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D N Stephens

Publications and source records attributed to D N Stephens.

At least 91 records · Page 5Linked to original sources
PubMed1988

Beta-carbolines as tools in memory research: animal data and speculations.

Benzodiazepines induce in animals, as in humans, almost exclusively anterograde amnesia. The mechanism of this effect is still unsettled; however, explanations like state dependency which may be based on sedative or emotional properties of benzodiazepines are usually favoured in contrast to an interpretation in terms of true amnesia. It is proposed that by the use of beta-carbolines with agonist, partial agonist, antagonist and partial inverse agonist properties, the nature of the amnesia induced by benzodiazepine receptor agonists may be characterised. From a series of experiments it is concluded that the major reason for benzodiazepine-induced amnesia might be an impaired ability to filter interfering stimuli; that is, an attentional deficit. Since the antagonist beta-carbolines may play a key role in providing evidence as to the GABAergic involvement in cognitive processes, the pharmacological profile of ZK 93426 is presented. The results of the interaction of beta-carbolines with scopolamine will provide a basis on which to speculate on the GABAergic control of cholinergic neurotransmission and its therapeutic implications.

Animals↗
PubMed1988

Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines.

Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behaviour were measured. The latter is thought to reflect working memory capacity at a rudimentary level. During an 8 min session, vehicle-treated mice performed 32.4 +/- 7.4 arm entries, 51.0 +/- 12.4% of which were organized in alternations (triplets). The two variables showed a negative correlation. Scopolamine (1.0 mg/kg) significantly enhanced activity, reduced alternation behaviour and diminished the correlation between the two variables. The effects of benzodiazepine receptor inverse agonist, antagonist and agonist beta-carbolines on this spontaneous behaviour and on the effects of scopolamine were examined. The effects of inverse agonists and agonists on locomotor activity were complex in interaction with both vehicle and scopolamine. The scopolamine-induced reduction of alternation behaviour was significantly reversed by the antagonist ZK 93426 but not by inverse agonists; furthermore, partial agonists and agonists showed no effects. It is hypothesized that the interaction of antagonist beta-carbolines with scopolamine is based on a direct GABA-ergic control of cholinergic neurotransmission, and suggests an ability of antagonist beta-carbolines to antagonize amnestic properties of scopolamine.

Animals↗
PubMed1987

Human studies on the benzodiazepine receptor antagonist beta-carboline ZK 93,426: preliminary observations on psychotropic activity.

The beta-carboline ZK 93,426, a benzodiazepine receptor antagonist, was administered intravenously to human volunteers at two different doses (0.01 mg/kg, 0.04 mg/kg) according to a double-blind, placebo controlled design. Vital functions (i.e. blood pressure, heart rate, ECG, EEG), peripheral (finger) skin temperature and performance in psychometric tests for psychotropic and cognitive effects were evaluated. Blood samples were collected in addition and certain pharmacokinetic parameters were estimated. ZK 93,426 in both doses was well tolerated and exhibited no side effects. A decrease in peripheral skin temperature and heart rate was observed. In a general estimation of behavioural changes, volunteers experienced a stimulant and activating effect of the drug. An improvement in performance was observed in two cognitive tasks, the "logical reasoning task" and "pictures differences task" which estimated concentration and attention, respectively. No effects were found in time estimation. Plasma levels 5 min after intravenous administration of ZK 93 426 were 16 +/- 10 ng/ml and 52 +/- 31 ng/ml for 0.01 mg/kg and 0.04 mg/kg, respectively. Total clearance was calculated as 46 +/- 22 ml/min/kg (0.04 mg/kg).

Adolescent↗
PubMed1987

Modulation of anxiety by beta-carbolines and other benzodiazepine receptor ligands: relationship of pharmacological to biochemical measures of efficacy.

Several beta-carbolines and other benzodiazepines (BZ) receptor ligands have been investigated for anxiolytic or anxiogenic action in 4 unrelated animal models of anxiety using rats. The substances could be grouped into essentially 2 groups. The first, anxiolytics, exhibited antipunishment activity in a lick-suppression test, antagonised the discriminative stimulus provided by pentylenetetrazol, resembled chlordiazepoxide (CDP) in a drug discrimination test, and reduced the rise in plasma corticosterone levels following swim stress. Such substances included several benzodiazepines, the beta-carboline ZK 93 423, and the triazolapyridazine CL 218 872. A subgroup of anxiolytics were active in only some of these tests. They included two beta-carbolines, ZK 91 296 and ZK 95 962, and the pyrazoloquinoline CGS 9896, and these 3 substances were also distinguishable in not producing rate-decreasing effects in any of the 3 operant tests. The second group were anxiogenic in that they produced a discriminative stimulus resembling that of PTZ, they antagonised the CDP cue, exhibited propunishment effects in the lick-suppression test, and themselves caused increases in plasma corticosterone in otherwise unstressed animals. Such substances included the beta-carbolines DMCM, FG 7142 and ZK 90 886, and the pyrazoloquinoline CGS 8216. Two substances, Ro 15-1788 and ZK 93 426 had little or only weak activity in any test. The classification of these substances into anxiolytics or anxiogenics could be predicted qualitatively both by their ability to enhance (anxiolytics) or decrease the binding of 35S-TBPS to rat brain membranes and by whether their own binding was increased (anxiolytics) by adding the GABA agonist muscimol to the in vitro incubation medium. For the limited number of substances for which full data was available, there was also a quantitative relationship between the degree of enhancement of 35S-TBPS binding by a substance and its potency in the CDP cue test when such potency was expressed as numbers of BZ receptors occupied at the ED50 value in the pharmacological test. Furthermore, for the anxiolytics, activity in the CDP cue correlated significantly with potency in 2 other tests. Otherwise, surprisingly weak correlations existed between potencies in the different tests. In particular, the beta-carboline ZK 95 962 was highly potent in antagonising the PTZ cue but inactive in both a conflict test and in protecting against stress. These results are discussed in terms of differences in the neuropharmacologies of the 4 tests and in selectivity of the BZ receptor ligands for subtypes of BZ receptor.

Animals↗
PubMed1987

Bidirectional effects of beta-carbolines and benzodiazepines on cognitive processes.

Experiments with benzodiazepine receptor ligands in two paradigms involving cognitive processing were performed in order to test whether the concept of bidirectional effects of benzodiazepine receptor ligands could also be applied to cognitive functions. Benzodiazepine receptor agonists like chlordiazepoxide, lorazepam, ZK 93423 and ZK 91296 induced amnesia in a passive avoidance paradigm. Mice treated with the benzodiazepine receptor antagonist, ZK 93426, reached a learning criterion after fewer foot-shocks than saline treated mice both in naive animals and in scopolamine pre-treated animals. Furthermore, ZK 93246, attenuated the amnesic effect of corneal electroshock. The inverse agonists FG 7142 and DMCM decreased the detrimental effect of scopolamine on retrieval. In a signal detection paradigm, chlordiazepoxide impaired signal detection. In aged rats ZK 93426, ZK 90886 and FG 7142 had no effect on signal detection but ZK 93426 and FG 7142 attenuated the impairment of signal detection induced by scopolamine. These effects of benzodiazepine receptor ligands may reflect changes in arousal/vigilance, suggesting that BZ inverse agonists may have useful properties in enhancing vigilance.

Animals↗
PubMed1986

Does the excitatory amino acid receptor antagonist 2-APH exhibit anxiolytic activity?

The activity of 2-amino-7-phosphonoheptanoic acid (2-APH), an antagonist of the NMDA subtype of glutamate receptor, was tested in several animal models of anxiolytic activity in rats and mice and compared with the activity of the standard benzodiazepine anxiolytic, diazepam. 2-APH was effective, but about 100 times less potent than diazepam in antagonising the suppressive effects of punishment on locomotor activity in the four-plate test in mice. 2-APH was also effective in enhancing exploration of the open, exposed arms of a plus maze, without altering exploration of the enclosed arms. Again 2-APH was about 100 times less effective than diazepam. In contrast to diazepam, 2-APH was ineffective in antagonising the pro-punishment properties of the anxiogenic beta-carboline DMCM in a modified four-plate test, and in antagonising the discriminative stimulus provided by pentylenetetrazol. These results are discussed in the context of the equivalence of the antagonism of excitatory mechanisms and the enhancement of inhibitory systems as anxiolytic treatments.

2-Amino-5-phosphonovalerate↗
PubMed1986

Effect on hypothalamic self-stimulation of the novel beta-carbolines ZK 93 426 (a benzodiazepine receptor antagonist) and ZK 91 296 (a putative partial agonist).

Low doses (300 micrograms/kg-1.0 mg/kg) of the novel beta-carboline, ZK 91 296, a putative agonist at the benzodiazepine receptor, produced a significant increase in the rate of variable-interval self-stimulation responding, similar to that found with typical benzodiazepines. This effect was blocked by simultaneous administration of the specific benzodiazepine-receptor antagonists Ro 15-1788 (2.0 mg/kg), and ZK 93 426 (10 mg/kg). Neither antagonist, ZK 93 426 (100 micrograms/kg-10 mg/kg) or Ro 15-1788 (2.0 mg/kg), had any effect on self-stimulation when given alone. Unlike all benzodiazepine-receptor agonists previously tested, higher doses of ZK 91 296 did not depress self-stimulation response rates, even at a dose-level 100 times greater than the maximally stimulant dose. It is uncertain why ZK 91 296 lacks depressant effects: available evidence does not conclusively favour any single current explanation, but is consistent with it acting as a "partial" agonist.

Animals↗
PubMed1986

Potentiation of the propunishment, but not the convulsant action of the beta-carboline DMCM by naltrexone.

The ability of naltrexone (NTX) to potentiate the propunishment and convulsant properties of DMCM, a benzodiazepine receptor inverse agonist, was studied in mice. Doses (0.39 and 1.56 mg/kg) of DMCM which were below the threshold for propunishment effects showed a marked ability to enhance the suppressive effects of punishment on locomotor activity in the presence of naltrexone (0.5 or 2.5 mg/kg IP), higher doses of DMCM and NTX (3.13 mg/kg and 10 mg/kg, respectively) had a depressant effect of their own on both punished and unpunished locomotor activity. DMCM given alone induced clonic convulsions (ED50: 5.7 mg/kg IP) but this activity was not changed in the presence of naltrexone. These results suggest an interaction of BZ receptors and opioid systems in the control of anxiety.

Animals↗
PubMed1985

Beta-carbolines can enhance or antagonize the effects of punishment in mice.

Six beta-carboline ligands at central benzodiazepine (BZ) receptors were tested for their anxiolytic or anxiogenic properties in mice in the four-plate test. ZK 93 423 and ZK 91 296 increased activity which had been suppressed by punishment (1 mA, 60 ms footshock) at doses which exerted no effect on unpunished locomotion. ZK 93 426, ZK 90 886, FG 7142, and DMCM exerted no antipunishment activity themselves, and antagonized the ability of diazepam to increase both punished and unpunished locomotor activity. DMCM, FG 7142, and ZK 90 886, but not ZK 93 426, also enhanced the ability of a reduced level of footshock (0.3 mA) to suppress activity. This propunishment activity of DMCM and ZK 90 886 took place at doses which had no effect on unpunished locomotion. The nature of the effect of the individual beta-carbolines on punishment was related to the nature of their interaction with the BZ/GABA receptor/chloride channel complex (GBC complex). Thus the antipunishment properties of ZK 93 423 and ZK 91 296 were associated with their ability to increase binding of 35S-t-butylbicyclo-phosphorothionate (TBPS) to its binding site associated with the chloride channel, whereas DMCM, FG 7142 and ZK 90 886, which exerted propunishment effects, reduced TBPS binding. ZK 93 426, which was neutral with respect to punished activity, had the weakest effect on TBPS binding. These results are discussed in the context of a possible role of GBC complex in anxiety.

Animals↗
PubMed1985

Tolerance to the benzodiazepine diazepam in an animal model of anxiolytic activity.

The antipunishment properties of diazepam (DZP) were investigated in mice treated acutely, or following nine daily treatments with either DZP (5 mg/kg, PO) or its vehicle. Acutely, or following chronic vehicle treatment, DZP produced a dose-related increase in activity punished by footshock. Following chronic DZP, test doses of DZP given 24 or 48 h following the last chronic treatment were no longer, or less effective in enhancing punished activity. Effects on unpunished activity were unaffected. In a study of the time course of tolerance development, tolerance was not seen after one or three daily treatments but was present after 6 days. Following establishment of tolerance by 9 days' treatment, the antipunishment activity of DZP reappeared after 8 days' withdrawal and was restored to acute levels after 16 days. Tolerance was not associated with changes in benzodiazepine (BZ) receptor affinity or numbers, but the ability of GABA to enhance BZ binding was increased. There was no change in the ability of DZP or the convulsant beta-carboline DMCM to modulate 35S-TBPS binding. The mechanism of tolerance to the antipunishment properties of DZP therefore remains unknown.

Animals↗
PubMed1985

Reversal learning in senescent rats.

The ability of old (24 months) and young (3 months) male rats to reverse a previously acquired discrimination was compared in 5 experiments. The old rats did not need more trials to learn a position habit in a T-maze to obtain water reward, but required more trials to reverse the position habit. The old rats showed a similar deficit in a second, but not in subsequent reversals of the position habit. In a second experiment, old rats were slower in learning to operate one of two levers in an operant chamber to obtain food reward on a CRF schedule, but by the session prior to reaching criterion for acquisition they showed response rates similar to the young animals. When the rats were required to operate the alternative lever to obtain reward, the young rats emitted 70% of their responses during the first reversal session on the newly-correct lever, but the old rats only 35%. Nevertheless, the groups were similar in the number of sessions required to reach a criterion of 95% of responses on the correct lever. In 3 subsequent reversals, old and young rats did not differ nor were there differences in the number of responses in 4 extinction sessions in the rats which had received reversal training. In experiment 3 with old and young rats which had received only acquisition training, old rats emitted fewer responses than young animals during extinction. From these experiments it was hypothesized that the apparent difficulty of old rats in learning a reversal task was due to the low probability of their emitting spontaneously a novel or previously unrewarded response, and not to a difficulty in forming a new association. This hypothesis was tested in two further experiments in which rats were required to learn a brightness discrimination in a T-maze. Old and young rats which had learned and reversed position habits in the T-maze in experiment 1, did not differ in either acquisition or reversal of the brightness discrimination, suggesting that old rats do not differ from young animals in reversal tasks when the motor response requirements for the task are already within the animals' behavioural repertoire. Consistent with this hypothesis, naive old rats were slower than young rats in acquiring a similar brightness discrimination but did not differ in the reversal task.

Aging↗
PubMed1984

Beta-carbolines with agonistic and inverse agonistic properties at benzodiazepine receptors of the rat.

The anxiogenic or anxiolytic properties of five beta-carbolines were assessed in rats trained in two-lever operant chambers to operate one lever to obtain food reward when treated with a training drug, and the other when treated with saline. Two such drug-discrimination tests were used, employing either chlordiazepoxide (CDP) or pentylenetetrazol (PTZ) as training drugs. The benzodiazepine (BZ) agonist, ZK 93 423, substituted for the CDP cue and antagonized the PTZ cue. The inverse agonists DMCM and FG 7142 showed the opposite effects. An antagonist, ZK 93 426, antagonized the CDP cue but did not substitute for PTZ, while a partial agonist was identified as CDP-like but only partially antagonized the PTZ cue. An anxiolytic profile (substitution for CDP and antagonism of PTZ) was associated with GABA ratios of about 2, and an anxiogenic profile with GABA ratios less than 1. The antagonist and partial agonist displayed intermediate values. These observations are generally consistent with the beta-carbolines modulating anxiety through their activity at BZ receptors influencing GABAergic neurotransmission.

Animals↗
PubMed1984

Discriminative stimulus properties of beta-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors.

The discriminative stimulus properties of three beta-carboline derivatives were studied in three groups of rats trained, respectively, to discriminate diazepam (2.5 mg/kg IP), chlordiazepoxide (CDP, 5 mg/kg IP) or pentylenetetrazol (PTZ, 15 mg/kg IP) from saline in standard procedures employing two-lever operant chambers. Two beta-carbolines, ZK 91296 and ZK 93423, substituted for the benzodiazepines in both CDP- and diazepam-trained rats. The neutral benzodiazepine antagonists Ro 15-1788 blocked the diazepam discriminative stimulus and the ability of ZK 91296 to substitute for diazepam. A third beta-carboline, FG 7142, was not identified as benzodiazepine-like in generalization tests in either diazepam- or CDP-trained rats, but when administered together with CDP antagonized the benzodiazepine discriminative stimulus. In rats trained to discriminate PTZ from saline (a discrimination which is thought to depend on the anxiogenic properties of PTZ) the PTZ cue was antagonized by diazepam and ZK 93423, and partially antagonized by ZK 91296. The PTZ cue generalized to FG 7142 and this generalization was partially antagonized by Ro 15-1788. These results suggest that the three beta-carbolines provide more than one kind of discriminative stimulus, consistent with the classification of ZK 93423 as an agonist at central benzodiazepine receptors, with ZK 91296 as a partial agonist, and with FG 7142 as an inverse agonist. Pharmacologically, ZK 93423 and ZK 91296 may exhibit anxiolytic qualities, whereas FG 7142 produces anxiogenic effects.

Animals↗
PubMed1984

ZK 91296, a partial agonist at benzodiazepine receptors.

5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a potent and selective ligand for benzodiazepine (BZ) receptors. Biochemical investigations indicate that ZK 91296 may be a partial agonist at BZ receptors. Such partial agonism may explain to some extent why ZK 91296 needs higher BZ receptor occupancy than diazepam for the same effect against chemical convulsants and for behavioural effects. The lack of sedative effects, and the very potent inhibition of reflex epilepsy, spontaneous epilepsy and DMCM-induced seizures suggest, furthermore, that ZK 91296 may possess pharmacological selectivity for a particular type of BZ receptor interaction, perhaps including topographic as well as receptor subtype differentiation.

Animals↗