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Biomedical subjects

J Mos

Publications and source records attributed to J Mos.

At least 37 records · Page 2Linked to original sources
PubMed1991

Ethopharmacological studies of anxiolytics and aggression.

This paper presents examples of the application of ethopharmacology to the study of aggression. Low doses of benzodiazepines may increase aggression under appropriate conditions. In various animal models in male and female rats and mice the aggression enhancing effects are particularly marked when aggression is inhibited by internal or external events. It is therefore suggested that benzodiazepines have no direct effect on aggression, but modulate inhibitory factors which regulate aggression.

Aggression↗
PubMed1991

The effects of idazoxan and 8-OH-DPAT on sexual behaviour and associated ultrasonic vocalizations in the rat.

Two experiments were performed studying the effects of 8-OH-DPAT and idazoxan on sexual behaviour and ultrasonic communication of male rats. In addition, the reactions of the females towards drug-treated males were studied. 8-OH-DPAT (a very specific 5-HT1A agonist) and idazoxan (an alpha 2-adrenergic antagonist) differentially affected sexual behaviour: 8-OH-DPAT (0.1 and 0.4 mg/kg IP) markedly facilitated ejaculations, a feature indicated by decreased numbers of mounts and intromissions preceding ejaculation and a reduction in ejaculation latency. This drug concomitantly reduced the postejaculatory refractory period. Idazoxan reduced the number of intromissions before ejaculation only at the highest dose (10 mg/kg IP), but did not markedly facilitate other parameters. Both drugs markedly and dose-dependently suppressed the postejaculatory 22 kHz ultrasounds normally recorded during the postejaculatory refractory period. Ultrasound frequencies above 30 kHz first appear at the end of the absolute refractory period, even when the refractory period is shortened by 8-OH-DPAT. Idazoxan increased the number of these 30 kHz ultrasounds, whereas 8-OH-DPAT had no effect on them. No effects were observed on ultrasound production (either 22 kHz or above 30 kHz) before an ejaculation. The behaviour of the females towards 8-OH-DPAT-treated males was also affected, with the females showing more darting and lordosis before and after ejaculation, but less sitting after ejaculation. Idazoxan treatment of the males resulted in more hopping and earwiggling of the females before ejaculation. Following ejaculation, females treated with the antagonist showed more darting, hopping, earwiggling and lordosis, but sitting was decreased. It has been suggested in the rat that the emergence of ultrasounds higher than 30 kHz indicates the end of the absolute refractory period and signals to the female that the male is capable of resuming sexual activity. The significance of 22 kHz ultrasound in sexual behaviour remains puzzling because these vocalizations could be easily uncoupled from the refractory period by drugs acting via different receptor mechanisms without disturbing sexual behaviour per se. A failure to produce postejaculatory sounds appears to disinhibit (proceptive) behaviour by the females.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Discriminative stimulus properties of flesinoxan.

Different groups of rats were trained to discriminate either 0.3 mg/kg of flesinoxan (N = 13) or 0.1 mg/kg of 8-OH-DPAT (N = 7) from saline in a two-lever operant drug discrimination task using a fixed ratio 10 schedule of reinforcement. Once trained, animals in both groups displayed a dose-related decrease in discriminative performance upon administration of lower doses of the drug used in training. In generalization tests, flesinoxan generalized to 8-OH-DPAT in 8-OH-DPAT-trained animals and 8-OH-DPAT substituted for flesinoxan in flesinoxan-trained animals. Buspirone substituted partially for both the flesinoxan and the 8-OH-DPAT cue. The results of the present study indicate similarity between the discriminative stimulus effects of flesinoxan and the stimulus produced by the 5-HT1A agonist 8-OH-DPAT. These results, coupled with the finding that flesinoxan has a significant affinity and selectivity for 5-HT1A binding sites, suggest that the stimulus effects of flesinoxan are mediated by a 5-HT1A mechanism.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Ethopharmacology: a creative approach to identification and characterisation of novel psychotropics.

The present contribution describes the basic fundamentals of animal models in ethopharmacology. After defining the role of ethopharmacology in the development of animal models of relevant human diseases, this methodology is used to classify different categories of aggression. Furthermore, the behavioural aspects of agonistic (aggressive) modelling are outlined and the various models used to describe offensive and defensive behaviours, and some miscellaneous models are summarized. Finally, some remarks on the new class of psychoactive drugs, serenics, are given.

Animals↗
PubMed1990

Behavioural pharmacology of the serenic, eltoprazine.

In this paper the effects of serenics (eltoprazine and fluprazine) are described in several animal models for offensive agonistic, defensive agonistic and predatory behaviour. They are compared with the effects of a number of other putative anti-aggressive compounds or drugs used clinically in order to ameliorate aggressive behaviour of psychiatric patients. In isolation-induced offensive aggression in mice, eltoprazine has a marked and potent anti-aggressive activity, although numerous other psychoactive drugs also exert anti-aggressive effects. The behavioural specificity of this anti-aggressive profile was investigated using an ethologically derived animal model, social interaction in male mice. In this model, eltoprazine has a very specific anti-aggressive (serenic) profile, inhibiting aggression while social interaction and exploration are not decreased but even enhanced; inactivity, a measure for sedation, is not affected. Such a profile contrasts sharply with that of neuroleptics (chlorpromazine, haloperidol), psychostimulants (d-amphetamine) or benzodiazepines (chlordiazepoxide), which exert severe sedation (neuroleptics) or even aggression-enhancing effects (BDZ). After subchronic treatment no tolerance for the anti-aggressive effects of eltoprazine occurred. The specific anti-aggressive effects of eltoprazine were also found in rat models of offensive agonistic behaviour. In one such model - resident-intruder aggression - eltoprazine reduced offensive behaviour specifically, leaving social interactions and exploration intact, and did not induce sedation or other unwanted side-effects. The neuroleptic haloperidol was very sedative in this model, as was the 5-HT1A-agonist buspirone. Benzodiazepines (chlordiazepoxide) have a biphasic effect in this paradigm, enhancing offence at low doses and decreasing it at higher doses, due to muscle relaxation. In another offensive model, colony-aggression, in which a dominant and subordinate male in a colony are confronted with a male intruder, eltoprazine reduced offensive behaviour of both the dominant and the subordinate against the intruder. In contrast, chlordiazepoxide enhanced aggression, at least at lower doses, whereas alcohol had, up to very high doses, no effect on the offensive behaviour. In a brain-stimulation induced offensive model--hypothalamically-induced aggression in rats--eltoprazine specifically reduces offence. Locomotion, a measure for sedation, was either unaffected or even somewhat enhanced, indicating the absence of any sedatory activity of this serenic compound. In contrast, haloperidol heavily sedated animals, making them incapable of aggression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Quantitative and comparative analyses of pro-aggressive actions of benzodiazepines in maternal aggression of rats.

The pro-aggressive effects of low doses of benzodiazepines on maternal aggression in rats were studied. Chlordiazepoxide, diazepam, oxazepam and alprazolam produced bell-shaped dose-response curves, with increased aggression at low doses. Only alprazolam significantly reduced aggression at higher doses. A comparison of the drug effects on different aggressive elements revealed that chlordiazepoxide and oxazepam increased the frequency of more elements of the aggressive repertoire than diazepam or alprazolam. Thus, although all benzodiazepine receptor agonists increased aggression, there were significant quantitative differences in their effects.

Aggression↗
PubMed1989

Serotonergic modulation of social interactions in isolated male mice.

Several serotonergic drugs were tested in isolation-induced aggressive behavior in male mice using ethological methodology. Eltoprazine, a mixed 5-HT1 agonist, reduced aggression but enhanced social interest and exploration. Several 5-HT1A agonists (8-OH-DPAT, ipsapirone, buspirone, 5-Me-ODMT) and a 5-HT uptake blocker (fluvoxamine) also reduced aggression. Although these drugs somewhat differentially affect aggressive behavior, the isolation-induced paradigm alone is not sensitive enough to successfully differentiate and screen the various serotonergic drugs with regard to their influence on social behavior in mice. It is argued that various animal paradigms in several species are necessary to describe specific effects of serotonergic drugs.

Aggression↗
PubMed1989

Brain 5-HT and inhibition of aggressive behavior in animals: 5-HIAA and receptor subtypes.

Evolutionary constant serotonin (5-HT) neuronal systems evolved along medial brain structures; yet, wide variations in functionality characterize serotonergic systems in mediating aggressive responses in species ranging from lobsters, ants, electric fish, and rodents to primates. So far, the attempts to correlate cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels with measures of aggression have revealed inverse, direct, or no correlations in different nonhuman primate species. It is difficult to harmonize the occasional correlations between CSF 5-HIAA and adaptive aggressive acts in nonhuman primates (a) with clinically diagnosed suicidal or impulsive individuals, and (b) with the biochemical, anatomical, and presumably functional differentiation of 5-HT pathways and receptor subtypes. Eltoprazine, a mixed 5-HT1A/B agonist, and meta-trifluoro-methylphenyl-piperazine HCl (TFMPP), a more selective 5-HT1B agonist, specifically decrease aggressive behavior in several animal species and situations in both sexes without detriment to other social, exploratory, or motoric activities. A definite role for 5-HT1A, 5-HT2, and 5-HT3 receptor subtypes in the mechanisms mediating aggressive behaviors has to await the development of selective agonists and antagonists, respectively.

Aggression↗
PubMed1987

Postpartum aggression in rats does not influence threshold currents for EBS-induced aggression.

Female Wistar rats were tested for aggressive behaviour induced by electrical brain stimulation (EBS) in the lateral hypothalamus. Threshold currents for the induction of aggression were determined on several days before the females were paired with experienced breeder males. Beginning in the second week of pregnancy threshold current values were measured once or twice weekly. No change in thresholds was observed either during pregnancy, the early postpartum period or after weaning. Lactation was the only period during which the females were spontaneously aggressive towards male intruders in their home cage, but not in the EBS cage. Analysis of bite targets revealed no difference between the bite patterns in the postpartum maternal aggression test and the EBS-induced attacks. The results demonstrate that the change in physiological and hormonal status in pregnant and lactating females has no influence on the propensity to attack during EBS. The similarity in wound patterns does not advocate a major difference in the types of aggression studied. We speculate upon the nature of EBS-induced attacks as the activation of a rigid, final pathway of aggression which is rather insensitive to mild modulations.

Aggression↗
PubMed1987

Modulatory actions of benzodiazepine receptor ligands on agonistic behaviour.

Several experiments were conducted to establish the role of benzodiazepine (BDZ) receptor ligands in aggressive behaviour in male and female rats. In particular, the pro-aggressive effects of BDZ agonists was subject of investigation. Predatory aggression (mouse killing) was facilitated by chlordiazepoxide (CDP) when tested in naive female rats, but CDP was unable to induce muricide in non-killing rats with extensive experience with mice. In experiments on maternal aggression in rats a post-hoc analysis revealed that the pro-aggressive action of CDP on maternal aggression was base line dependent: the increase in aggression in spontaneously low aggressive females was significantly higher than in females with a higher base line level. A further study aimed at unravelling the underlying factors contributing to this pro-aggressive action by determining the role of opponent size on the effects induced by CDP. Normally large opponents evoke less aggression from lactating females than smaller opponents and CDP exerted its pro-aggressive effect particularly strongly in the 'large opponent' situation. An ethological analysis was made of lateral display--an ambivalent posture frequently occurring in agonistic behaviour--to establish whether CDP indirectly increases aggression by reducing fear by means of its anxiolytic properties. The data partly support this hypothesis. These findings stress the importance of environmental and experiential factors in the possible outcome of CDP effects on aggression. Moreover, they point to possible explanations of seemingly contradictory data. In two final experiments an inverse benzodiazepine receptor agonist (beta-CCE) was tested in maternal aggression. beta-CCE reduced aggression, although not in a completely specific way. A neutral BDZ-receptor antagonist (Ro 15-1788) was tried in an attempt to antagonize the pro-aggressive effects of CDP in maternal aggression. Ro 15-1788 did not counteract the pro-aggressive action of CDP, but antagonized CDP effects on exploration. The modulatory role of the benzodiazepine receptor complex in aggression remains an intriguing area of research in which many subtleties in testing conditions play a role and in which more BDZ agonists, inverse agonists and antagonists have to be tested.

Aggression↗
PubMed1987

Analysis of survival data on aging rat cohorts: pitfalls and some practical considerations.

Experimental aging research is very dependent on the determination of the survival characteristics of the animal species or strain under study. Such data are generally inferred from mortality curves of cohorts of animals that are set aside at an early age for aging studies. Rectangular survival curves and the presence of multiple pathological lesions are a prerequisite for aging studies so as to resemble the situation in man. From 1977 onwards, many rat cohorts have been formed in the Institute for Experimental Gerontology (IVEG) for the study of aging processes. Data from these have been analysed for a period of 5 years up to and including 1982. (Males and females of the WAG/Rij and BN/BiRij strains were used.) The 50% survival and the maximum survival of cohorts varied considerably, but showed no consistent trend over the years. The median (50%) survival between the cohorts differed by as much as 7.9-10.7 months for the strains and sexes studied. Maximum survival between the cohorts varied from 3.7 to 9.9 months. Median and maximal survival were greater for the females. Maximum survival and 50% survival correlated significantly, the relation between the two being approximately linear. The effect of removing animals from cohorts on the estimation of 50% survival was only minor, whereas maximum survival was clearly diminished by this procedure. The wide variation in survival characteristics, even between successive cohorts, cautions against too simple a measure of the animals survival in only one number for median or maximal survival in months. An indication of the variance of 50% survival and of maximum survival should therefore be included in scientific publications. Moreover, the 50% survival is the parameter of choice to define cohorts, not only because this can be most reliably estimated with good confidence limits, but also because this measure is the least sensitive to removing animals from the cohorts. As this will often be the case in many research institutions, it might be of practical importance to order old animals from different cohorts since this diminishes the chance of using an extremely short or long lived cohort. Finally, the analysis revealed that combining intact or incomplete cohorts into larger survival curves resulted in nearly identical graphs. An attempt was made to calculate the minimum cohort size which yields survival curves with constant 95% confidence limits.

Aging↗
PubMed1987

Maternal aggression towards different sized male opponents: effect of chlordiazepoxide treatment of the mothers and d-amphetamine treatment of the intruders.

Lactating female rats vigorously attack equally sized conspecific males introduced into their home cage. Under conditions of such high aggression, the previously reported pro-aggressive action of a low (5 mg/kg) dosage of chlordiazepoxide (CDP) is hardly detectable. When opponents are large, the intensity of the aggression is less than what is seen with small ones. In this situation treatment of the females with CDP increases aggression levels substantially. The importance of intruders evoking aggression was further investigated by treating different sized opponents with d-amphetamine. d-Amphetamine treatment did not lead to major changes in the defensive capacities of either types of intruder. The data demonstrate that drug effects, such as pro-aggressive actions, may be observed using larger sized opponents that are not so easily defeated and show more adequate defense than small ones. The subtleness of the dyadic interactions in maternal aggression indicates that drug effects should be considered carefully before extrapolation to other conditions.

Aggression↗
PubMed1986

RO 15-1788 does not influence postpartum aggression in lactating female rats.

Recently, Hansen et al. (1985) suggested behavioural similarities between lactating rats and non-maternal rats treated with benzodiazepines (BDZ), indicating that lactation may be associated with an increased activity state at the GABA/BDZ receptor complex similar to BDZ treatment. A logical prediction of this hypothesis is that BDZ antagonists should decrease typical maternal behaviours involved, such as aggression. We tested this hypothesis by measuring the behavioural effects of the BDZ antagonist RO 15-1788 (1.25-10 mg/kg IP) on aggressive behaviour of lactating female rats confronted with male intruders. We could not support the hypothesis; no consistent behavioural effects of RO 15-1788 on aggression were found. The implications of this finding for the proposed hypothesis are discussed.

Aggression↗
PubMed1986

Maternal aggression in rats: lack of interaction between chlordiazepoxide and fluprazine.

In a paradigm of female aggression, maternal aggression, low doses of chlordiazepoxide (CDP) enhanced aggression, whereas the serenic drug fluprazine dose-dependently decreased aggression. In this study one selected dose of CDP (5 mg/kg PO) clearly enhanced aggression of female lactating rats against a naive male intruder. This dose of CDP however, was not able to antagonize the dose-dependent decrease observed after fluprazine treatment (5, 10, 20 mg/kg IP). These data suggest that fluprazine and CDP do not simply have opposite effects at the same site of action. It is suggested that fluprazine decreased the offensive motivation of animals, whereas CDP increased attacks indirectly by reduction of the approach-avoidance conflict in a social context.

Aggression↗