[Household chaos and borderline personality features in adolescents and young adults]. / Chaos in de thuissituatie en borderlinekenmerken bij adolescenten en jong­volwassenen.

BACKGROUND: A complex pattern of individual and environmental factors is involved in the etiology of borderline personality disorder (BPD). Household chaos might be a factor of importance in this interaction. Studies report a relationship between household chaos and various problem areas, some of which are also related to BPD features. It is unclear if and how these factors are correlated. AIM: To investigate a possible association between household chaos and BPD features in adolescents and young adults. In addition, we investigated the effect of age within this association. METHOD: A clinical sample of 452 adolescents and young adults, aged 12-26 completed questionnaires on household chaos and BPD features. RESULTS: Adolescents and young adults who experienced a higher level of household chaos, reported more BPD features. No evidence was found for an effect of age on the association between household chaos and BPD features. CONCLUSION: Adolescents and young adults in a clinical population who experience a higher level of household chaos seem to report more BPD features. Age doesn’t seem to have an effect on this association. This research is a first step in understanding associations between household chaos and BPD features. In order to gain more insight in the transactions between household chaos and BPD features in adolescents and young adults, more longitudinal research is needed.

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.

Ultrasonic vocalizations in rat pups: effects of serotonergic ligands.

Ligands with varying intrinsic activity and selectivity for the various subtypes of the serotonin receptor were tested in the rat pup ultrasonic vocalization (USV) model, a putative animal model reflecting anxiety. USV were elicited by isolating rat pups from their mother and littermates by placing them on a warm (37 degrees C) or a cold (18 degrees C) plate. Concurrently, the negative geotaxic (NG) response and rectal temperature were determined to assess the potentially sedative and hypothermic effects of putative anxiolytics. USV were reduced at low doses and in both temperature conditions by the full 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin.HBr) and the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378 (2-[4-[4-[2-pyrimidinyl]-1,2-piperazinyl]butyl]-1,2-benzi-isoth iozol-3-(2H)one-1,1-dioxide. 2HCl). The 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)-butyl]piperazide.2H Cl), (+/-)-WAY 100,135 (+/-)-(N-tert-butyl-3(4-(2-methoxy phenyl)piperazin-1 -yl)-2-phenyl propionamine.2HCl), and ((S)-UH-301 (S)-5-fluoro-8-hydroxy-2-(di-n-propyl-amino)tetralin.HBr) reduced USV at higher doses and only in one of both test conditions. The selective 5-HT1A receptor antagonist DU 125530 (2-[4-[4[(7-chloro-2,3dihydro-4-benzodioxin-5-yl)-1-piperazi nyl]butyl]-1,2-benzisothiazol-3(2H)-one-1,1, dioxide, monomesylate), did not influence USV at the cold plate up to high doses, although concomitantly the negative geotaxis was disturbed. The negative geotaxis was impaired after all 5-HT1A receptor ligands, except BMY 7378 and (+/-)-WAY 100,135. Hypothermia coincided with USV-suppression, except for NAN-190 and (S)-UH-301. The USV-suppressing action of flesinoxan (3 mg/kg) could be antagonized by DU 125530, but not its NG effect. However, the hypothermia induced by flesinoxan was antagonized by DU 125530. USV were also suppressed by the 5-HT uptake inhibitors fluvoxamine (both warm and cold plate) and clomipramine (only warm plate). The tricyclic antidepressant imipramine only decreased USV on the cold plate, however, in a U-shaped dose-response curve. At the highest dose tested, no decrease was present. The 5-HT uptake stimulant tianeptine reduced USV under both conditions. Fluvoxamine had no side effects, clomipramine induced hypothermia and tianeptine clearly had sedative properties. The 5-HT1B/2C receptor agonist TFMPP (trifluorometaphenylpiperazine) stimulated USV at a low dose at the cold plate and suppressed USV at a high dose under both conditions. The 5-HT2A/2C receptor antagonist ketanserine enhanced USV at low doses under both conditions and had no effect at a higher dose. Concurrently heavy sedation and hypothermia occurred. The 5-HT3 receptor agonist phenylbiguanide and the 5-HT3 receptor antagonist ondansetron had no effect in this paradigm. Clearly, subtypes of the 5-HT receptor affect rat pup USV differentially.

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.

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.

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.

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.

Maternal aggression in rats: effects of chlordiazepoxide and fluprazine.

Although maternal aggression in rats is confined to a restricted post-partum period, the high and stable aggression level and the constancy of its behavioural structure make it an attractive experimental procedure for studying the behavioural effects of psychotropic drugs. Female rats were tested against naive male intruder rats for 5 or 10 min on post-partum days 3-9, during which aggression is stable. Chlordiazepoxide (CDP; 5, 10 and 20 mg/kg, orally) had a biphasic effect on aggression; it increased aggression considerably at 5 and (to a lesser extent) at 10 mg/kg. At 20 mg/kg aggression returned to control level. CDP shortened the latency to the first attack at 5 mg/kg, but not at higher dosages. CDP enhanced aggression, particularly in the first 2 min of an encounter. It did not change the structure of the aggressive behaviour, but did induce a dose-dependent increase in feeding. Fluprazine (Flu; 5, 10 and 20 mg/kg IP), a specific antiaggressive (serenic) drug, induced a dose-dependent decrease in aggression and exerted its largest effect in the first 2 min of an encounter. In accordance with the reduced aggression, latencies to the first attack increased. Maternal aggression in rats represents an extension to other (male) aggression paradigms in psychopharmacology. First, it has no male counterpart. Secondly, the hormonal mechanisms underlying this behaviour differ from those of male aggression. Thirdly, the morphology of maternal aggression is different from that shown in male models of agonistic behaviour (e.g. resident-intruder). These features make maternal aggression an attractive paradigm for pharmacological studies of female behaviour.

Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats.

Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the "noise test" 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0-30.0 mg/kg) and desmethylimipramine (DMI, 2.5-10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with fluvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6-5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT1A receptor agonist flesinoxan (0.3-3.0 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs.

Guinea pigs possess central 5-HT1D receptors similar to humans but different from rats and mice. In order to study the role of this receptor on animal behaviour, it may be of interest to develop a paradigm measuring affective states in the guinea pig. Therefore we assessed the effects of a variety of psychotropic drugs on guinea pig pup isolation calls. Anxiolytic compounds such as the benzodiazepine receptor agonists diazepam and alprazolam, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, and alcohol reduced isolation calling by the guinea pig pup. Moreover, mixed antidepressant/anxiolytic compounds like the 5-HT uptake inhibitors fluvoxamine and clomipramine or the MAO-inhibitor clorgyline as well as the antidepressant NA uptake inhibitors desipramine and maprotiline suppressed vocalizations. The 5-HT1D/1A receptor agonist 5-CT was also very effective in reducing separation calls. Remarkably, the partial 5-HT1A receptor agonists buspirone and BMY 7378 did not affect calling. The neuroleptic haloperidol, the psychostimulant d-amphetamine, the putative anxiogenics DMCM and m-CPP and the putative anxiolytics ondansetron and CI-988 had no effect on isolation calls of guinea pig pups. We propose this paradigm could be helpful to assess behavioural effects of anxiolytic and antidepressant drugs in a species different from rat or mouse, and in which the effects of 5-HT1D receptor ligands may possibly be established.

Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs.

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.

Discriminant analysis of the localization of aggression-inducing electrode placements in the hypothalamus of male rats.

Over 400 sites in the hypothalami of 270 male CPB/WE-zob rats were electrically stimulated in order to induce fights between males. The localization of electrodes inducing fights seems to differ from the localization of electrodes in which no fights can be induced. The differences in localization were detected and tested by a non-parametric discriminant analysis. The results were plotted by computer in a stereotaxic atlas of the hypothalamus of the CPB/WE strain. The method delimits areas within the hypothalamus where the probability to induce aggression is high, intermediate or low. Moreover, the procedure allows discrimination between areas where the thresholds for attack behaviour are generally lower than elsewhere and where the fiercest forms of attack are induced. None of the areas delimited coincide with a classical subdivision of the hypothalamus. Parts of the perifornical, anterior, lateral and ventromedial hypothalamus seem to be involved. The methods developed here may help to relate stimulation-induced aggression to other characteristics of the 'aggressive' area which cannot be obtained directly from fighting rats such as cytological, endocrinological, biochemical or physiological data. In addition, the procedure may help to settle disputes on the specificity of the localization of neural substrates of other stimulation-induced behaviours. The methods to discriminate between overlapping 3-dimensional reconstructions validated here for aggressive responses, can also be applied to other types of stereotaxic data and other types of effects, such as electrical, hormonal or other physiological responses. They may be especially useful if the localization of the neural population involved is not yet known, and unknown current-spread or diffusion of substances complicates the interpretation of stereotaxic data.

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.

The effects of intraventricular administration of eltoprazine, 1-(3-trifluoromethylphenyl)piperazine hydrochloride and 8-hydroxy-2-(di-n-propylamino)tetralin on resident intruder aggression in the rat.

Various serotonergic agents may reduce aggression in rats, but how they act in different parts of the brain is unknown. This study attempted to unravel part of this question by application of different serotonergic ligands into the lateral ventricle (i.c.v.) of male rats (resident-intruder aggression). 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin; 1 and 10 micrograms), a specific 5-HT1A agonist, affected neither aggression nor any other behaviour. The mixed 5-HT1A,B,C agonist, TFMPP (1-(3-trifluoromethylphenyl)piperazine hydrochloride), and the 5-HT1A/1B agonist, eltoprazine ((1-(2,3)-dihydro-1,4-benzodioxin-5-yl)piperazine hydrochloride), suppressed aggression at i.c.v. doses of 10 and 30 micrograms. This reduction was not caused by sedation. These data suggest a role of postsynaptic 5-HT1B receptors in mediating the anti-aggressive effects of mixed 5-HT1 agonists.

The effects of dorsal raphe administration of eltoprazine, TFMPP and 8-OH-DPAT on resident intruder aggression in the rat.

To evaluate the role of somatodendritic 5-HT1A receptors in the mediation of aggressive behaviour, eltoprazine, TFMPP (1-(3-trifluoromethylphenyl)piperazine hydrochloride) and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) were administered locally into the dorsal raphe nucleus of rats. 8-OH-DPAT (1 and 10 micrograms) and eltoprazine (10 and 30 micrograms) reduced aggression, but concomitantly reduced social interest and increased inactivity. TFMPP (1 and 10 micrograms) did not reduce aggression. As 8-OH-DPAT and to a lesser extent eltoprazine affect 5-HT1A receptors, it is proposed that a general reduction of serotonergic neurotransmission by activation of somatodendritic serotonergic autoreceptor leads to a non-specific reduction of aggression. As TFMPP has a significantly lower affinity for 5-HT1A receptors than 8-OH-DPAT or eltoprazine, the lack of effect of TFMPP supports this view.

Discriminative stimulus properties of flesinoxan: effects of enantiomers, (S)-UH301 and WAY-100635.

Rats were trained to discriminate the specific 5-HT1A receptor agonist (+)-flesinoxan (R(+)-N(-)[2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4- benzodioxin-5-yl)-1-piperazinyl]ethyl]-4-fluorobenzoamide) (1.5 mg/kg p.o.) from water in a two-lever operant procedure. Generalization tests were conducted with the enantiomers and racemate of flesinoxan and the 5-HT1A receptor antagonists (S)-UH301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) and WAY-100635 ((N(-)[2(-)[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). (S)-UH301, WAY-100635 and fentanyl were investigated for their antagonistic properties. The (+)-flesinoxan stimulus generalized to (-)-flesinoxan and the racemate. The ED50 values for generalization corresponded well with the affinities of the enantiomers and the racemate for the 5-HT1A receptor. The flesinoxan cue could not be mimicked by (S)-UH301 or WAY-100635, but (S)-UH301 reduced response rates. Antagonism tests showed that both (S)-UH301 and WAY-100635 dose dependently antagonized the flesinoxan cue, with ID50 values of 0.52 and 0.03 mg/kg s.c., respectively. Fentanyl had no significant antagonistic properties. It is concluded that rats can learn to discriminate orally administered (+)-flesinoxan from water. The generalization of flesinoxan to the (-)-enantiomer and the antagonism of flesinoxan's cue by specific 5-HT1A receptor antagonists are further evidence for the involvement of flesinoxan's 5-HT1A receptor agonistic properties in its discriminative stimulus effects.

The corticosterone-enhancing effects of the 5-HT1A receptor antagonist, (S)-UH301, are not mediated by the 5-HT1A receptor.

We tried to antagonize the endocrine and behavioural changes induced by the selective 5-HT1A receptor agonist, flesinoxan, with the putative 5-HT1A receptor antagonist, (S)-UH301 ((S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin). The interaction of (S)-UH301 (3 and 10 mg/kg s.c.) with flesinoxan (3 mg/kg s.c.) showed no antagonistic effects of (S)-UH301 on flesinoxan-induced corticosterone secretion. In fact, like flesinoxan (1 and 3 mg/kg s.c.), (S)-UH301 (3 and 10 mg/kg s.c.) itself dose dependently increased plasma corticosterone levels. Unlike flesinoxan, (S)-UH301 did not induce hyperglycemia, lower lip retraction and flat body posture. Moreover, flesinoxan-induced hyperglycemia and behavioural changes were effectively antagonized by (S)-UH301, showing potent 5-HT1A receptor antagonistic effects of (S)-UH301. Therefore we conclude that (S)-UH301 is a potent 5-HT1A receptor antagonist and that the (S)-UH301-induced corticosterone secretion is mediated by a non-5-HT1A receptor mechanism.

The putative 5-HT1A receptor antagonist DU125530 blocks the discriminative stimulus of the 5-HT1A receptor agonist flesinoxan in pigeons.

Twelve homing pigeons were trained to discriminate the 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT(1A/1B) receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT(1B/2C) receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-he xane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ), (+/-)-pindolol and (S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (+/-)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, (S)-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT1A receptor and that DU125530 acts as a full antagonist on the 5-HT1A receptor.

Rat pup ultrasonic vocalization: effects of benzodiazepine receptor ligands.

The involvement of the GABA(A)-benzodiazepine receptor complex in rat pup ultrasonic vocalisations was studied by testing benzodiazepine receptor ligands with varying intrinsic activity and selectivity for benzodiazepine subtype receptors. Ultrasonic vocalisations were recorded under two temperature conditions (37 degrees C and 18 degrees C), presumably reflecting a low and high stress state. The latency to the negative geotaxis response, a measure of motor coordination and the rectal temperature were determined to assess putative side effects of drugs. The full, non-selective benzodiazepine receptor agonists diazepam, chlordiazepoxide, alprazolam and oxazepam suppressed ultrasonic vocalisations both at 37 degrees C and 18 degrees C conditions, although more efficaciously at 37 degrees C. The partial, non-selective benzodiazepine receptor agonist bretazenil and the partial benzodiazepine, selective receptor agonist alpidem significantly reduced ultrasonic vocalisations at 37 degrees C, but not at 18 degrees C. The full benzodiazepine, selective receptor agonist zolpidem behaved like other full, non-selective benzodiazepine receptor agonists by reducing ultrasonic vocalisations under both high and low temperature. The effects of zolpidem indicate that activation of benzodiazepine, receptors alone already suffices to suppress ultrasonic vocalisations. The non-selective, benzodiazepine receptor antagonist flumazenil and the partial, non-selective benzodiazepine receptor inverse agonist FG 7142 (N'-methyl-beta-carboline-3-carboxamide) and the full, non-selective benzodiazepine receptor inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) had no significant effect on ultrasonic vocalisations under both temperature conditions. The involvement of benzodiazepine receptors in rat pup ultrasonic vocalisations (37 degrees C-condition) was confirmed by antagonism of the ultrasonic vocalisations reducing effects of chlordiazepoxide by flumazenil (1 or 3 mg/kg). Using the rat pup ultrasonic vocalisations paradigm under 18 degrees C and 37 degrees C conditions combined with measurements of negative geotaxis-latencies and rectal temperatures it is possible to (1) distinguish benzodiazepine receptor agonists from other anxiolytics because of dissimilar dose response curves at 37 degrees C and 18 degrees C, (2) differentiate partial from full receptor agonists by absence of effects at the 18 degrees C condition, (3) suggest a key role for benzodiazepine, receptors in the modulation of ultrasonic vocalisations. These data contribute to the predictive validity of pup vocalizations as an animal model of anxiety.