Biomedical subjects

B J Cao

Publications and source records attributed to B J Cao.

15 recordsLinked to original sources

PubMed1998

Comparative effects of novel 5-HT1A receptor ligands, LY293284, LY315712 and LY297996, on plus-maze anxiety in mice.

In contrast to the variable efficacy of 5-HT1A receptor full and partial agonists in animal models of anxiety, recent findings in our laboratory have revealed remarkably consistent anxiolytic-like effects for 5-HT1A receptor antagonists in the murine elevated plus-maze paradigm. In the present study, ethological techniques were used directly to compare the plus-maze profiles of three novel ligands varying in intrinsic efficacy at 5-HT1A receptors: LY293284 (full agonist; 0.01-0.3 mg/kg), LY315712 (partial agonist; 0.3-3.0 mg/kg), and LY297996 (antagonist; 0.03-10.0 mg/kg). At the lowest dose tested, LY293284 tended to enhance several indices of anxiety, whereas higher doses suppressed all active behaviours. Although few behavioural effects were observed with LY315712 under present test conditions, a selective reduction in risk assessment was apparent at 1.0-3.0 mg/kg. In contrast to these profiles, LY297996 (3.0-10.0 mg/kg) produced robust anxiolytic-like effects on conventional and ethological parameters but, importantly, did not alter general activity levels. These results provide further support for the anxiolytic potential of 5-HT1A receptor antagonists and are discussed in relation to possible factors underlying inter-laboratory variation in the effects of these agents in animal models of anxiety.

Analysis of Variance↗

PubMed1998

Tolerance to acute anxiolysis but no withdrawal anxiogenesis in mice treated chronically with 5-HT1A receptor antagonist, WAY 100635.

Anxiolytic-like activity in the mouse elevated plus-maze has recently been demonstrated for a range of compounds varying in degree of selectivity as 5-HT1A receptor antagonists. As tolerance and dependence liability are among the major clinical disadvantages of benzodiazepine therapy, the present study examined the effects of acute drug challenge on the plus-maze profiles of mice following daily treatment for 20 days with saline, chlordiazepoxide (CDP; 10.0 mg/kg) or the selective 5-HT1A receptor antagonist, WAY 100635 (0.1-1.0 mg/kg). To assess the development of physical dependence (withdrawal anxiogenesis), the study incorporated independent groups of animals tested on the maze 24 h after the final dose. Challenge with CDP or WAY 100635 produced behavioural changes indicative of anxiety reduction in mice that had received daily handling/saline for 20 days, thereby demonstrating that the chronic injection regimen per se had not compromised the acute efficacy of either agent. The absence of a similar response to acute drug challenge in mice treated chronically with CDP or WAY 100635 suggested the development of tolerance to the acute anxiolytic effects of both compounds under present test conditions. Despite these observations, however, no signs of enhanced anxiety were evident 24 h following discontinuation of chronic treatment with either compound. In a further experiment, the absence of withdrawal anxiogenesis at 24 h was replicated and extended to discontinuation periods of 36 and 48 h for both drugs. Although present results show that tolerance develops to the acute anxiolytic effects of CDP and WAY 100635 in the murine plus-maze, they also suggest that enhanced anxiety is not an inevitable consequence of abrupt cessation of chronic treatment with either compound.

Animals↗

PubMed1997

Dopamine D4 receptor and anxiety: behavioural profiles of clozapine, L-745,870 and L-741,742 in the mouse plus-maze.

The dopamine D4 receptor has been implicated in the therapeutic effects of the atypical antipsychotic, clozapine. As it has been proposed that anxiolytic-like activity may contribute to the efficacy of this agent in ameliorating the negative symptoms of schizophrenia, the current study employed ethological methods to fully characterize the acute behavioural profiles of clozapine and two more selective dopamine D4 receptor antagonists, L-745,870 (3-[{4-(4-chlorophenyl)piperazin-1-yl)]methyl}-1 H-pyrrolo[2,3b]pyridine) and L-741,742 (5-(4-chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)is oxazole), in the mouse elevated plus-maze test. Results showed that while clozapine (0.3-6.0 mg/kg) dose-dependently inhibited all active behaviours (arm entries, exploration, rearing) and increased grooming and immobility, it failed to alter the major anxiety indices (percent open entries and open time). In contrast, L-745,870 (0.02-1.5 mg/kg) and L-741,742 (0.04-5.0 mg/kg) did not produce any significant behavioural changes under present test conditions. These data, which contrast markedly with the robust anxiolytic profile of the reference compound, chlordiazepoxide (10.0 mg/kg), provide little support for the suggestion that clozapine possesses anxiolytic-like properties and further indicate that selective dopamine D4 receptor antagonists are ineffective in the modulation of anxiety-related behaviours in the plus-maze.

Animals↗

PubMed1997

Anxiolytic-like profile of p-MPPI, a novel 5HT1A receptor antagonist, in the murine elevated plus-maze.

Recent research on the effects of selective 5-HT1A receptor antagonists in animal models of anxiety has yielded inconsistent findings. In the present study, the behavioural effects of the novel 5-HT1A receptor antagonist, 4-(2'-methoxy-phenyl)-1-[2'-(n-2"-pyridinyl) -p-iodobenzamido]-ethyl-piperazine (p-MPPI), were examined in male mice using an ethological version of the elevated plus-maze test. Results show that at lower doses (0.5-4.5 mg/kg), p-MPPI produced a significant and dose-related anxiolytic profile on both conventional (open arm avoidance) and ethological (risk assessment) measures. However, these effects were lost at a higher dose (13.5 mg/kg) which, instead, increased grooming and immobility. The behavioural profile of p-MPPI is contrasted with those previously obtained with other 5-HT1A receptor ligands (agonists, partial agonists and antagonists), and it is suggested that 5-HT1A receptor antagonists may possess therapeutic advantages in anxiety disorders.

Aminopyridines↗

PubMed1997

Comparative behavioural profiles of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in the murine elevated plus-maze.

It has been suggested that in vivo formation of the metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) may be a major drawback in the use of buspirone as an anti-anxiety agent. To test this hypothesis, the effects of buspirone, alone or with proadifen (an inhibitor of liver microsomal enzymes) pretreatment, were contrasted with those of 1-PP in the murine elevated plus-maze test of anxiety. At 3.0 mg/kg (but not lower doses), buspirone per se had modest anxiolytic-like effects (increased percentage of open arm entries; reduced stretched-attend postures and flatback approach) that were associated with increased grooming and immobility. However, in proadifen-pretreated mice, buspirone produced behavioural depression only, with marked effects evident both at 1.0 and 3.0 mg/kg. As proadifen blocks the biotransformation of buspirone to 1-PP, these data suggest that any anxiolytic activity of buspirone in the murine plus-maze may be attributable to its principal active metabolite. Consistent with this hypothesis, 1-PP (0.5-13.5 mg/kg) produced dose-dependent anti-anxiety effects on both conventional and ethological measures that were not confounded by motoric impairment. Results are discussed in relation to biochemical and electrophysiological studies suggesting that 1-PP has a direct action at 5-HT1A receptors.

Animals↗

PubMed1997

Influence of 5-HT1A receptor antagonism on plus-maze behaviour in mice. II. WAY 100635, SDZ 216-525 and NAN-190.

To understand further the role of 5-hydroxytryptamine receptor subtype 1A (5-HT1A) mechanisms in anxiety, the behavioural effects of 5-HT1A receptor antagonists with different selectivity and intrinsic activity were examined using an ethological version of the murine elevated plus-maze test. WAY 100635 (0.03-9.0 mg/kg) produced a behavioural profile indicative of an anxiolyticlike effect, with an apparent bell-shaped dose-response relationship and increases in nonexploratory behaviours at the largest dose tested. SDZ 216-525 exerted a dose-dependent antianxiety action at doses of 0.05-0.8 mg/kg, with some loss of activity at 3.2 mg/kg. In contrast, smaller doses of NAN-190 had a significant effect, whereas higher doses (2.5-10.0 mg/kg) decreased locomotor activity and other active behaviours, a profile similar to that produced by the alpha1-adrenoceptor antagonist prazosin (2.5 mg/kg), which also inhibited open arm activity. Findings are discussed in relation to 5-HT1A receptor and alpha1-adrenoceptor antagonism and corresponding neurochemical changes. The results of the present series support the view that 5-HT1A receptor antagonists have therapeutic potential in the management of anxiety.

Animals↗

PubMed1997

Influence of 5-HT1A receptor antagonism on plus-maze behaviour in mice. I. Pindolol enantiomers and pindobind 5-HT1A.

Studies on the behavioural effects of 5-hydroxytryptamine receptor subtype 1A (5-HT1A) antagonists may provide important clues to the precise role of 5-HT1A receptor mechanisms in anxiety. In the first of a series of experiments designed to address this issue, the effects of mixed 5-HT1A and beta-adrenergic receptor antagonists pindolol enantiomers and pindobind 5-HT1A and of metoprolol and ICI 118,551 (selective beta1- and beta2-adrenoceptor antagonists, respectively) were assessed in the mouse elevated plus-maze using ethological techniques. Results showed that, at lower doses, (-)pindolol (0.1-1.6 mg/kg) and pindobind 5-HT1A (0.1-0.5 mg/kg) produced changes in both conventional and ethological measures (increased percentage of open arm time and reduced risk assessment) indicative of anxiety reduction. However, these anxiolyticlike actions were less evident at higher doses. In contrast, (+)pindolol (0.1-6.4 mg/kg), metoprolol (2.0-18.0 mg/kg) and ICI 118,551 (1.0-9.0 mg/kg) were behaviourally inert under present test conditions. These data suggest that antagonist actions at 5-HT1A receptors (but not beta-adrenoceptors) are involved in the anxiolyticlike effects of (-)pindolol and pindobind 5-HT1A in the murine elevated plus-maze test.

Adrenergic beta-Antagonists↗

PubMed1997

Animal models of anxiety: an ethological perspective.

In the field of anxiety research, animal models are used as screening tools in the search for compounds with therapeutic potential and as simulations for research on mechanism underlying emotional behaviour. However, a solely pharmacological approach to the validation of such tests has resulted in distinct problems with their applicability to systems other than those involving the benzodiazepine/GABAA receptor complex. In this context, recent developments in our understanding of mammalian defensive behaviour have not only prompted the development of new models but also attempts to refine existing ones. The present review focuses on the application of ethological techniques to one of the most widely used animal models of anxiety, the elevated plus-maze paradigm. This fresh approach to an established test has revealed a hitherto unrecognized multidimensionality to plus-maze behaviour and, as it yields comprehensive behavioural profiles, has many advantages over conventional methodology. This assertion is supported by reference to recent work on the effects of diverse manipulations including psychosocial stress, benzodiazepines, GABA receptor ligands, neurosteroids, 5-HT1A receptor ligands, and panicolytic/panicogenic agents. On the basis of this review, it is suggested that other models of anxiety may well benefit from greater attention to behavioural detail.

Animals↗

PubMed1994

Antagonism of clonidine antinociception by buspirone and 1-(2-pyrimidinyl)-piperazine.

The effects of pretreatment with buspirone and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) on antinociception produced by clonidine were investigated in mice. Buspirone and 1-PP dose dependently attenuated the antinociceptive action of s.c. administered clonidine in the writhing and tail-flick assays. In both assays, 1-PP was more potent than buspirone in antagonizing clonidine-induced antinociception. After s.c. pretreatment with buspirone (8 mg/kg) and 1-PP (4 mg/kg), the antinociceptive ED50 values of s.c. clonidine were significantly increased. The antagonistic effects of buspirone and 1-PP on clonidine-induced antinociception may be due to their alpha 2-adrenoceptor antagonist activity.

Analgesics↗

PubMed1994

Buspirone and 1-(2-pyrimidinyl)-piperazine attenuate xylazine-induced antinociception in the mouse.

The effects of subcutaneous pretreatment with buspirone and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) on the antinociceptive effect of xylazine were examined using the mouse acetic acid assay. Both buspirone and 1-PP dose-dependently attenuated the antinociceptive action of subcutaneously administered xylazine (0.8 mg kg-1), with ED50 values of 7.3 mg kg-1 for buspirone and 3.4 mg kg-1 for 1-PP. Pretreatment with either buspirone (8 mg kg-1) or 1-PP (4 mg kg-1) increased the antinociceptive ED50 of xylazine 3-4-fold. These data support the involvement of alpha 2-adrenoceptor and 1-PP in the pharmacological activity of buspirone.

Analgesics↗

PubMed1993

Magnesium valproate attenuates hyperactivity induced by dexamphetamine-chlordiazepoxide mixture in rodents.

A mixture of dexamphetamine and chlordiazepoxide induces hyperactivity in both mice and rats. This type of hyperactivity has been proposed as an animal model of mania. Magnesium valproate itself had little influence on the activity of normal mice and rats. Acute pretreatment of mice with magnesium valproate (75-300 mg/kg p.o., 37.5-150 mg/kg i.v.) attenuated the mixture-induced hyperactivity. Pretreatment of rats with a single dose of magnesium valproate (75-300 mg/kg, p.o. or i.p.) also counteracted the locomotor hyperactivity caused by the mixture. The effects of magnesium valproate in the mixture-treated mice and rats could be abolished by bicuculline and picrotoxin, but not isoniazid. These findings suggest that the antimanic effect of valproate may be related to its ability to enhance the postsynaptic effects of gamma-aminobutyric acid (GABA).

Analysis of Variance↗

PubMed1993

A new computational method for cable theory problems.

We discuss a new computational procedure for solving the linear cable equation on a tree of arbitrary geometry. The method is based on a simple set of diagrammatic rules implemented using an efficient computer algorithm. Unlike most other methods, this technique is particularly useful for determining the short-time behavior of the membrane potential. Examples are presented and the convergence and accuracy of the method are discussed.

Algorithms↗

PubMed1992

Analgesic and anti-inflammatory effects of Ranunculus japonicus extract.

The analgesic and anti-inflammatory effects of Ranunculus japonicus extract after parenteral administration were determined in several animal models. The extract inhibited the mice writhing responses caused by acetic acid and raised the pain thresholds of mice in the hot-plate test. The extract also inhibited the paw edema of rats induced by carrageenin, ear swelling of mice caused by xylene, mice vascular permeability increase induced by acetic acid, and granuloma formation in rats.

Analgesics↗

PubMed1990

[Neuromuscular blocking and respiratory depressing actions of sodium ammonium dimethyl-2-(propano-1,3-dithiosulfate) monohydrate].

The neuromuscular blocking and respiratory depressing actions of the new insecticide sodium ammonium dimethyl-2-(propano-1,3-dithiosulfate) monohydrate (SCD) were investigated. In peroneal-tibialis anterior nerve-muscle preparations of urethane anesthetized rabbit, SCD 6.5 mg/kg iv completely depressed the indirectly elicited twitch tension but not the directly elicited one. This compound also caused initial potentiation of the indirectly elicited twitch tension. In the partially paralyzed preparations, potentiation of contractions occurred following a brief period of indirectly tetanic stimulation. Nereistoxin but not SCD blocked the indirectly elicited twitch tension of isolated rat diaphragm. The neuromuscular blockade induced by SCD and nereistoxin was antagonized by neostigmine and 4-aminopyridine. SCD and nereistoxin had little or no effect on arterial blood pressure and phrenic nerve discharge of rabbits. The results indicated that SCD-poisoned rabbits died of respiratory paralysis following the neuromuscular blockade.

Animals↗

PubMed1990

[Antidotal effects of sulfhydryl compounds on acute poisonings by sodium ammonium dimethyl-2-(propane-1,3-dithiosulfate) monohydrate, nereistoxin and cartap].

Sodium dimercaptopropanesulphonate (DMPS) and sodium dimercaptosuccinate (DMS) were discovered to be effective antidotes for acute poisoning of insecticides SCD [sodium ammonium dimethyl-2-(propane-1,3-dithiosulfate) monohydrate], nereistoxin (4-N,N-dimethylamino-1,2-dithiolane) and cartap (dihydronereistoxin dicarbamate). In mice, DMPS (250 mg/kg) or DMS (1000 mg/kg) ip 20 min before SCD increased LD50 of ig SCD from 97 to 374 or 251 mg/kg, respectively. The prophylactic effect of DMPS was better than that of DMS. Administration of DMPS prior to cartap increased LD50 of ig cartap from 130 to 375 mg/kg. The therapeutic effect of DMPS was also demonstrated in SCD-poisoned conscious rabbits. DMPS 62.5 mg/kg or DMS 500 mg/kg iv completely antagonized the neuromuscular blockade and respiratory depression caused by SCD, nereistoxin and cartap in anesthetized rabbits. The antagonism of SCD-induced neuromuscular blockade by cysteine (400 mg/kg, iv) was less effective and of shorter duration than that by DMPS and DMS. Dimercaprol 50 mg/kg im showed little effect on SCD-induced paralysis. The antagonistic actions of sulfhydryl compounds on neuromuscular blockade induced by these insecticides probably belong to chemical antagonism.

Animals↗