hypotheses have been advanced: either 1) ABC acts as a partial agonist or 2) ABC acts as a full agonist, but only at a sub-population of BZD receptors. The present experiment used cross-tolerance profiles between BZDs and ABC to differentiate these hypotheses based upon predictions of receptor theory: tolerance produced to a full agonist should confer even greater cross-tolerance to a partial agonsit. Rats were trained in a three-choice drug discrimination procedure to detect the benzodiazepine, midazolam (MDZ, 1.0 mg/kg) from pentylenetetrazole (PTZ, 20 mg/kg) from saline. Tested acutely, MDZ and ABC substituted for MDZ with similar potencies. Following chronic treatment with the BZD-agonist diazepam (DZP; 20 mg/kg per 8 h for 7 days), both the MDZ and ABC dose-effect curves were significantly shifted to the right, and both drugs showed a comparable three-fold decrease in potency. The chronic administration of ABC (4.0 mg/kg per 8 h for 7 days) produced a different spectrum of results. No significant shift occurred in the MDZ dose-effect curve, but there was a significant seven-fold shift to the right of the ABC dose-effect curve. Throughout all test, PTZ-lever responding rarely occurred and did not account for more than 20% of lever selections for any individual test. These data support the hypothesis that ABC acts as a full agonist at a sub-population of BZD receptors, which mediate its substitution for MDZ.

Animals↗
PubMed1995

Abecarnil enhances GABA-induced currents in acutely isolated cerebellar Purkinje cells.

The effect of abecarnil, a beta-carboline derivative acting at central gamma-aminobutyric acid (GABAA)/benzodiazepine receptors, on the response to GABA of isolated Purkinje cells acutely dissociated from rat cerebellar slices was studied. Using a rapid superfusion system to apply drugs and whole-cell voltage-clamp recording configuration, abecarnil was found to be of similar efficacy to diazepam (DZP) in enhancing GABA-mediated responses. Abecarnil potentiated GABA-induced chloride currents maximally by 241%, while DZP showed a maximal potentiation of 217%. However, abecarnil was more potent than DZP and exhibited different potentiation kinetics. While the response to DZP was fast and reversible, abecarnil after a 1-3 sec application initially produced only a very small enhancement of the GABA response. The effect then developed gradually even after cessation of abecarnil application, and depended on both abecarnil concentration and exposure time. It is suggested that abecarnil accumulates in the lipid membrane resulting in slow effect kinetics and prolonged presence at the benzodiazepine binding site. Abecarnil is a full agonist at the GABAA/benzodiazepine receptor on Purkinje cell somatic membranes.

Animals↗
PubMed1995

Discriminative stimulus properties of the stereoisomers of the phosphodiesterase inhibitor rolipram.

The discriminative stimulus properties of the specific type IV phosphodiesterase inhibitor, rolipram, and its two stereoisomers were assessed using standard two-lever drug discrimination procedures in which responding on the appropriate lever was reinforced on a FR10 schedule. In three separate drug cues based on training rats to discriminate the racemate (0.2 mg/kg, IP), the (-)-isomer (0.1 mg/kg), or the (+)-isomer (2 mg/kg) from vehicle, all forms substituted for one another, differing only in potency. In keeping with published reports, the (-)-isomer was the more potent form, the (+)-isomer being approximately 10 times less potent. Several phosphodiesterase (PDE) inhibitors were found to substitute for the racemate cue, their potencies in the behavioural measure correlating with their potency in displacing [3H]rolipram from its forebrain binding sites in vivo (r = 0.95), suggesting that the discriminative stimulus depends on an action of the drug upon this site. Because rolipram has been reported to possess antidepressant activity, the ability of the tricyclic antidepressant imipramine to substitute for rolipram was investigated; doses of 10 and 20 mg/kg did not substitute. Amphetamine (0.156-1.25 mg/kg) also was inactive. Lisuride gave rise to drug-appropriate responding in 50% of rats only at a dose of 0.078 mg/kg, which severely disrupted responding. It is concluded that the rolipram discriminative stimulus is dependent on the selective PDE inhibitory activity of the drug, and that it does not constitute a cue based on the antidepressant property of rolipram.

Animals↗
PubMed1995

Experimental studies on an efficient catheter array imaging system.

A new synthetic aperture system for intraluminal imaging has been tested using a 32 element, 20 MHz circular array wrapped around the surface of a catheter appropriate for coronary artery applications. This system is based on an optimal reconstruction method that has been extended to reduce grating lobes using a slight modification to classic synthetic aperture data acquisition. Optimal reconstruction filters have been derived for two different operating modes based on this new data acquisition strategy. Imaging results on a wire target phantom show that spatial resolution is a simple linear function of depth, reaching a minimum 6 dB beam width of approximately 2.2 wavelengths. Sidelobe levels are inherently high for this system because of the small number of firings used to synthesize an aperture. Optimal reconstruction filters, however, can reduce these sidelobes to at least -20 dB in all cases. Finally, images of an excised segment of porcine femoral artery demonstrate the overall performance of the system as an intraluminal imager.

Animals↗
PubMed1994

Comparison of several benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies.

This study compared the effects of the beta-carboline anxiolytic, abecarnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was related to the fraction of BZR occupied by the drug. Abecarnil was efficacious in both tests and showed anxiolytic effects comparable with alprazolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor activity suppressed by footshock (punished crossings). None of these compounds significantly altered non-punished crossings. In contrast, diazepam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20-60%). The number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor occupancy). Alpidem had very weak anxiolytic-like effects in this test and markedly reduced unpunished crossings at relatively low receptor occupancies (> 15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equal to that observed following diazepam or alprazolam administration. Bretazenil and ZK 95962 had weak effects on the measures of anxiolytic activity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The effects of ibotenic acid lesions of the basal forebrain on visual discrimination performance in rats.

Rats were trained to stable performance in a conditional brightness discrimination task and then received infusions of ibotenic acid or vehicle into the basal forebrain. Following 2 weeks of recovery, animals were retested in the original discrimination. Lesioned rats tended to performed badly on the first day of testing as measured by all parameters (percent correct responding, latency to respond, and missed trials) but thereafter, most rats recovered quickly to prelesion levels. In keeping with previous reports, an approximately 30% reduction in choline acetyltransferase activity was observed in the lesioned animals. Four rats showed no recovery over a period of several months; however, an analysis of the choline acetyltransferase in several brain regions revealed no obvious differences to those animals in which performance recovered. Postlesion testing with the putative nootropic beta-carboline ZK 93426 showed no major differences to the effects observed in control animals. Scopolamine had similar negative effects in both groups tested. These data indicate that deficits induced by lesions of the basal forebrain do not correlate with reductions in cholinergic activity.

Animals↗
PubMed1993

Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats.

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly "forgetting" curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a marked delay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a marked delay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Kindling to the benzodiazepine receptor inverse agonist, FG 7142: evidence for involvement of NMDA, but not non-NMDA, glutamatergic receptors.

Repeated administration of the beta-carboline FG 7142 to mice leads to the development of kindled convulsions. In order to investigate a role for glutamatergic mechanisms in the processes underlying FG 7142 kindling, the N-methyl-D-aspartate (NMDA) antagonist, 2-amino-7-phosphono-heptanoic acid (AP7; 25 nmol), was administered intracerebroventricularly (i.c.v.) daily before administration of FG 7142 (40 mg/kg, i.p.). Under these conditions, kindling to FG 7142 did not occur. Administration of two antagonists at non-NMDA excitatory amino acid receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and gamma-D-glutamylaminomethylsulphonic acid (gamma-D-GAMS; both 25 nmol) did not prevent the development of seizures; these doses were, however, adequate and selective in protecting against seizures induced by respectively quisqualic and kainic acids given by i.c.v. The susceptibility of mice kindled with FG 7142 to seizures induced by NMDA, or kainate or quisqualate was similar in mice which had shown 5 kindled seizures to that seen in drug-naive mice; mice which had shown 10 kindled seizures showed a decreased sensitivity to NMDA-induced convulsions (ED50 was increased from 0.24 to 0.31 nmol). No changes were seen in the convulsant thresholds of either NMDA or non-NMDA agonists. These observations suggest that although NMDA receptors appear to be involved in the processes underlying FG 7142 kindling, such kindling is not necessarily associated with an increased sensitivity of glutamate receptors, and in animals which have convulsed, a decreased sensitivity to NMDA agonists occurs.

Animals↗
PubMed1993

Long-term treatment with abecarnil does not induce diazepam-like dependence in mice.

Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a metabolically stable anxiolytic and anticonvulsant beta-carboline derivative with few sedative and muscle relaxant effects in rodents. Abecamil binds with high affinity to benzodiazepine receptors. Because long-term treatment with benzodiazepines leads to development of dependence, we evaluated in mice whether abecarnil also possesses a potential for producing dependence, using electroencephalographic and electromyographic monitoring, and behavioral assessment of anxiety to detect withdrawal responses after chronic treatment. Diazepam was used as a reference. Mice withdrawn from chronic treatment with diazepam (15 mg/kg/day for 12 days) showed a time-related evolution of anxiety, muscle rigidity and seizures between days 4 and 21 after discontinuation of the treatment. A period between withdrawal days 1 and 3 was symptom free. Mice withdrawn from chronic administration of abecarnil (6 mg/kg/day for 12 days) showed no anxiety and no changes in seizure susceptibility and muscle tone. The doses of diazepam and abecarnil used for chronic treatment were equivalent in terms of kinetics and binding to benzodiazepine receptors. These data indicate that long-term treatment with abecarnil does not induce benzodiazepine-like dependence in mice. Thus, it may be predicted that chronic treatment with abecarnil in humans may offer an important alternative to benzodiazepines in the treatment of anxiety.

Animals↗
PubMed1993

Effect of the beta-carboline abecarnil on spinal reflexes in mice and on muscle tone in genetically spastic rats: a comparison with diazepam.

Abecarnil is a beta-carboline agonist at benzodiazepine receptors with potent anxiolytic activity but no muscle relaxant side effects in rodents. Clinical experience suggests that changes in the muscle tone induced by benzodiazepines are related to their effects on spinal reflexes. The authors therefore analyzed the effect of treatment with abecarnil on spinal monosynaptic (Hoffmann reflexes) and polysynaptic (flexor) reflexes in mice and the influence of abecarnil on muscle tone in genetically spastic rats. The i.v. administration of abecarnil in mice (dose range, 0.02-1 mg/kg) depressed flexor reflexes in a dose-dependent manner; Hoffmann reflexes remained unchanged. Administration of diazepam i.v. (0.01-1 mg/kg) also reduced flexor reflexes and had little or no effect on Hoffmann reflexes. In genetically spastic rats, i.v. administration of abecarnil (10-30 mg/kg) decreased the muscle tone in a dose- and time-dependent manner. A similar muscle relaxant effect was observed in such rats after i.v. administration of diazepam (0.1-0.8 mg/kg). By contrast, i.p. administration of abecarnil in mice did not influence spinal reflexes up to the dose of 1 mg/kg and, in genetically spastic rats, did not affect muscle tone up to the dose of 100 mg/kg. Administration of diazepam i.p. (1 mg/kg) depressed flexor reflexes in mice and over the range 0.2 to 5 mg/kg produced a dose- and time-dependent decrease of muscle tone in genetically spastic rats. The muscle relaxant effect of i.p. diazepam could be antagonized by i.p. administered abecarnil. These studies thus demonstrate that i.v. but not i.p. administration of abecarnil may result in muscle relaxant action in mice and in genetically spastic rats.

Animals↗
PubMed1992

Alterations in medial perforant path and mossy fiber induced field potentials in amygdala and beta-carboline (FG 7142) kindled rats.

We tested in rat hippocampal slices whether kindling causes sprouting of mossy fibers thereby augmenting excitatory coupling and epileptogenicity. Field potentials (fp's) evoked by orthodromic stimulation of the medial perforant path (MPP) and antidromic stimulation of mossy fibers in slices from control, amygdala kindled (AK) and beta-carboline (FG 7142) kindled rats were recorded in the dentate gyrus granule cell layer. Orthodromic paired pulse inhibition was increased in both groups of kindled animals. In contrast, neither in normal medium nor under additional application of the GABAA receptor antagonist bicuculline nor in Mg(2+)-free artificial cerebrospinal fluid (ACSF) there was evidence for an excitatory field EPSP component upon stimulation of mossy fibers in any of the investigated groups. The results indicate that functional mossy fiber sprouting does not occur as an obligatory step in the induction of kindling epilepsy.

Amygdala↗
PubMed1992

Excitatory amino acid antagonists protect mice against MPP+ seizures.

Administration of 1-methyl-4-phenyl-pyridinium ion (MPP+) into the lateral ventricle of mice induced clonic convulsions and lethality in a dose- and age-dependent manner. MPP+ failed to induce seizures in 4-day-old mice, and the convulsant response to MPP+ was enhanced in aged mice. The seizures triggered by MPP+ in adult mice were blocked by coadministration of L-glutamate antagonists active at kainate/AMPA receptors such as gamma-D-glutamylaminomethylsulphonate and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline. The N-methyl-D-aspartate (NMDA) antagonist 2-amino-7-phosphonoheptanoate, but not kynurenate, also protected mice against MPP+ convulsions. Similarly, the benzodiazepine midazolam and the adenosine A1 agonist 2-chloroadenosine, but not antiepileptic drugs such as phenobarbital, trimethadione, ethosuximide, or acetazolamide, showed a protective efficacy against seizures. Additionally, the excitatory amino acid antagonists as well as phenobarbital, midazolam and 2-chloroadenosine protected mice against MPP+ lethality. These data suggest that convulsant action of MPP+ and its lethality in rodents may be mediated by excitatory amino acids.

Aging↗
PubMed1992

Effects of cholinergic and non-cholinergic drugs on visual discrimination and delayed visual discrimination performance in rats.

The effects of several centrally active drugs were investigated using two visual discrimination tasks: a two-lever food-rewarded conditional brightness discrimination, and a similar conditional brightness discrimination where a delay was introduced between the disappearance of the stimulus and the opportunity to respond on the levers for food. The substances tested (amphetamine, scopolamine, methylscopolamine, physostigmine, diazepam and beta-carboline benzodiazepine receptor antagonist, ZK 93426), all produced differing profiles of action on the performance parameters recorded. In the simple conditional visual discrimination, amphetamine increased omissions without significant effects on accuracy or response latency. Physostigmine enhanced response latencies and failures to respond without significant effects on accuracy. ZK 93426 had no consistent effects on accuracy although at higher doses, some increase in response latency was seen in the delayed responding version of the visual discrimination task. Diazepam had negative effects on all parameters in both discrimination procedures. Scopolamine disrupted responding, but not accuracy in the simple discrimination, whereas accuracy was reduced in a dose, but not delay dependent manner in the delayed discrimination. A similar effect to that observed with scopolamine was observed following methylscopolamine in the delayed discrimination procedure. In the simple visual discrimination small increases in accuracy were recorded, accompanied by increased response latencies.

Animals↗